Anatomy, Physiology, and Pathophysiology of Erectile Dysfunction

Anatomy, Physiology, and Pathophysiology ofErectile Dysfunctionjsm_1624 445..475

Christian Gratzke, MD,* Javier Angulo, PhD,† Kanchan Chitaley, PhD,‡ Yu-tian Dai, MD, PhD,§

Noel N. Kim, PhD,¶ Jaw-Seung Paick, MD, PhD,** Ulf Simonsen, MD, PhD,†† Stefan Ückert, PhD,‡‡

Eric Wespes, MD, PhD,§§ Karl E. Andersson, MD, PhD,¶¶ Tom F. Lue, MD,*** andChristian G. Stief, MD, PhD*

*Department of Urology, Ludwig-Maximilians-Universität, München, Germany; †Department of Urology, Hospital GregorioMaranon, Madrid, Spain; ‡University of Washington, Seattle, WA, USA; §Department of Urology, Nanjing, China; ¶Institutefor Sexual Medicine, San Diego, CA, USA; **Department of Urology, Seoul National University, Seoul, South Korea;††Department of Pharmacology, University of Aarhus, Denmark; ‡‡Department of Urology, Hannover Medical School,Hannover, Germany; §§Department of Urology, Centre Hospitalier Universitaire, Charleroi, Belgium; ¶¶Wake ForestUniversity, Institute for Regenerative Medicine, Wake Forest, NC, USA; ***Department of Urology, University of Californiaat San Francisco, San Francisco, CA, USA

DOI: 10.1111/j.1743-6109.2009.01624.x

A B S T R A C T

Introduction. Significant scientific advances during the past 3 decades have deepened our understanding of thephysiology and pathophysiology of penile erection. A critical evaluation of the current state of knowledge is essentialto provide perspective for future research and development of new therapies.Aim. To develop an evidence-based, state-of-the-art consensus report on the anatomy, physiology, and pathophysi-ology of erectile dysfunction (ED).Methods. Consensus process over a period of 16 months, representing the opinions of 12 experts from sevencountries.Main Outcome Measure. Expert opinion was based on the grading of scientific and evidence-based medicalliterature, internal committee discussion, public presentation, and debate.Results. ED occurs from multifaceted, complex mechanisms that can involve disruptions in neural, vascular, andhormonal signaling. Research on central neural regulation of penile erection is progressing rapidly with theidentification of key neurotransmitters and the association of neural structures with both spinal and supraspinalpathways that regulate sexual function. In parallel to advances in cardiovascular physiology, the most extensive effortsin the physiology of penile erection have focused on elucidating mechanisms that regulate the functions of theendothelium and vascular smooth muscle of the corpus cavernosum. Major health concerns such as atherosclerosis,hyperlipidemia, hypertension, diabetes, and metabolic syndrome (MetS) have become well integrated into theinvestigation of ED.Conclusions. Despite the efficacy of current therapies, they remain insufficient to address growing patient popula-tions, such as those with diabetes and MetS. In addition, increasing awareness of the adverse side effects of commonlyprescribed medications on sexual function provides a rationale for developing new treatment strategies that minimizethe likelihood of causing sexual dysfunction. Many basic questions with regard to erectile function remain unan-swered and further laboratory and clinical studies are necessary. Gratzke C, Angulo J, Chitaley K, Dai Y-T, KimNN, Paick J-S, Simonsen U, Ückert S, Wespes E, Andersson KE, Lue TF, and Stief CG. Anatomy,physiology, and pathophysiology of erectile dysfunction. J Sex Med 2010;7:445–475.

Key Words. Erectile Function; Penis, Corporal Smooth Muscle; Nitric Oxide; Cavernous Nerve; EndothelialDysfunction

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Brain, Autonomic Nervous System,and Neurotransmission

P enile erection is initiated after central pro-cessing and integration of tactile, visual, olfac-

tory, and imaginative stimuli. Signals to theperipheral tissues involved are generated, and thefinal response is mediated by coordinated spinalactivity in the autonomic pathways to the penisand in the somatic pathways to the perineal stri-ated muscles. The central regulation of penileerection involves many transmitters and transmit-ter systems, the details of which are still incom-pletely known. Some of the anatomical areas of thebrain that relate to sexual function have beendefined, including the medial amygdala, medialpreoptic area (MPOA), paraventricular nucleus,the periaqueductal gray, and ventral tegmentum[1–3]. In rats, electrical stimulation of the MPOA[4], the paraventricular nucleus [5], or the hippoc-ampal formation [6] can elicit an erectile response.

Spinally, there seems to be a network consistingof primary afferents from the genitals, spinal inter-neurons, and sympathetic, parasympathetic, andsomatic nuclei. This network appears capable ofintegrating information from the periphery andeliciting reflexive erections, and also to be therecipient of supraspinal information [7]. Thedegree of preservation of sensory function inthe T11-L2 dermatomes could be used to deter-mine the potential for psychogenic erectileresponses in men with spinal cord injury [8].

Peripherally, the balance between factors thatcontrol the degree of contraction of the smoothmuscle of the corpora cavernosa determines thefunctional state of the penis. Many details of neu-rotransmission, impulse propagation, and intra-cellular transduction of signals in penile smoothmuscles remain to be elucidated. However, theinformation on central control mechanismsinvolved in erection is rapidly expanding, and newdetails are continuously added [1,9–16].

Central NeuromediationThe central mechanisms controlling erectioninclude supraspinal as well as spinal pathways. Thecurrent knowledge about these mechanisms islargely based on experimental data from animals(mainly, rats).

DopamineCentral dopaminergic neurons project to theMPOA and the paraventricular nucleus [17]. Fur-thermore, dopaminergic neurons have been iden-tified that travel from the caudal hypothalamus to

innervate the autonomic and somatic nuclei in thelumbosacral spinal cord [18,19]. Thus, dopaminecan be expected to participate in the regulation ofboth the autonomic and somatic components ofthe penile reflexes.

Both the two major families of dopamine recep-tors, D1-like (D1, D5) and D2-like (D2, D3, D4)receptors [20], have been associated with centralerectile functions; however, the D2-like receptorsubtype seems to have the predominating effect.The nonselective dopamine receptor agonist, apo-morphine, when administered systemically to malerats, was found to induce penile erection [21],simultaneously producing yawning and seminalemission. Similarly, low-dose systemic administra-tion of other dopamine agonists initiates erection[1]. The effects of these agonists can be attenuatedby centrally but not peripherally acting dopaminereceptor antagonists.

OxytocinOxytocinergic spinal projections from thesupraoptic and paraventricular nuclei of the hypo-thalamus are likely to influence the sacral auto-nomic outflow more than the somatic outflow[22,23]. The finding that immunoreactiveoxytocin-containing spinal neurons associate withsacral preganglionic neurons supports the idea thatoxytocin has an important role in the autonomicspinal circuitry that mediates penile erection[24,25]. Oxytocin is a potent inducer of penileerection when injected into the lateral cerebralventricle, the paraventricular nucleus, or the hip-pocampus of laboratory animals; intrathecal oxy-tocin can also initiate an erection. These erectionscan be blocked by the administration of oxytocinantagonists given intracerebroventricularly (i.c.v.)or intrathecally, or by electrolytic lesion of theparaventricular nucleus. Additionally, noncontacterections can be reduced by a selective oxytocinreceptor antagonist administered into the lateralventricles, which supports the view that oxytocinmediates this response [26].

Adrenocorticotropic Hormones (ACTH) andRelated PeptidesAdministered i.c.v., the ACTH and a-melanocyte-stimulating hormones (a-MSH) are able to inducepenile erection, along with grooming, stretching,and yawning [1,2,27]. These effects are most prob-ably mediated via stimulation of melanocortin(MC) receptors, of which five different subtypeshave been cloned and characterized [28,29].Alpha-MSH/ACTH seem to act in the hypo-thalamic periventricular region, and grooming,

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stretching, and yawning, but not penile erection,was reported to be mediated by MC4 receptors[27,30]. It is unclear, however, what MC receptorsubtype(s) can be linked to the erectile responses.For example, the MC3 receptor is found in highdensity in the hypothalamus and limbic systems[31], regions known to be important for erectilefunctions. The site and mechanism of actionresponsible of a-MSH/ACTH seem to be differ-ent from those involving dopamine or oxytocin[15].

Martin et al. [32] concluded that current evi-dence indicates that the MC4 receptor subtypecontributes to the pro-erectile effects observedwith MC pan-receptor agonists. However, theputative receptor subtypes, pathways, and mecha-nisms implicated in mediating the pro-erectileeffects of MCs remain to be fully elucidated. Mel-anotan II, a synthetic analogue of a-MSH, whengiven subcutaneously, was shown to have pro-erectile effects in men with psychogenic impo-tence [33]. Still, the therapeutic potential ofa-MSH analogues remains to be established[34–36].

Nitric Oxide (NO)Several investigators have shown that within thecentral nervous system, NO can modulate sexualbehavior and penile erection [37–41]. NO may actin several discrete brain regions, e.g., in theMPOA [40,41] and the paraventricular nucleus[5,30]. NO production increases in the paraven-tricular nucleus of male rats during noncontactpenile erections and copulation, confirming thatNO is a physiological mediator of penile erectionat the level of the paraventricular nucleus [39].

As mentioned previously, injection of NO syn-thase (NOS) inhibitors i.c.v. or in the paraven-tricular nucleus prevents penile erectile responsesinduced by dopamine agonists, oxytocin, andN-methyl-D-aspartate (NMDA) in rats. NO mayalso mediate the actions of ACTH/a-MSH and5-HT2C agonists, which elicit erections wheninjected into the intracerebroventricular system,according to mechanisms unrelated to oxytociner-gic neurotransmission [38]. The inhibitory effectof NOS inhibitors was not observed when thesecompounds were injected concomitantly withL-arginine, the substrate for NO [38].

Excitatory Amino AcidsMicroinjections of L-glutamate into the MPOAelicits an increase in intracavernous pressure [4],and behavioral studies have shown that NMDAincreases the number of penile erections when

injected into the paraventricular nucleus [42–44].Furthermore, NMDA, amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid, or trans-1-amino-1,3-cyclo-pentadicarboxylic acid increasesintracavernosal pressures (ICPs) when injectedinto the paraventricular nucleus [45]. The effect ofNMDA was prevented by intracerebroventricularadministration of an oxytocin antagonist [42]. TheNOS signal transduction pathway is considered tomediate the effect of NMDA. Injection of theamino acid leads to an increased concentration ofNO metabolites in the paraventricular nucleus[46], and the administration of NOS inhibitorsinto the paraventricular nucleus and i.c.v. blockedthe NMDA effect [42,47].

SerotoninNeurons containing serotonin (5-hydroxytryptamine, 5-HT) can be found in themedullary raphe nuclei and ventral medulla reti-cular formation, including the rostral nucleusparagigantocellularis, and bulbospinal neuronscontaining 5-HT project to the lumbar spinal cordin the rat and cat [1]. Some serotonergic fibersoccur in close apposition with sacral preganglionicneurons and motoneurons, and synapses weredemonstrated at the ultrastructural level [25].These morphological findings support theinvolvement of 5-HT in both the supraspinal andspinal pharmacology of erection, with participa-tion in both the sympathetic and parasympatheticoutflow mechanisms.

In animals, 5-HT seems to exert a generalinhibitory effect on male sexual behavior [48],although the amine may be inhibitory or facilita-tory depending upon its action at different sitesand at different 5-HT receptors within the centralnervous system [49,50]. This may explain conflict-ing reports of 5-HT agonists either enhancing ordepressing sexual function. Yonezawa et al. [51]found that p-chloroamphetamine, an indirect sero-tonin (5-HT) agonist, elicited both penile erectionand ejaculation simultaneously in anesthetizedrats. It was suggested that these effects weremainly produced by the release of 5-HT as limitedto the lower spinal cord and/or peripheral sites.The use of selective 5-HT receptor agonists andantagonists can reveal different components ofmale copulatory behavior [9].

Gamma-Aminobutyric Acid (GABA)Cumulative data resulting from investigations onthe role of GABA in penile erection indicate thatthis neurotransmitter may function as an inhibi-tory modulator in the autonomic and somatic

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reflex pathways involved in penile erection [52].Activation of GABAA receptors in the paraven-tricular nucleus of male rats reduced penile erec-tion and yawning in response to apomorphine,N-methyl-D-aspartate (NMDA), and oxytocin[52]. Dorfman et al. examined age-related changesof the GABAB receptor in the lumbar spinal cordof Sprague Dawley rats of different ages usingquantitative autoradiography [53]. GABAB recep-tor affinity showed significant age-dependent andregional increases. The GABAB receptor decreasein aged rats did not seem, however, to be related tothe inhibitory function in penile erection.

CannabinoidsAdministration of endogenous and exogenous can-nabinoids was shown to be associated with changesin penile erection and modulation of male sexualbehavior [54,55]. The cannabinoid CB1 receptorantagonist SR 141716A was shown to potentiatethe penile erection responses to apomorphine inrats [56]. Also, it was shown that cannabinoid CB1receptors present in the paraventricular nucleusmay influence erectile function and sexual activitypossibly by modulating paraventricular oxytocin-ergic neurons mediating erectile function [57]. Itwas also demonstrated that SR 141716 inducedpenile erection by a mechanism involving excita-tory amino acid neurotransmission causing activa-tion of neuronal NOS (nNOS) in paraventricularoxytocinergic neurons [58].

Opioid PeptidesAvailable information supports the hypothesis thatopioid m-receptor stimulation centrally preventspenile erection by inhibiting mechanisms thatconverge upon central oxytocinergic neurotrans-mission [1]. In rats, morphine injected into theparaventricular nucleus prevents noncontactpenile erections (i.e., when penile erection isinduced in the male by the presence of an inacces-sible receptive female) and impaired copulation.These morphine effects are apparently mediatedby prevention of the increased NO productionthat occurs in the paraventricular nucleus duringsexual activity [59]. Morphine also preventsapomorphine-, oxytocin-, NMDA- andnoncontact-induced penile erection and yawningby inhibiting NOS activity in the paraventricularnucleus [60–62].

ProlactinLong-term hyperprolactinemia can depress sexualbehavior, reduce sexual potency in men, anddepress genital reflexes in rats [50,63]. Acute and

chronic central prolactin treatment in rats,however, may have stimulatory and inhibitoryeffects on male sexual behavior, respectively [64].Correspondingly, striatal dopaminergic activitywas shown to be increased and decreased by acuteand 5-day central prolactin treatment [64], sup-porting the view that the effects of prolactin areassociated with changes in striatal dopaminergicactivity. Prolactin has been shown to inhibit thedopaminergic incerto-hypothalamic pathway tothe MPOA [65]. In humans, it is still unclearwhether the negative effects of hyperprolactinemiaon erectile function are mediated centrally by wayof reduction in sexual interest and sex drive [66], orthrough a direct effect of prolactin on corpus cav-ernosum smooth muscle contractility. In dogs, adirect effect on the corpus cavernosum was sug-gested [67]. In any case, the effect seems indepen-dent of circulating testosterone levels and gonadalaxis function [68].

Sexual HormonesAndrogens, particularly testosterone, are neces-sary (although not sufficient) for sexual desire inmen. They are essential in the maintenance oflibido and have an important role in regulatingerectile capacity [69–73]. In men with normalgonadal function, however, there is no correlationbetween circulating testosterone levels and mea-sures of sexual interest, activity, or erectile func-tion [74]. Following castration in the male (whichmay reduce plasma testosterone levels by 90%[75]), or other causes leading to a reduction inandrogen levels, there is generally a decline inlibido, and sometimes in erectile and ejaculatoryfunctions. Testosterone administration restoressexual interest and associated sexual activity inhypogonadal or castrated adult men [76–78].The testosterone dose–response relationships forsexual function and visuospatial cognition differ inolder and young men, higher testosterone dosesneeded in the elderly for normal sexual function-ing [72]. El-Sakka et al. [79] assessed the pattern ofage-related testosterone depletion in patients witherectile dysfunction (ED). They found a signifi-cant decrease in testosterone level throughout the4-year follow-up in patients with ED. Patientswith decreasing testosterone were older thanpatients with a steady testosterone level. Whencastration has been performed in humans, theresultant sexual function may range from a com-plete loss of libido to continued normal sexualactivity. Thus, the role of androgens in erectilefunction is complex, and androgen deprivation

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may not always cause erectile impotence, either inman [80], or in rats [81].

Perspectives and ConclusionsOngoing and future studies assessing the efficacyand tolerability of centrally acting agents for malesexual dysfunction will reveal which targets are themost promising. Based on current literature, clini-cal trials have shown benefits for some drugsacting on mediator systems discussed above.However, today, none of the available agents canbe regarded as a major player in the practical treat-ment of ED. In light of the relatively large fractionof the ED patients that does not respond to ordoes not tolerate phosphodiesterase type 5 (PDE5)inhibitors, additional centrally acting drugs modu-lating sexual responses may be a potential solution.It cannot be expected that these drugs will work inpatients with severe end-organ damage; however,they may potentially add to existing therapy bymodifying arousability and sexual desire. Thecentral regulation of the erectile process is stillonly partly known. Central transmitter systems,which seem to be dependent on androgens as wellas NO, may be the targets of future drugs aimed atthe treatment of ED. Increased knowledge of thecentral (and peripheral) changes associated withED may lead to an increased understanding ofthese pathogenetic mechanisms and therefore newtreatments and possibly even prevention of thedisorder.

Regulation of Smooth Muscle Function

The penile corpora cavernosa are highly special-ized vascular structures that are morphologicallyadapted to their function of becoming engorgedduring sexual arousal. The trabecular smoothmuscle constitutes approximately 40–50% oftissue cross-sectional area, as assessed by histo-morphometric analysis [82,83]. Most of theremaining cavernosal tissue area is occupied byextracellular matrix, which provides a fibro-elasticframework and consists predominantly of collagentypes I, III, and IV, and elastin [84–87]. Collagentypes V and XI are also synthesized by the caver-nosal smooth muscle at detectable levels. Althoughsmaller in number, endothelial cells and neuronsplay critical roles in maintaining and regulatingvascular smooth muscle cell (VSMC) tone.

This complex architecture is maintained by theactive and dynamic expression of numerousgrowth factors. Well established as a regulator oflimb morphogenesis, sonic hedgehog (Shh) has

also been identified in the penis [88,89]. Studiesindicate that inhibition of Shh in the adult leads torapid atrophy and disorganization of the corpuscavernosum [88,89], suggesting that Shh is a criti-cal protein in the development and maintenance ofpenile cavernosal tissue structure. In addition, Shhhas been shown to stimulate the expression of vas-cular endothelial growth factor (VEGF) and NOSin the penis [89]. Numerous other growth factorsare expressed in the penis and are also likely to playimportant roles in maintaining cavernosal tissuestructure and function. However, most studieshave examined the use of exogenously appliedgrowth factors in therapeutic capacities, ratherthan investigating the roles of endogenously pro-duced growth factors.

As a major constituent and primary effector ofthe vascular structures in the genitals, the VSMCis highly adaptable and multifunctional. The twoprimary functions of VSMCs are contraction andsynthesis/maintenance of extracellular matrix.However, these two categories are considered tobe extremes that are manifested under in vitroconditions and it is likely that a range of interme-diary phenotypes exist in any given tissue in vivo[90,91].

Mechanism of Smooth Muscle ContractionChanges in smooth muscle tone are crucial forregulating erectile function. Unlike striatedmuscle, the molecular contractile units of inter-digitating actin (thin) and myosin (thick) filamentsare not regularly aligned with one another and canbe oriented in multiple directions [92–94]. Smoothmuscle myosin is a large hexameric protein, con-sisting of two heavy chains and four light chains.The heavy chains are identical and have bothglobular and linear domains. The linear domainsform coiled structures that result in the tail of themyosin molecule, while the globular domainspossess actin-binding sites and ATPase catalyticactivity. Actin filaments are composed of two longstrands of globular actin that intertwine into adouble helical arrangement.

The contractile response of the smooth musclecell is tightly associated with the intracellularconcentration of free Ca2+ and its regulatoryaction through calmodulin. Calmodulin-activatedmyosin stimulates phosphorylation events that ini-tiate cross-bridge movement along the actin fila-ment and generation of force. Myosin light chainphosphatase (MLCP) dephosphorylates myosinand inactivates cross-bridge movement. At anygiven level of intracellular Ca2+, the contractile


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apparatus may become further sensitized by theinhibition of MLCP, increasing the efficiency ofmyosin phosphorylation by myosin light chainkinase.

The activity of MLCP can be modulated by avariety of factors. A well-recognized mechanisminvolves the Rho/Rho kinase pathway. Rho pro-teins are small GTPases and can be activated by thebinding of agonists to G-protein-coupled receptors[95]. Activated Rho can in turn activate Rho kinase,a serine/threonine kinase. Rho kinase can thenphosphorylate multiple substrates includingMLCP, the 17 kD protein kinase C-potentiatedinhibitor protein, and myosin light chain (MLC20)[96,97]. In genital smooth muscle, the RhoA/ROKpathway and its effects on MLCP have been shownto play an important role in regulating smoothmuscle contractility in both male and female genitalsmooth muscle, whereas the importance of MLC20

phosphorylation by Rho kinase remains unclear[98–101].

Pathways Regulating VSMC TonePathways that regulate smooth muscle contrac-tility ultimately influence intracellular Ca2+ levelsand/or alter the calcium sensitivity of the con-tractile proteins (Figure 1). Vasoactive sub-stances induce changes in smooth muscle tone bypharmacomechanical coupling and/or changes incell membrane potential via electromechanicalcoupling.

Pharmacomechanical CouplingInositol 1,4,5-trisphosphate (IP3), 1,2-diacylglycerol (DAG), and proteinkinase C (PKC)The binding of vasoconstrictor agonists, such asnorepinephrine (NE), endothelin-1 (ET-1), angio-tensin II (AT-II), prostaglandin (PG) F2a andthromboxane (Tx) A2, to their respective receptors

stimulates phospholipase C beta (PLC-b). Thismembrane-bound enzyme hydrolyzes phosphati-dylinositol 4,5-bisphosphate (PIP2) to liberate IP3

and DAG. IP3 binds to specific receptors (IP3R) onthe smooth endoplasmic reticulum (SER) tostimulate the release of Ca2+ from intracellularstores. IP3Rs act as Ca2+-activated Ca2+ channels.Binding of IP3 to these receptors not only activatesthe channel, but also increases the sensitivity of theIP3R to Ca2+ and facilitates Ca2+-induced release ofCa2+ [102]. Upon dissociation of agonists fromtheir receptors, free Ca2+ is recycled back into theSER by the SER Ca2+-ATPase pump. It restoresintracellular Ca2+ levels to the basal state andthereby is an important mechanism of signaltermination.

DAG is also an important intracellular secondmessenger generated by PLC. DAG directly acti-vates PKC. With regard to smooth muscle tone,PKC can regulate ion channels or phosphorylatemultiple substrates to facilitate contraction[93,103]. PKC may also mediate Ca2+-independentcontraction, since several of the PKC isoforms areinsensitive to Ca2+ while still being activated byDAG. In VSMCs, termination of DAG/PKC sig-naling is accomplished predominantly by hydroly-sis of DAG by lipases to yield free fatty acids andglycerol [103].

Cyclic NucleotidesGeneration of cyclic nucleotides (cyclic guanosinemonophosphate [cGMP] and cyclic adenosinemonophosphate [cAMP]) by guanylyl and adenylylcyclases is a primary mode of mediating penilevascular and nonvascular smooth muscle relax-ation. Vasodilators such as vasoactive intestinalpolypeptide (VIP) and PGs E and D activateG-protein (Gs)-coupled receptors that can stimu-late plasma membrane-associated adenylyl cyclase,whereas soluble guanylyl cyclase (sGC) can bedirectly activated by NO or carbon monoxide (CO)

�

Figure 1 Signal transduction pathways regulating smooth muscle tone. Pathways mediating contraction are shown in panelA and pathways mediating relaxation are shown in panel B. Red arrows indicate association, binding, and/or activation,whereas yellow arrows indicate inhibitory regulation. Indirect or putative interactions are indicated by dashed arrows.AM = actin-myosin contractile apparatus; BKCa = calcium-activated maxi-K+ channel; CaM = calmodulin; CaMK = calmodulin-dependent kinase; cAK = cAMP-dependent protein kinase; cGK = cGMP-dependent protein kinase; CO = carbon monoxide;DAG = 1,2-diacylglycerol; IP3 = inositol 1,4,5-trisphosphate; IP3R = IP3 receptor; IRAG = IP3R-associated cGK substrate;KATP = ATP-dependent K+ channel; MLCP = myosin light chain phosphatase; MLCK = myosin light chain kinase; NO = nitricoxide; PI3K = phosphoinositide 3-kinase; PIP2 = phosphatidylinositol 4,5-bisphosphate; PIP3 = phosphatidylinositol 3,4,5-trisphosphate; PKC = protein kinase C; PLCb = phospholipase C beta; PLmb = phospholamban; ROC = receptor-operatedchannel; SER = smooth endoplasmic reticulum; SERCA = SER calcium ATPase. Adapted from Kim NN. Vascular physiologyof erectile function. In: Carson CC, Kirby RS, Goldstein I, Wyllie MG, eds. Textbook of erectile dysfunction, 2nd edition. NewYork: Informa Healthcare; 2009.

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by binding to the heme moiety of the enzyme.Increased levels of intracellular cAMP and cGMPcause the activation of cAMP-dependent andcGMP-dependent protein kinases (cAK and cGK)[104–106]. Thus, in addition to specific activation,there is potential cross-activation of cAK (alsocalled protein kinase A) and cGK (also calledprotein kinase G), which may be a mechanistic basisfor signal cross talk. However, it has been postu-lated that activation of cGK by cGMP is the mainmechanism to mediate relaxation of penile erectilesmooth muscle. cGK are derived from two differentgenes that encode type I (cGKI) and type II(cGKII). In smooth muscle, only cGKI is expressedand exists as two splice variants (cGKI alpha andcGKI beta). While specific roles of the two differ-ent cGKI isoforms are an area of continuing inves-tigation, there is evidence that both isoforms differconsiderably in their functional properties [107–109]. Immunoprecipitation studies indicate that insmooth muscle cells, cGKI is associated with IP3Rand a protein known as IP3R-associated cGK sub-strate (IRAG), both of which act as substrates forthe kinase [110]. Phosphorylation of IP3R andIRAG decreases agonist-induced Ca2+ release fromthe SER [111]. In addition, cGKI is known tophosphorylate phospholamban, a small membrane-associated protein that constitutively inhibits theSER Ca2+-ATPase. Phosphorylation of phosphola-mban inactivates its inhibitory control of ATPaseactivity and increases Ca2+ reuptake into the SER,where Ca2+ is bound to proteins such as calseques-trin. Protein kinase A can also phosphorylate phos-pholamban to increase Ca2+ reuptake [112]. Thus,the combined actions of cGKI and cAK can inhibitCa2+ release from intracellular stores or stimulateCa2+ re-uptake.

Additional and perhaps equally important phar-macomechanical mechanisms by which cGMPand/or cGKI may cause relaxation also involveinhibition of Rho kinase and stimulation of MLCP[113]. Some studies suggest that Rho kinase andMLCP can both be phosphorylated by cGKI toantagonize Rho kinase activity and stimulateMLCP. In the penis, immunostaining for cGKIalpha and cGKI beta has been observed within thesmooth musculature and the endothelium of cav-ernous arteries and sinusoids. Double-stainingprotocols revealed the colocalization of alpha-actin, cGMP, endothelial NOS (eNOS), and cGKIisoforms [114]. Findings from in vitro functionalstudies are also in support of a significance of thecGKI in the control of human penile erectile tissue[115,116].

PDEs

One of the main mechanisms by which cyclic nucle-otide signaling is terminated is by the action ofPDEs, a heterogenous group of hydrolyticenzymes. PDEs are classified according to theirpreference or affinity for cAMP and/or cGMP,kinetic parameters of cyclic nucleotide hydrolysis,relative sensitivity to inhibition by various com-pounds, allosteric regulation by other molecules,and chromatographic behavior on anion exchangecolumns. Out of 11 families of PDEs consisting ofmore than 50 isoenzymes identified to date [117–119], six (PDE 1, 2, 3, 4, 5, and 11) have beenproven to be of pharmacological importance. Sincethe distribution and functional significance of PDEisoenzymes varies in different tissues, isoenzyme-selective inhibitors have the potential to exert spe-cific effects on the target tissue. Preferentialexpression of PDE5 in the corpus cavernosum andthe cGMP-mediated relaxation of the cavernoussmooth muscle during sexual stimulation havemade inhibition of this enzyme by sildenafil, vard-enafil, or tadalafil a clinical benefit in the manage-ment of ED. The purified protein is a homodimerof 99.6 kDa subunits and binds two zinc atoms permonomer which are necessary for catalysis.

Since PDEs form a biochemically and structur-ally diverse family of proteins, there might bemore than one PDE isoenzyme or isogene servingas potential drug target in the treatment of ED. Inthe 1990s, the presence of PDE isoenzymes 2, 3, 4,and 5 was reported in cytosolic supernatants ofhuman erectile tissue [120]. In addition, theexpression of mRNA transcripts specificallyencoding for 14 different human PDE isoenzymesand isoforms in human cavernous tissue was shownby means of real-time polymerase chain reaction(RT-PCR) and Northern blot analysis: PDE1A,PDE1B, PDE1C, PDE2A, and PDE10A, whichhydrolyze both cAMP and cGMP; the cAMP-specific PDE isoenzymes PDE3A, PDE4 (A-D),PDE7A, and PDE8A, and the cGMP-specificPDEs PDE5A and PDE9A [121]. The intracellu-lar level of cAMP in human erectile tissue ismainly regulated by the cAMP-degrading PDEisoenzymes 3 and 4. Results obtained in vitrosuggest that PDE3 and PDE4 might be the pre-dominant isoenzymes in the human corpus caver-nosum [122]. Interestingly, it has also been shownthat the reversion of tension mediated by analpha1-adrenoceptor of isolated human corpuscavernosum induced by sildenafil and tadalafil wasreversed by the cAK inhibitor Rp-8-CPT-cAMPS,

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suggesting an involvement of cAMP-mediatedmechanisms in the action of PDE5 inhibitors[115]. On the basis of these observations, animportant complementary role might be consid-ered for the adenylyl cyclase/cAMP/cAK pathwayin the control of cavernous smooth muscle tone.

Electromechanical CouplingPathways that regulate VSMC tone and that areassociated with changes in membrane potential aredefined as electromechanical coupling mecha-nisms. The primary electromechanical mechanismof contraction in VSMCs involves depolarizationand the opening of voltage-gated L-type Ca2+

channels to allow influx of extracellular Ca2+. Con-tractile responses caused by NE, ET-1, and AT-IIare partly mediated by L-type Ca2+ channels [123–125]. Recent studies indicate that L-type Ca2+

channels can be activated by phosphatidylinositol3,4,5-trisphosphate (PIP3) which is derived fromPIP2 through the action of phosphoinositide3-kinases (PI3K) [123]. PI3Ks are associated withthe plasma membrane and can be activated byG-protein-coupled receptors or tyrosine kinases.

A major mechanism of VSMC relaxation is theactivation of K+ channels. Activation of cGK andcAK has been associated with the opening of Ca2+-activated maxi K+ (BKCa) channels in the plasmamembrane, causing hyperpolarization. Variousmechanisms involving direct and indirectphosphorylation/dephosphorylation events medi-ated by cGK or cAK have been postulated for theactivation of BKCa channels in smooth muscle fromdifferent vascular beds. However, the precisemechanisms remain undefined. Hyperpolarizationmediated by BKCa channels has been shown to be animportant mechanism of NO-cGK-dependentrelaxation in the cavernosal smooth muscle of thepenis [126]. Some vasodilators that stimulate cAMPproduction have also been shown to activate ATP-sensitive K+ channels in penile cavernosal tissue andresistance arteries [127,128]. Collectively, changesin membrane potential due to increased K+ effluxinactivate L-type Ca2+ channels to inhibit Ca2+

influx. NO may also cause VSMC hyperpolariza-tion independent of cGMP and cGK. In aorticsmooth muscle cells, NO has been shown todirectly activate BKCa channels [129].

Endogenous Regulators of Penile CavernosalVSMC ContractilityNONO is the primary mediator of nonadrenergic,noncholinergic (NANC) parasympathetic input

and endothelium-dependent relaxation in thecorpus cavernosum [1]. NO can regulate a widearray of physiological functions in mammals. It issynthesized on demand from the amino acidL-arginine and molecular oxygen by a family ofenzymes known as NOS. Three distinct isoformsof NOS have been identified which were origi-nally named after the tissues in which theywere first described. nNOS (NOS type I) andeNOS (or NOS type III) are Ca2+/calmodulin-dependent, constitutive isoforms. Inducible NOS(iNOS or NOS type II) is a Ca2+-independentisoform that is mainly expressed in macrophagesand tissues following an immunological stimulus[130]. NO can readily cross plasma membranes toenter target cells and promote the synthesis andaccumulation of cGMP by the activation of thesGC. sGC is a heterodimeric protein that containsa prosthetic heme attached to a histidine residueof the b-subunit, which is required for the activa-tion of the enzyme. Although the binding of NOoccurs in the b-subunit, both subunits arerequired for the stimulation of enzyme activity[131,132].

PGsPGs are produced by the action of cyclooxygena-ses on the common precursor arachidonic acid[133]. Human corpus cavernosum smooth musclecells in culture have been shown to produce pros-taglandin E (PGE2) and PGF2a. It has been dem-onstrated that prostanoids can induce bothrelaxation and contraction in penile corpus caver-nosum. PGE is the only endogenous PG thatappears to elicit relaxation of human trabecularsmooth muscle, the others causing constriction orhaving no effect on smooth muscle tone. Exog-enous PGE1 and PGE2 relax isolated cavernosaltissue at submicromolar concentrations, whilePGE2 causes contraction at concentrations of10 mM or greater. Prostaglandin E receptor (EP)receptors, which mediate the response to PGE,have been the most extensively studied and arecategorized into four pharmacologic subclasses(EP1–EP4) [134,135]. Several different isoforms ofthe EP3 receptor have been identified and arisefrom alternative splicing of a single gene product.In general, the EP1, EP3I, and EP3III receptorsmediate smooth muscle contraction by stimulatingphosphatidylinositol hydrolysis or inhibiting ade-nylyl cyclase, while EP2, EP3II, and EP4 receptorsmediate smooth muscle relaxation by coupling toGs protein and stimulating adenylyl cyclase toincrease intracellular cAMP [136].


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Peptide Regulators—VIP and ETThe density and distribution of VIPergic nerveswithin the penis has led many to postulate thatVIP, in addition to NO, is an important NANCneurotransmitter regulating penile erection. VIP-immunoreactive nerves are widely distributedthroughout the male genitourinary system, andVIP and NOS containing nerves are often colocal-ized in penile tissue [1]. Isolated corpus caverno-sum tissue from various species, including human,exhibits relaxant responses to VIP. These effectsare accompanied by an increase in tissue levels ofcAMP. The role of endogenous VIP in mediatingpenile erection is further supported by the obser-vations that anti-VIP antibodies and VIP receptorantagonists inhibit nerve-mediated relaxation inisolated cavernosal tissue strips [1]. However, therole of VIP as a modulator of trabecular smoothmuscle tone remains inconclusive since the effectsof the peptide in vivo are not necessarily consistentwith ex vivo or in vitro findings. Intracavernosaladministration of VIP in humans has yieldedvarying results, ranging from no effect to partialtumescence to full erection. Thus, while descrip-tive studies are supportive of VIP’s potential rolein mediating or enhancing the onset and mainte-nance of penile erection, the mechanisms under-lying its regulation and action have yet to becompletely elucidated.

ET-1 is one of the most potent vasoconstrictorsyet described [137,138]. This peptide has also beenshown to have growth factor activity, stimulatingmitogenesis in fibroblasts, smooth muscle, andendothelial cells. Similar to NO, ET release fromthe intimal lining of blood vessels can be inducedby shear stress. In human corpus cavernosum,ET-1 is synthesized by the endothelium and elicitsstrong, sustained contractions of corpus caverno-sum smooth muscle [139,140]. Both ET receptorsubtypes (ETA and ETB) have been identified inpenile corpus cavernosum. They are distributed onboth the endothelium and the smooth muscle andare distinguished by their binding affinity for ET-3[141]. Exogenous ET-1 or ET-2 cause equipotentcontraction in isolated cavernosal tissue strips,whereas ET-3 induces much weaker contraction incorpus cavernosum. While the receptor-bindingaffinity of ET-1 and ET-2 is not necessarily greaterthan that of other contractile factors, the rate ofdissociation is significantly slower than manyligands [141]. This may account for the uniqueability of ETs to maintain long-lasting, sustainedcontraction in corpus cavernosum smooth muscle.It has been suggested that ET may also exert

vasodilatory effects at low concentrations througha “super-high” affinity form of the ETB receptor.Although this vasodilatory role of ET in penileerection remains unclear, it has been demonstratedin the rat that ET-3 and submaximal doses of ET-1increase ICP, potentially by stimulating NO pro-duction [142].

Noncontractile Responses in VSMCsChanges in VSMC growth and extracellularmatrix production can have a profound impact onthe function of genital tissues. The extracellularmatrix itself is a dynamic structure that plays animportant role in modulating cell morphology,movement, growth, differentiation, and survival byregulating cell adhesion, cytoskeletal machinery,and intracellular signaling. It has been postulatedthat smooth muscle cells may transform from con-tractile to synthetic cells (or vice versa) in responseto changes in their environment (e.g., chronicdisease states or acute injury). Alternatively, theremay be an inherently heterogeneous population ofVSMCs in a given vascular tissue at any one time.In addition to growth factors and cytokines, vaso-active factors have also been shown to have trophiceffects in the vasculature, suggesting that many ofthe same intracellular mediators that cause con-traction or relaxation are also involved in trophicresponses in VSMCs.

Synthetic VSMCs are primarily characterizedby a significantly decreased expression of contrac-tile proteins. Thus, activation of signaling path-ways that may have mediated tonic responses incontractile VSMCs can modulate cell growth ormatrix production in a synthetic VSMC. However,the specific mechanisms regulating gene expres-sion and cell growth remain, in large part, to beelucidated. For example, the NO-cGK pathwayand its effects on gene expression is an area ofactive study. While it appears that cGKI modulatesthe exracellular signal-regulated kinase (ERK)pathway (also called mitogen-activated proteinkinase or MAP kinase) to modulate proliferationand migration of VSMCs, the molecular targets ofERK that eventually control gene transcriptionhave not been clearly defined [143].

Many growth factors stimulate cell surfacereceptors with intrinsic tyrosine kinase activity intheir cytoplasmic domains. This tyrosine kinaseactivity is considered essential to regulating cellgrowth. Several of these receptors have beenlinked with the activation PLC-g. Also, phospho-lipase D (PLD) may be more important for medi-ating trophic responses than contractile responses.

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Some variations in responses to growth factors andvasoactive substances may be due to the differentmechanisms of activation for different PLC iso-forms. Stimulation of PKC has been shown tohave both proliferative and antiproliferative effectsto platelet-derived growth factor, epidermalgrowth factor, and AT-II [103]. While the reasonsfor this variability remain unclear, it must bestressed that multiple isoforms of PKC exist andeach isoform has numerous substrates. PKC hasalso been shown to modulate DNA synthesis,potentially through the phosphorylation of tran-scription factors [103].

Summary and PerspectiveAn impressive amount of knowledge has beenaccumulated regarding smooth muscle biologyand vascular physiology. Future concepts in genitaltissue pharmacology will benefit from theseinsights. To date, it is widely accepted that severaldisorders of the male sexual response, such as maleED and orgasmic dysfunctions, can be therapeuti-cally approached by influencing the function of thevascular and nonvascular smooth musculature ofthe genital tract. In order to achieve a pronounceddrug effect without significant adverse events,especially on the cardiovascular system, a certaindegree of tissue selectivity is mandatory. Selectiveintervention in intracellular pathways regulatingsmooth muscle tone has become a promising strat-egy to modulate tissue function.

Diabetes and MetS

Diabetics are at increased risk for maladies, includ-ing retinopathy, neuropathy, nephropathy, andvascular disease. ED is often characterized in partby insufficient NANC nerve stimulus, and/or aninability to dilate feeder arterioles of the penisresultant from vascular disease. As the diabeticpopulation is susceptible to these changes, ED isindeed prevalent in this cohort. Although PDE5inhibitors have revolutionized the field of EDtreatment, these drugs are less effective in certainsubsets of the population, including diabetics. Forthe sake of this amended chapter, the work out-lined will review mainly type 2 diabetic ED andthe MetS, highlighting studies of type 1 diabeticED when relevant. Some valuable reviews include:Hidalgo-Tamola et al. [144], Moore et al. [145],Vrentzos et al. [146], Musicki et al. [147], andDiSanto [148].

Epidemiolgic DataDiabetes MellitusDiabetes mellitus is a common chronic disease,affecting 0.5–2% worldwide. The prevalenceof diabetes as a comorbidity has remained at20–25%, irrespective of whether treating clinicsare endocrine based or andrology based [149,150].ED in diabetics is more common than retinopathyor nephropathy [151]. The Massachusetts MaleAging Study reported that up to 75% of men withdiabetes have a lifetime risk of developing ED,much higher rates than 52% (40–70 years of age)[152–154]. The onset of ED occurs in the earlierage for those with diabetes, presenting within 10years of the diabetic onset in more than 50% ofpatients with any type of diabetes [155].

MetSMetS, which is also called insulin resistance syn-drome or syndrome X, includes glucose intoler-ance, insulin resistance, obesity, dyslipidemia, andhypertension. Several epidemiological data haveidentified MetS as potential risk factors of ED.Grover et al. [156] evaluated the effect of variouscardiovascular risk factors on ED in a primary caresetting. ED was found in 49.4% according to ascore of less than 26 on the International Index ofErectile Function-erectile function (IIEF-EF)domain in a cross-sectional survey of 3,921 Cana-dian men. The presence of diabetes (odds ratio3.13), undiagnosed hyperglycemia (odds ratio1.46), impaired fasting glucose (odds ratio 1.26),and MetS (odds ratio 1.45) were identified as inde-pendent risk factors for ED.

Clinical FindingsDiabetes MellitusIn 12% of type 1 diabetic men, ED was the firstsymptom of diabetes [157]. The prevalence of coro-nary artery disease (CAD) (20%) and peripheralvascular disease (5%) among men with diabetes isfar higher than in the general population. Patho-logic changes in the cavernous arteries [158], ultra-structural changes in the cavernous smooth muscle[159],andimpairedendothelium-dependentrelaxa-tion of the corporeal smooth muscle [160] have alsobeen noted in penile specimens from diabetic menwith ED.

The presence of ED in diabetic patients could bethe harbinger of fatal cardiovascular disease. Gaz-zaruso et al. [161] demonstrated a higher preva-lence of ED in diabetic patients with silent CADthan those without any evidence of myocardialischemia. ED was associated with more than 14


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times higher risk for silent CAD in diabetic men. Ina subsequent study, ED was associated with highermajor cardiovascular morbidity and mortality indiabetic patients with silent CAD [161].

Hemoglobin (Hb)A1c levels have been shownto increase with the severity of ED [162,163] andwas found to be an independent predictor of theEF score in 78 men with type 2 diabetes [164].However, there have been conflicting results aboutthe beneficial effects of strict glycemic control onerectile function. Some studies reported improvederectile function following the reduction ofHbA1c, while others reported no significantchange despite the aggressive blood sugar control[165,166].

Hypogonadism is often associated with diabeticED patients. Corona et al. found hypogonadism in24.5% of men with diabetes and ED vs. 12.6% inthe rest of the men with ED [167]. Testosteronesupplementation in human diabetics with EDreceiving pharmacological treatment might beadvantageous in the diabetic men in whom PDE5inhibitors given for ED do not work [168].

MetSMetS and increased waist-to-hip ratio have beenassociated with a higher proportion of moderate-to-severe ED in men older than 50 years [169].Conversely, ED may be predictive of MetS pres-ence in men with a body mass index (BMI) of<25 kg/m [145,170]. These interesting findingssuggest that ED may be a warning sign for MetS inmen otherwise considered at low cardiovascularrisk.

Studies indicated the possible role of inflamma-tion and endothelial dysfunction in the develop-ment of ED for patients with MetS. Men withMetS had an increased prevalence of ED, reducedendothelial function score, and higher circulatingconcentrations of high sensitivity C-reactiveprotein (CRP) compared with men without meta-bolic disorders [171]. This and other studiesclearly showed the relationship between MetS, theinflammatory endothelial activation, and theprevalence of ED [171,172].

As mentioned earlier, low circulating androgenlevels are clearly a risk factor for MetS and thereverse relationship is true as well. ED mightoccur as a possible consequence of hypogonadismand MetS. A recent study by Zhody et al. [173]elegantly related hypogonadism to ED and MetSby analyzing BMI measurements in 158 obesemen. With increasing BMI, the frequency ofhypogonadism and ED increased, while total

serum T showed a strong negative correlation. Toassess the effect of BMI on vasculogenic ED, theauthors examined this relationship in the absenceof other risk factors and found that for a BMI <25,three out of 13 men (23.1%) had vasculogenic EDas compared with 32 out of 54 men (59.3%) with aBMI �25.

Currently, no direct pharmacologic therapy forMetS is available. Esposito et al. [174] assessed theeffect of weight loss and increased physical activityon men with ED associated with obesity. BMIdecreased significantly in the intervention group,and was associated with a decrease in serum con-centrations of interleukin-6 and CRP. Erectilefunction scores improved significantly with lif-estyle intervention but remained stable in thecontrol group. In multivariate analyses, changes inBMI, physical activity, and CRP were indepen-dently associated with erectile function improve-ment. Thus, lifestyle changes are associated withimproved sexual function and lowered inflamma-tion in obese men with ED.

Basic Science MechanismsThe majority of basic science studies, to date, thatexamine mechanisms of diabetic ED have done sousing animal models of type I diabetes. Availablestudies outlining ED in animal models of type 2diabetes and MetS have recently been reviewed[144].

Nitrergic DysfunctionErection is activated by NO release from nNOS atNANC nerve terminals. Maintenance of cavern-osal vasodilation is thought to occur through theactivation of eNOS in endothelial cells, presum-ably in response to shear stress. Impaired vaso-dilator signaling often results from NANC nervedysfunction and/or endothelial dysfunction,leading to ED. Numerous studies have demon-strated type I diabetic animals to have impairedcavernosal relaxation to electrical field stimulationas well as decreased ICP following electrical cav-ernosal nerve stimulus, indicative of nitrergic dys-function [175–181]. Decreased penile nNOScontent was detected in various rodent models oftype 2 diabetes [182–184]. Impaired nitrergic-mediated relaxation in type 2 diabetic mice hasalso been reported; however, the extent of theimpaired relaxant response was modest, leadingthe authors to question the true pathophysiologicrelevance of this finding to the ED phenotype[185].

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Endothelial DysfunctionEndothelial dysfunction is characterized bylowered NO bioavailability resulting fromdecreased eNOS expression or activity, orincreased NO scavenging. It is clear that anattenuation of endothelium-dependent vasodila-tion of cavernosal tissue is present in severalanimal models of type 1 and type 2 diabetes[144,147,184–186]. The activation of eNOS canoccur by hemodynamic stimuli, such as shearstress, as well as through protein signaling, such asby VEGF, leading to eNOS phosphorylation onserine 1177 [147,187]. In addition to phosphory-lation events, eNOS activity and subsequent NOproduction are regulated by substrate concentra-tion, cofactor availability, and enzyme coupling.Relevance of dysfunctional eNOS enzyme regula-tion remains speculative in regard to diabetic ED(see citation [147] for review).

Oxidative StressChronic hyperglycemia induces free radical pro-duction through formation of advance glycationend-products (AGE), lipid peroxidation, polyolpathway activation, superoxide production, andactivation of PKC [188]. Increased penile andserum AGE and reactive oxygen species (ROS)levels have been detected in type I diabetic rodents[189,190]. Impairments in NO-mediated cavern-osal relaxation in these rodents are prevented withsuperoxide dismutase or a peroxynitrite decompo-sition catalyst, supporting a delirious role of ROSin type I diabetic ED [191–193].

Studies examining oxidative stress in animalmodels of type 2 diabetes or MetS are scant.Decreased antioxidant levels, such as glutathione(GSH), may result in elevated ROS/oxidativestress in type 2 diabetic men. Kovanecz et al. foundprolonged treatment with pioglitazone, a peroxi-some proliferator-activated receptor (PPAR)-gagonist said to have anti-inflammatory effects andto improve the glutathione/glutathione disulphide(GSH/GSSH) ratio [194], suggesting thatglycemic-stabilizing agents may also have benefitin decreasing damaging ROS.

Cavernosal HypercontractilityIncreased contractile function of the cavernosumcan result from heightened sympathetic activationor potentiated intracellular contractile signaling ofsmooth muscle cells. Many animal models of dia-betic ED have pointed to cavernosal hypercon-tractility as a pertinent mechanism underlying thedisease phenotype. A recent review extensively

outlines potential pro-signaling pathways in thepenile smooth muscle cell that may contribute todiabetic ED [148].

Studies by Carneiro et al. and Luttrell et al.have suggested the presence of increased contrac-tion in response to sympathetic activation in typeII diabetic ED [185,195]. Wingard et al. found theheightened contractile signaling in the type 2 dia-betic rodent in response to phenylephrine andET-1 to be mediated by overactivity of PKC andRho kinase, two primary kinases mediatingsmooth muscle cell tone [186].

Veno-occlusive DysfunctionThe limiting of blood outflow through mechanicalcompression of the emissary veins against thetunica albuginea is essential for the maintenance ofelevated corporal pressures and a rigid erection.Studies in animal models of type 2 diabetes havesuggested that a veno-occlusive disorder mayunderlie the ED phenotype. Kovanecz et al. foundZucker diabetic fat rats to have an inability tosustain adequate intracorporal pressure after thecessation of penile saline infusion, suggesting thepresence of a veno-occlusive disorder [194]. Thesestudies have recently been validated in the db/dbmouse model of type 2 diabetes [185].

ConclusionsThe numbers of patients with type 2 diabetes andMetS continue to rise. Current pharmacologictreatments remain insufficient for these popula-tions, and the need for improved therapeutics isevident. Organic ED in these cohorts is under-lined by multifaceted, complex mechanisms,involving nerve, vascular, and hormonal signalingat its core. It is clear that more clinical and basicscience studies are warranted.

ED and Cardiovascular Disease

The vascular system is responsible for providingadequate blood supply to the erectile tissue facili-tating the corporo-veno-occlusive mechanismrequired for erection. Thus, any alteration of thevascular system may compromise erectile function.Vascular disease in arteries supplying blood to thepenis obviously impedes erectile function by lim-iting blood flow, but systemic vascular dysfunctionis also intimately related to ED. Cardiovasculardisease shares with ED the same risk factors,namely hypertension, hypercholesterolemia, dia-betes, and smoking [152,196].


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Atherosclerosis/Vascular Ischemia and EDAssociation of ED to systemic vascular diseases isclear. On one hand, there is a high prevalence ofED in patients having CAD [197,198], peripheralarterial disease [199], and cerebrovascular disease[200]. In addition, the prevalence of ED seems tobe increased as the severity of vascular disease aug-ments [201]. Patients with lesions in two or morecoronary arteries had worse erectile function thanpatients with normal coronary arteries or single-vessel CAD [202].

On the other hand, cardiovascular diseases areprevalent among patients with ED. In fact, CADhas been revealed in patients reporting EDwithout any other symptomatology of vasculardisease [203]. ED has also been associated to thepresence of peripheral atherosclerotic lesions.Among patients with ED, 66.4% presented ath-erosclerotic lesions, while lesions were onlypresent in 36.5% of patients without ED [204]. Inmost cases, ED symptoms preceded CAD symp-toms [197,201]. Thus, ED would be a sentinelsymptom that warns of a probable underlying sys-temic vascular disease [205].

Chronic ischemia provoked by atheroscleroticstenosis of the proximal iliac artery in rabbits isalso associated with functional changes in thedistal part of the penile vasculature such asdecreased NOS activity, increased production ofcontractile Tx, and PG formation. Neurogeniccontractions were potentiated, while endothelium-dependent and neurogenic NO-mediated relaxa-tions were reduced in cavernosal tissue [206,207].A time-dependent reduction of the expression ofnNOS and eNOS in the cavernosal tissue fromthese animals, with a parallel increase of theexpression of iNOS, was demonstrated [208].Reduced NOS activity and impaired endothelium-dependent and neurogenic NO-mediated relaxa-tion of cavernosal tissue have been confirmed in arabbit model of cavernosal ischemia withouthyperlipidemia [209]. An elevation of the cavern-osal content of endogenous inhibitors of NOSwas proposed to be responsible for these effects[209]. The apolipoprotein E knockout mouse, aknown experimental model of atherosclerosis,shows reduced erectile responses and impairedNO/cGMP pathway [210,211].

Hyperlipidemia and EDAssociation of ED to hyperlipidemia has beenfound in several clinical studies. High concentra-tions of low-density lipoprotein seem to be relatedto ED [212], although low levels of high-density

lipoproteins have been shown to be predictive ofED [213]. Hypercholesterolemia at baseline wasalso shown as a predictor of ED 25 years later[214]. In contrast, a survey of 1,899 men aged30–79 years in Boston area revealed the absence ofassociation of untreated hyperlipidemia and ED[215].

Chronic hypercholesterolemia reducesendothelium-dependent relaxations, but not theendothelium-independent relaxations in rabbitcorpus cavernosum [216,217]. In contrast, the neu-ronal vasodilation does not appear affected in theseanimals [207]. The selective action of the endothe-lial NO/cGMP pathway in hypercholesterolemiacould be due to increased superoxide production[217] by nicotinamide adenine dinucleotide phos-phate (NADPH) oxidase [218] or to increasedplasma levels of asymmetric dimethylarginine(ADMA), an endogenous inhibitor of NOS [219].VEGF and VEGF receptor 2 are downregulated incorporal tissue of rats’ high-cholesterol diet [220].Intracavernosal administration of VEGF and fibro-blast growth factor-2 improved endothelial func-tion, increased the expression of nNOS, andactivated eNOS [221,222].

Hypertension and EDThe analysis of a representative care claims data-base identifying 273,325 patients with ED in theUnited States revealed that the prevalence ofhypertension in this ED population was as high as41.6% [223]. Conversely, a high prevalence of EDis generally observed in hypertensive patient popu-lations [224–226]. However, hypertension is a riskfactor not only for ED but also for cardiovasculardisease. Then, the impact of hypertension on erec-tile function is contributed by the cardiovascularcomplications following hypertension are associ-ated to even higher prevalence of ED [152,227].Some studies have detected lower levels of serumtestosterone in hypertensive patients [228,229], afact that could be relevant to the development ofED in these patients. In hypertensive population,ED was associated to older age, longer duration ofhypertension, and a more severe hypertension. EDwas also related to the antihypertensive therapy[224].

Erectile responses were markedly inhibited inspontaneously hypertensive rats (SHR) after nor-malization by mean arterial pressure (MAP),although moderately reduced absolute increases inICP were observed [230,231]. Reduction of ICP/MAP response in SHR preceded the developmentof hypertension. The impairment of cavernosal

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endothelium-dependent and NO donor-inducedrelaxations also occurred before systemic vascularalterations were manifested [231]. This suggeststhat erectile tissue is at the front line of the devel-opment of endothelial dysfunction and would bean early target end organ. Oxidative stress mayplay a significant role in the alterations caused byhypertension on erectile function. In fact, an aug-mented production of superoxide anions couldresult from increased activity of NADPH oxidasedriven by AT-II [232].

Cigarette Smoking and EDCigarette smoking is clearly related to ED. Activeand passive smokers are at higher risk for ED thanmen not exposed to smoke, and the risk increasesas the exposure increases [233,234]. Some studiessuggest that smoking is associated to ED inde-pendently of cardiovascular disease [235,236].Although a causative effect cannot be proven incross-sectional studies, this hypothesis is sup-ported by the dose–response shown in severalstudies [234,236,237] and the fact that erectilefunction is improved after smoking cessation[238,239].

A reduction of penile NOS activity and nNOSexpression was observed after passive smoking inrats, although erectile responses were not reduced[240]. Cigarette smoking would be related todownregulation of NO/cGMP pathway in peniletissue, probably related to increased oxidativestress [241,242], although an elevated activity andexpression of arginase together with an increase ofthe content of the endogenous NOS inhibitor,ADMA, could participate [243]. On the otherhand, acute nicotine administration caused a sig-nificant reduction of physiological erectileresponses to erotic films in healthy nonsmokermen [244].

Pathophysiological Mechanisms in Vascular EDIncreased VasoconstrictionRhoA/Rho kinase pathway plays an important rolein calcium sensitization and tonic contraction ofsmooth muscle. Cardiovascular diseases are asso-ciated with an enhancement of RhoA/Rho kinaseactivity [245]. RhoA and Rho kinase expression iselevated in the cavernosal tissue from hypertensiverats, possibly contributing to reduced erectilefunction in these rats [246]. ET-1 levels areelevated in plasma from patients with hyperten-sion and hypercholesterolemia [247,248]. Patients

with organic ED also show higher venous andcavernosal ET-1 levels [249]. In cavernosal tissuefrom DOCA-salt hypertensive rats (specific animalmodel), contractile responses to ET-1 wereincreased and relaxation caused by ETB activationwas reduced [250]. A decrease in ETB receptors incavernosal tissue from hypercholesterolemicrabbits was also detected [251]. AT-II has beendetected in endothelial and smooth muscle cells ofhuman corpus cavernosum [252] and caused itscontraction [253]. AT-II converting enzymeexpression is upregulated in rats with arteriogenicED [254]. In fact, administration of an AT1

antagonist has been shown to improve erectilefunction in hypertensive patients [255].

Impaired Neurogenic VasodilatationImpaired neurogenic relaxation of cavernosaltissue has been observed in a rabbit model of cav-ernosal ischemia [209], in SHR, affecting both NOneurotransmission and CO neurotransmission[256] and after cigarette extract administration[241] while was unaffected in a rabbit model ofhypercholesterolemia [207].

Endothelial DysfunctionCoronary endothelial dysfunction has beenassociated with the presence of ED [257].Endothelium-dependent flow-mediated dilation(FMD) of the brachial artery was significantlyreduced in ED patients, although nitroglycerine-induced dilation was also impaired [258,259]. Theimpairment of FMD correlates to the severity ofED [260]. Endothelium-dependent penile bloodflow increases generated by reactive hyperemiawere reduced in patients with ED. At the sametime, endothelial function in the forearm vascu-lature was not significantly altered in ED patients[261].

Penile Structural AlterationsObjective reduction of smooth muscle cells hasbeen demonstrated in patients with organic ED[262]. A decrease in cavernous trabecular smoothmuscle and an increase in connective tissue arecorrelated with diffuse venous leakage and a failureof the veno-occlusive mechanism, hence resultingin ED [263,264]. SHR show hyperproliferation ofsmooth muscle in cavernosal tissue and penile vas-culature, which correlates with blood pressurevalues. Increased fibrosis was also observed [265].Hypertension-induced alterations were improvedafter antagonism of type 1 AT-II receptors (AT1)[266].


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Drugs Causing ED

ED is a common symptom among older men andwill inevitably coexist with other physical condi-tions prevalent in this population such as depres-sion, diabetes, and cardiovascular disease whichare themselves risk factors for ED [152,227,267].In addition, sexual symptoms related to medica-tion can involve a combination of complaints con-cerning sexual desire, arousal, and orgasm ratherthan being concentrated on ED alone. Self-reported and questionnaire data concerning ED asa side effect of medication should therefore beinterpreted with caution.

Cardiovascular Drugs and Erectile FunctionED and heart disease have common risk factors[214,227], but comparing untreated and treatedpatients with heart disease or hypertensionrevealed that medication increases the relative riskfor development of ED [268].

Treatment of Hypertension and EDCurrent recommendations for treatment of hyper-tension suggest thiazide diuretics as first-linetherapy, while angiotensin-converting enzyme(ACE) inhibitors, AT1 receptor antagonists,calcium channel blockers, and beta-adrenoceptorantagonists are indicated as first-line agents in spe-cific high-risk conditions [269]. Often, two or moreantihypertensive medications will be required toachieve a blood pressure <140/90 mm Hg (or<130/80 mm Hg in diabetic patients) in hyperten-sive patients [269]. All drugs have ED listed as apotential side effect, but well-designed controlledclinical trials give conflicting results concerningcausative relationships [270]. Animal studies dosuggest possible mechanisms using in vitro and invivo methodology [271].

DiureticsThis class of drug has been extensively studiedfollowing early trials which showed a high preva-lence of self-reported ED. Possible mechanismsinclude decreased vascular resistance and loweredzinc levels leading to reduced androgen produc-tion. Appropriate controlled studies with ED as anend point give consistent results despite trendstoward lower-dosage schedules [225]. Similar find-ings were documented from the Treatment ofMild Hypertension Study (TOMHS) where theprevalence of ED at 2 years in men taking a low-dose thiazide was twice that of both the placebogroup and those on alternative agents [272]. Inter-estingly, after 4 years of treatment, prevalence of

ED in the placebo group approached that of thethiazide group, a finding not fully explained bydropouts. It may be that thiazide therapy unmaskslatent ED at an earlier stage rather then beingdirectly causal. Thus, it is likely that thiazidediuretics are associated with ED in men withhypertension, although this may representunmasking of an existing problem and the effectcan be reduced by lifestyle changes.

b- and a-Adrenoceptor AntagonistsIn penile tissue, activation of b-adrenoceptors leadsto corporal relaxation [1] and vasodilation of penilearteries [273]. This response is attenuated in vitroby nonselective drugs such as propanolol, possiblyby blocking postjunctional b2-adrenoceptors[273,274], but not by cardiac selective agents suchas practolol and atenolol. Depending on the lipo-philicity of the b-adrenoceptor antagonists (e.g.,propranolol is hydrophobic, while atenolol ishydrophilic), they may also exert an inhibitoryeffect within the central nervous system, perhapsleading to lowered sex hormone levels [275]. Theeffect of b-adrenoceptor antagonists on erectilefunction to a large degree can be explained bytheir mechanisms of action (e.g., they are eithergeneral b-adrenoceptor antagonists, selective b1-adrenoceptor antagonists, or also possess vasodila-tatory properties) (Figure 2). Nonselective drugssuch as propanolol were associated with higherprevalence of ED compared with patients treatedwith placebo or ACE inhibitors [276,277]. Latertrials using agents with higher selectivity for theb1-adrenoceptor such as acebutolol have shown asubstantial reduction in ED as a side effect with nodifference being found against the placebo andACE inhibitor groups [272]. This also applies tothe use of selective b1-adrenoceptor antagonistsin the prophylaxis of angina [278]. The generalb-adrenoceptor antagonists which also causevasodilation by blocking a1-adrenoceptors,e.g., carvedilol, have, in a crossover study, beenreported to be associated with worsening in sexualfunction [279]. Some of the recently introducedb1-adrenoceptor antagonists such as nebivolol havealso vasodilatatory effects mediated by release ofNO. In crossover studies, nebivolol, in contrast tothe selective b1-adrenoceptor antagonists, meto-prolol, and atenolol, did not decrease sexual inter-course activity in hypertensive men, and may evenhave positive effects on erectile function [280,281].

In clinical trials, a1-adrenoceptor antagonists(e.g., doxazosin) used to treat hypertension [272]or lower urinary tract symptoms [282] are not

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associated with complaints of ED and indeed hadlower rates than placebo groups. Drugs stimula-tory to the a2-adrenoceptors such as clonidineresult in diminished erectile function both clini-cally and experimentally by peripheral and centralmechanisms [274,283].ACE Inhibitors and AT1 Receptor AntagonistsIn addition to circulating AT-II, ACE and chymaseare expressed in erectile tissue, and functional aswell as binding studies suggest that AT-II inducescontraction by activation of AT1 receptors [270].Moreover, AT-II increases during the detumes-cence phase in man [284]. The ACE inhibitor cap-topril does not cause any significant adverse effecton sexual function in awake rats [274], and enala-pril may even improve erectile function in SHR[285]. This is also supported by clinical studiescomparing an ACE inhibitor with other agentsand placebo. All three studies found either no dif-ference compared with placebo or improved sexualfunction from baseline compared with other anti-hypertensive drugs [272,275,276,286].

In studies of hypertensive animals, AT1 receptorantagonists (e.g., losartan, valsartan, and cande-sartan) reverse structural changes in the penile vas-culature and appear to conserve erectile function[285,287–289]. Moreover, in clinical cross-sectional studies, AT1 receptor antagonists, in con-trast to other antihypertensive drugs, even tend toimprove erectile function [225]. In direct compari-son with the b-adrenoceptor antagonist carvedilol,valsartan has a beneficial effect on existing sexualdysfunction at baseline and has no adverse sexualeffects during 12 months of treatment [279]. In thecase of losartan, 3-month treatment was alsoreported to improve sexual function [290].Calcium Channel BlockersSmooth muscle contraction requires increasedcytosolic calcium derived from internal stores andextracellular fluid. It would, therefore, be antici-pated that calcium channel blockers would have apermissive effect on penile erection but mightinhibit bulbospongiosal contraction during ejacu-lation. This is supported by findings of in vitro

Figure 2 b-adrenoceptor antagonists and erectile function. Propranolol is a general b-adrenoceptor antagonist, whilecarvedilol and labetalol also block a1-adrenoceptors. Metoprolol, bisoprolol, and atenolol are selective b1-adrenoceptorantagonists, and nebivolol, in addition, leads to release of nitric oxide (NO).


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studies which demonstrated a modest relaxanteffect on isolated cavernosal smooth muscle [283]and penile arteries [291]. Clinical studies havedemonstrated no adverse effect on erection andejaculatory complaints seem short-lived [275]. Inthe TOMHS, there was no significant excess riskof ED in the amlodipine group compared withplacebo-treated patients [272]. Another study alsoshowed no increase in the prevalence of ED whenhypertension was treated with diltiazem alone orin combination with an ACE inhibitor [292]. Acomparative study of two calcium channel antago-nists showed that neither had any significant effecton sexual function, although two patients with-drew from the nifedipine arm because of reducedlibido [293].

Treatment of Heart Disease and EDED is highly prevalent among patients with heartfailure, because of neurohumeral changes, animbalance of circulating vasomodulators, reducedcardiac capacity, depression, and potential adverseeffects of heart failure medical treatment [294]. Anarray of drugs is applied for the treatment of heartdisease. In most cases, a multiple drug regimen isapplied for conditions such as chronic heartfailure, where patients are treated with diureticsfor removal of surplus liquid, ACE inhibitorsand/or AT1 receptor antagonists to cause periph-eral vasodilation, digoxin as positive inotropicagent, antithrombotics, antiarrhythmics, antico-agulants, and hypolipidemic drugs. In addition,the aldosterone receptor antagonists, spironolac-tone and eplerenone, and b-adrenoceptor antago-nists such as metoprolol, bisaprolol, carvedilol,and recently, nebivolol have been found toenhance survival in patients suffering from heartfailure [295–297]. Standard heart frequencytherapy with b-adrenoceptor antagonists, digoxin,and thiazide diuretics may worsen sexual dysfunc-tion owing to medication side effects, but evidenceregarding the effect on erectile function of most ofthese drugs is sparse [270].

Lipid-Lowering Drugs (Fibrates, Statins)ED was reported to be a frequent side effect oftreatment of hyperlipidemic subjects using clofi-brate [298] or gemfibrozil [299]. In patientsreferred to a clinic for primary hyperlipidemia, anincreased risk of ED was also observed in patientstreated with fibrates [300]. Fibrates interact withPPARs [301], which in the liver stimulatesmicrosomal esterification of estradiol and test-

osterone [302]. That may explain the increasedprevalence of ED reported in patients treated withfibrates.

In patients with hyperlipidemia and treatedwith statins such as simvastatin and pravastatin andreferred to a clinic for primary hyperlipidemia, anincreased risk for ED was reported [300,303]. It iscontroversial whether simvastatin is associatedwith ED [304–306], and so far, in patients treatedwith simvastatin, underlying diseased vasculaturerather than the drug appears to be the cause of ED.In contrast to simvastatin, positive effects on erec-tile function was reported for atorvastatin on erec-tile function [307–310]. These reported positiveeffects of atorvastatin, in contrast to simvastatin,on erectile function suggest that the effect ofstatins is not a class effect of statins. Moreover, inan observational prospective study, it was reportedthat differences in dose, relative efficacy, or relativelipophilicity of statin did not show correlation withchanges in IIEF score over a 6-month period[311]. However, statins are structurally a heterog-enous group of compounds and, therefore, othermechanisms than the lipid-lowering effects mayhave significance for the effect of a statin on erec-tion [246,312,313].

Aldosterone Receptor AntagonistsTreatment with spironolactone and eplerenoneincreased survival in systolic chronic heart failure.In addition to being an aldosterone receptorantagonist, spironolactone also blocks androgenreceptors (ARs) and that may explain why it isassociated with sexual dysfunction. In contrast,the newer aldosterone receptor antagonist,eplerenone, is devoid of effects on sex hormonereceptors.

Psychotropic MedicationAntipsychoticsIt is difficult to separate disease from drug effect, aswell as to obtain reliable information from patientswith psychotic illness. There is a paucity of con-trolled studies. Mainly, older antipsychotic drugsresult in decreased erection and anorgasmia, whilenewer antipsychotics appear to have lower inci-dence of sexual dysfunction. Among newer antip-sychotics, risperidone appears to have highest rateof sexual dysfunction, while there are insufficientdata on aripiprazole and ziprasidone.

Antidepressive and Anxiolytic DrugsDepression by itself makes it difficult to separateeffect of illness from additive effect of drugs, as

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mood disorders may lead to lack of interest andemotional withdrawal from the sexual partner.Antidepressants can have numerous effects onsexual function including altered sexual desire,erection difficulties, and orgasm problems. Selec-tive serotonin reuptake inhibitors (SSRIs) and ven-lafaxine can negatively affect all the steps of themale sexual response cycle (desire–arousal–excitement–orgasm). Bupropion, nefazodone, andmirtazapine have lower rates of sexual dysfunctionthan SSRIs. The evidence has been summarized ina recent Cochrane review of 15 randomizedstudies [314]. The main conclusion regardingcomedication to correct ED was an effect ofsildenafil in three of the clinical trials, while theavailable evidence was insufficient regarding otherstrategies for correction of ED. Anxiolytic agentssuch as bupropion, acting mainly by inhibitingdopamine reuptake, and buspirone, which acts on5-HT1A receptors, are not associated with sexualside effects in placebo-controlled trials [315] andcan be used to alleviate sexual symptoms caused byother antidepressant medication [316]. There areinsufficient randomized data assessing effect ofdose reduction, e.g., drug holidays, on sexual func-tion in patients treated with antidepressants.

OpiatesLong-term intrathecal administration of opiatesresults in hypogonadotropic hypogonadism andassociated sexual dysfunction that can be restoredwith appropriate supplementation [317]. Adminis-tration of opioid antagonists to older men withED, however, did not improve erectile functionmeasured objectively by nocturnal penile tumes-cence monitoring [318]. Opioids do have a gener-alized depressant effect on sexual function whendirectly administered to the MPOA in rat brain,but treatment with the opioid receptor antagonist,naloxone, had no sexual effect on healthy malevolunteers [283].

Anti-AndrogensThese drugs cause partial or near-complete block-ade of circulating androgens by inhibiting produc-tion or antagonism at the AR. Nonsteroidal drugssuch as flutamide and bicalutamide have relativelypure effects on the AR, while the steroidal antian-drogen, cyproterone acetate, also has inhibitoryeffects on the hypothalamus. Even at a low dose of50 mg, bicalutamide therapy resulted in half thepatients in one placebo-controlled study sufferingloss of erectile function [319]. In summary, anti-androgen drugs produce the expected effects of

sexual desire and erection commensurate with thedegree of androgen ablation achieved.

Corresponding Author: Christian Stief, MD, PhD,Department of Urology, University-Hospital Grosshad-ern, Ludwig-Maximilians-Hospital Munich, 81377Munich, Germany. Tel: +49 89 7095 2971; Fax: +49 897095 8890

Conflict of Interest: T.F. Lue, Speakers Bureau for Pfizer,Bayer, AMS, Medtronic and Lilly; J. Angulo, SpeakersBureau for Pfizer; N.N. Kim, Employee AlaginResearch LLC, Research Funding from Pfizer, andAdvisory Board for Boehringer-Ingelheim.

References

1 Andersson KE, Wagner G. Physiology of erection.Physiol Rev 1995;75:191–236.

2 Argiolas A. Neuropeptides and sexual behaviour.Neurosci Biobehav Rev 1999;23:1127–42.

3 Heaton JP. Central neuropharmacological agentsand mechanisms in erectile dysfunction: The roleof dopamine. Neurosci Biobehav Rev 2000;24:561–9.

4 Giuliano F, Rampin O, Brown K, Courtois F,Benoit G, Jardin A. Stimulation of the medial pre-optic area of the hypothalamus in the rat elicitsincreases in intracavernous pressure. Neurosci Lett1996;209:1–4.

5 Chen KK, Chan SH, Chang LS, Chan JY. Partici-pation of paraventricular nucleus of hypothalamusin central regulation of penile erection in the rat.J Urol 1997;158:238–44.

6 Chen KK, Chan JY, Chang LS, Chen MT, ChanSH. Elicitation of penile erection following activa-tion of the hippocampal formation in the rat. Neu-rosci Lett 1992;141:218–22.

7 Giuliano F, Rampin O. Central neural regulationof penile erection. Neurosci Biobehav Rev2000;24:517–33.

8 Sipski M, Alexander C, Gómez-Marín O, SpaldingJ. The effects of spinal cord injury on psychogenicsexual arousal in males. J Urol 2007;177:247–51.

9 Andersson KE, Burnett AL, Chen KK, Christ GJ,Rampin O, Stief C. Current research and futuretherapies. In: Jardin A, Wagner G, Khoury F,Giuliano F, Padma-Nathan H, Rosen R, eds. Erec-tile dysfunction. Plymouth, UK: Health Publica-tion Ltd.; 2000:139–203.

10 Rampin O, Bernabe J, Giuliano F. Spinal controlof penile erection. World J Urol 1997;15:2–13.

11 McKenna KE. Central nervous system pathwaysinvolved in the control of penile erection. AnnuRev Sex Res 1999;10:157–83.

12 Steers WD. Neural pathways and central sitesinvolved in penile erection: Neuroanatomy andclinical implications. Neurosci Biobehav Rev 2000;24:507–16.


J Sex Med 2010;7:445–475

13 Argiolas A, Melis MR. Central control of penileerection: Role of the paraventricular nucleus of thehypothalamus. Prog Neurobiol 2005;76:1–21.

14 Toda N, Ayajiki K, Okamura T. Nitric oxide andpenile erectile function. Pharmacol Ther 2005;106:233–66.

15 Argiolas A, Melis M. Neuromodulation of penileerection: An overview of the role of neurotransmit-ters and neuropeptides. Prog Neurobiol 1995;47:235–55.

16 Andersson KE, Argiolas A, Burnett A, Chen KK,Mills TM, Steers WD. Future treatment targets.In: Lue TF, Basson R, Rosen R, Giuliano F,Khoury S, Montorsi F, eds. Sexual medicine:Sexual dysfunctions in men and women. Paris:Health Publications; 2004:569–603.

17 Björklund A, Lindvall O, Nobin A. Evidence of anincerto-hypothalamic dopamine neurone system inthe rat. Brain Res 1975;89:29–42.

18 Skagerberg G, Björklund A, Lindvall O, SchmidtRH. Origin and termination of the diencephalo-spinal dopamine system in the rat. Brain Res Bull1982;9:237–44.

19 Skagerberg G, Lindvall O. Organization of dien-cephalic dopamine neurones projecting to thespinal cord in the rat. Brain Res 1985;342:340–51.

20 Sibley DR. New insights into dopaminergic recep-tor function using antisense and genetically alteredanimals. Annu Rev Pharmacol Toxicol 1999;39:313–41.

21 Benassi-Benelli A, Ferrari F, Quarantotti BP.Penile erection induced by apomorphine and N-n-propyl-norapomorphine in rats. Arch Int Pharma-codyn Ther 1979;242:241–7.

22 Tang Y, Rampin O, Giuliano F, Ugolini G. Spinaland brain circuits to motoneurons of the bulbo-spongiosus muscle: Retrograde transneuronaltracing with rabies virus. J Comp Neurol 1999;414:167–92.

23 Argiolas A, Melis MR. The role of oxytocin and theparaventricular nucleus in the sexual behaviour ofmale mammals. Physiol Behav 2004;83:309–17.

24 Tang Y, Rampin O, Calas A, Facchinetti P,Giuliano F. Oxytocinergic and serotonergic inner-vation of identified lumbosacral nuclei controllingpenile erection in the male rat. Neuroscience1998;82:241–54.

25 Véronneau-Longueville F, Rampin O, Freund-Mercier MJ, Tang Y, Calas A, Marson L, McKennaKE, Stoeckel ME, Benoit G, Giuliano F. Oxyto-cinergic innervation of autonomic nuclei control-ling penile erection in the rat. Neuroscience1999;93:1437–47.

26 Melis MR, Spano MS, Succu S, Argiolas A.The oxytocin antagonist d(CH2)5Tyr(Me)2-Orn8-vasotocin reduces non-contact penile erections inmale rats. Neurosci Lett 1999;265:171–4.

27 Argiolas A, Melis MR, Murgia S, Schiöth HB.ACT H—and alpha—MSH-induced grooming,

stretching, yawning and penile erection in malerats: Site of action in the brain and role of melano-cortin receptors. Brain Res Bull 2000;51:425–31.

28 Wikberg JE. Melanocortin receptors: Perspectivesfor novel drugs. Eur J Pharmacol 1999;375:295–310.

29 Wikberg JE, Muceniece R, Mandrika I, Prusis P,Lindblom J, Post C, Skottner A. New aspects onthe melanocortins and their receptors. PharmacolRes 2000;42:393–420.

30 Vergoni AV, Bertolini A, Mutulis F, Wikberg JE,Schiöth HB. Differential influence of a selectivemelanocortin MC4 receptor antagonist (HS014)on melanocortin-induced behavioral effects in rats.Eur J Pharmacol 1998;362:95–101.

31 Argiolas A, Melis MR, Mauri A, Gessa GL.Paraventricular nucleus lesion prevents yawningand penile erection induced by apomorphine andoxytocin but not by ACTH in rats. Brain Res1987;421:349–52.

32 Martin WJ, MacIntyre DE. Melanocortin recep-tors and erectile function. Eur Urol 2004;45:706–13.

33 Wessells H, Levine N, Hadley ME, Dorr R, HrubyV. Melanocortin receptor agonists, penile erection,and sexual motivation: Human studies with Mel-anotan II. Int J Impot Res 2000;12(4 suppl):S74–9.

34 Giuliano F. Control of penile erection by the mel-anocortinergic system: Experimental evidencesand therapeutic perspectives. J Androl 2004;25:683–91.

35 Wessells H, Blevins JE, Vanderah TW. Melano-cortinergic control of penile erection. Peptides2005;26:1972–7.

36 Giuliano F, Clément P, Droupy S, Alexandre L,Bernabé J. Melanotan-II: Investigation of theinducer and facilitator effects on penile erection inanaesthetized rat. Neuroscience 2006;138:293–301.

37 Lorrain DS, Matuszewich L, Howard RV, Du J,Hull EM. Nitric oxide promotes medial preopticdopamine release during male rat copulation. Neu-roreport 1996;8:31–4.

38 Melis MR, Argiolas A. Role of central nitric oxidein the control of penile erection and yawning. ProgNeuropsychopharmacol Biol Psychiatry 1997;21:899–922.

39 Melis MR, Succu S, Mauri A, Argiolas A. Nitricoxide production is increased in the paraventricularnucleus of the hypothalamus of male rats duringnon-contact penile erections and copulation. Eur JNeurosci 1998;10:1968–74.

40 Sato Y, Horita H, Kurohata T, Adachi H, Tsuka-moto T. Effect of the nitric oxide level in themedial preoptic area on male copulatory behaviorin rats. Am J Physiol 1998;274:R243–7.

41 Sato Y, Christ GJ, Horita H, Adachi H, Suzuki N,Tsukamoto T. The effects of alterations in nitric

464 Gratzke et al.

J Sex Med 2010;7:445–475

oxide levels in the paraventricular nucleus on copu-latory behavior and reflexive erections in male rats.J Urol 1999;162:2182–5.

42 Melis MR, Stancampiano R, Argiolas A. Penileerection and yawning induced by paraventricularNMDA injection in male rats are mediated by oxy-tocin. Pharmacol Biochem Behav 1994;48:799–804.

43 Melis MR, Stancampiano R, Argiolas A. Nitricoxide synthase inhibitors prevent N-methyl-D-aspartic acid-induced penile erection and yawningin male rats. Neurosci Lett 1994;179:9–12.

44 Melis MR, Succu S, Spano MS, Argiolas A. Effectof excitatory amino acid, dopamine, and oxytocinreceptor antagonists on noncontact penile erec-tions and paraventricular nitric oxide production inmale rats. Behav Neurosci 2000;114:849–57.

45 Zahran AR, Vachon P, Courtois F, Carrier S.Increases in intracavernous penile pressure follow-ing injections of excitatory amino acid receptoragonists in the hypothalamic paraventricularnucleus of anesthetized rats. J Urol 2000;164:1793–7.

46 Melis MR, Succu S, Iannucci U, Argiolas A.N-methyl-D-aspartic acid-induced penile erectionand yawning: Role of hypothalamic paraventricularnitric oxide. Eur J Pharmacol 1997;328:115–23.

47 Argiolas A. Nitric oxide is a central mediator ofpenile erection. Neuropharmacology 1994;33:1339–44.

48 Bitran D, Hull EM. Pharmacological analysis ofmale rat sexual behavior. Neurosci Biobehav Rev1987;11:365–89.

49 Rehman J, Christ G, Melman A, Fleischmann J.Intracavernous pressure responses to physical andelectrical stimulation of the cavernous nerve inrats. Urology 1998;51:640–4.

50 De Groat WC, Booth AM. The autonomicnervous system. In: Maggi CA, ed. Nervouscontrol of the urogenital system. London, UK:Harwood Academic; 1993:465–524.

51 Yonezawa A, Watanabe C, Ando R, Furuta S,Sakurada S, Yoshimura H, Iwanaga T, KimuraY. Characterization of p-chloroamphetamine-induced penile erection and ejaculation in anesthe-tized rats. Life Sci 2000;67:3031–9.

52 Melis MR, Spano MS, Succu S, Argiolas A. Acti-vation of gamma-aminobutyric acid (A) receptorsin the paraventricular nucleus of the hypothalamusreduces apomorphine-, N-methyl-D-aspartic acid-and oxytocin-induced penile erection and yawningin male rats. Neurosci Lett 2000;281:127–30.

53 Dorfman VB, Vega MC, Coirini H. Age-relatedchanges of the GABA-B receptor in the lumbarspinal cord of male rats and penile erection. LifeSci 2006;78:1529–34.

54 Ferrari F, Ottani A, Giuliani D. Inhibitory effectsof the cannabinoid agonist HU 210 on rat sexualbehaviour. Physiol Behav 2000;69:547–54.

55 Shrenker P, Bartke A. Suppression of male copu-latory behavior by delta 9-THC is not dependenton changes in plasma testosterone or hypothalamicdopamine or serotonin content. PharmacolBiochem Behav 1985;22:415–20.

56 da Silva GE, Fernandes MS, Takahashi RN. Poten-tiation of penile erection and yawning responses toapomorphine by cannabinoid receptor antagonistin rats. Neurosci Lett 2003;349:49–52.

57 Melis MR, Succu S, Mascia MS, Argiolas A.Antagonism of cannabinoid CB1 receptors in theparaventricular nucleus of male rats induces penileerection. Neurosci Lett 2004;359:17–20.

58 Melis MR, Succu S, Mascia MS, Sanna F, Melis T,Castelli MP, Argiolas A. The cannabinoid receptorantagonist SR-141716A induces penile erection inmale rats: Involvement of paraventricular glutamicacid and nitric oxide. Neuropharmacology 2006;50:219–28.

59 Melis MR, Succu S, Spano MS, Argiolas A. Mor-phine injected into the paraventricular nucleus ofthe hypothalamus prevents noncontact penile erec-tions and impairs copulation: Involvement of nitricoxide. Eur J Neurosci 1999;11:1857–64.

60 Melis MR, Stancampiano R, Gessa GL, Argiolas A.Prevention by morphine of apomorphine- andoxytocin-induced penile erection and yawning:Site of action in the brain. Neuropsychopharma-cology 1992;6:17–21.

61 Melis MR, Succu S, Argiolas A. Prevention bymorphine of N-methyl-D-aspartic acid-inducedpenile erection and yawning: Involvement of nitricoxide. Brain Res Bull 1997;44:689–94.

62 Melis MR, Succu S, Iannucci U, Argiolas A. Pre-vention by morphine of apomorphine- andoxytocin-induced penile erection and yawning:Involvement of nitric oxide. Naunyn Schmiede-bergs Arch Pharmacol 1997;355:595–600.

63 Rehman J, Christ G, Alyskewycz M, Kerr E,Melman A. Experimental hyperprolactinemia in arat model: Alteration in centrally mediated neuro-erectile mechanisms. Int J Impot Res 2000;12:23–32.

64 Cruz-Casallas PE, Nasello AG, Hucke EE, FelicioLF. Dual modulation of male sexual behavior inrats by central prolactin: Relationship with in vivostriatal dopaminergic activity. Psychoneuroendo-crinology 1999;24:681–93.

65 Lookingland KJ, Moore KE. Effects of estradioland prolactin on incertohypothalamic dopaminer-gic neurons in the male rat. Brain Res 1984;323:83–91.

66 Carani C, Granata AR, Fustini MF, Marrama P.Prolactin and testosterone: Their role in malesexual function. Int J Androl 1996;19:48–54.

67 Ra S, Aoki H, Fujioka T, Sato F, Kubo T, YasudaN. In vitro contraction of the canine corpus caver-nosum penis by direct perfusion with prolactin orgrowth hormone. J Urol 1996;156:522–5.


J Sex Med 2010;7:445–475

68 Sato F, Aoki H, Nakamura K, Taguchi M, AokiT, Yasuda N. Suppressive effects of chronic hyper-prolactinemia on penile erection and yawningfollowing administration of apomorphine topituitary-transplanted rats. J Androl 1997;18:21–5.

69 Mills TM, Reilly CM, Lewis RW. Androgens andpenile erection: A review. J Androl 1996;17:633–8.

70 Mills TM, Lewis RW. The role of androgens inthe erectile response: A 1999 perspective. MolUrol 1999;3:75–86.

71 Gooren LJ, Saad F. Recent insights into androgenaction on the anatomical and physiological sub-strate of penile erection. Asian J Androl 2006;8:3–9.

72 Gray PB, Singh AB, Woodhouse LJ, Storer TW,Casaburi R, Dzekov J, Dzekov C, Sinha-Hikim I,Bhasin S. Dose-dependent effects of testosteroneon sexual function, mood, and visuospatial cogni-tion in older men. J Clin Endocrinol Metab2005;90:3838–46.

73 Everitt B, Bancroft J. Of rats and men: The com-parative approach to male sexuality. Annu Rev SexRes 1991;2:77–118.

74 Krause W, Muller HH. Relation of sexual dysfunc-tion to hormone levels, diseases and drugs used inandrological patients. Urol Int 2000;64:143–8.

75 Walsh PC. Physiologic basis for hormonal therapyin carcinoma of the prostate. Urol Clin North Am1975;2:125–40.

76 Davidson JM, Camargo CA, Smith ER. Effects ofandrogen on sexual behavior in hypogonadal men.J Clin Endocrinol Metab 1979;48:955–8.

77 Skakkebaek NE, Bancroft J, Davidson DW,Warner P. Androgen replacement with oral test-osterone undecanoate in hypogonadal men: Adouble blind controlled study. Clin Endocrinol1981;14:49–61.

78 O’Carroll R, Shapiro C, Bancroft J. Androgens,behaviour and nocturnal erection in hypogonadalmen: The effects of varying the replacement dose.Clin Endocrinol 1985;23:527–38.

79 El-Sakka AI, Hassoba HM. Age related testoster-one depletion in patients with erectile dysfunction.J Urol 2006;176:2589–93.

80 Ellis WJ, Grayhack JT. Sexual function in agingmales after orchiectomy and estrogen therapy.J Urol 1963;89:895–9.

81 Hart BL. Testosterone regulation of sexual reflexesin spinal male rats. Science 1967;155:1283–4.

82 Nehra A, Azadzoi KM, Moreland RB, Pabby A,Siroky MB, Krane RJ, Goldstein I, Udelson D.Cavernosal expandability is an erectile tissuemechanical property which predicts trabecular his-tology in an animal model of vasculogenic erectiledysfunction. J Urol 1998;159:2229–36.

83 Nehra A, Goldstein I, Pabby A, Nugent M, HuangYH, de las Morenas A, Krane RJ, Udelson D,Saenz de Tejada I, Moreland RB. Mechanisms ofvenous leakage: A prospective clinicopathological

correlation of corporeal function and structure.J Urol 1996;156:1320–9.

84 Bossart MI, Spjut HJ, Scott FB. Ultrastructuralanalysis of human penile corpus cavernosum. Itssignificance in tumescence and detumescence.Urology 1980;15:448–56.

85 Luangkhot R, Rutchik S, Agarwal V, Puglia K,Bhargava G, Melman A. Collagen alterations in thecorpus cavernosum of men with sexual dysfunc-tion. J Urol 1992;148:467–71.

86 Moreland RB, Traish A, McMillin MA, Smith B,Goldstein I, Saenz de Tejada I. PGE1 suppressesthe induction of collagen synthesis by transforminggrowth factor-beta 1 in human corpus cavernosumsmooth muscle. J Urol 1995;153:826–34.

87 Raviv G, Kiss R, Vanegas JP, Petein M, Danguy A,Schulman C, Wespes E. Objective measurement ofthe different collagen types in the corpus caverno-sum of potent and impotent men: An immunohis-tochemical staining with computerized-imageanalysis. World J Urol 1997;15:50–5.

88 Podlasek CA, Zelner DJ, Jiang HB, Tang Y,Houston J, McKenna KE, McVary KT. Sonichedgehog cascade is required for penile postnatalmorphogenesis differentiation, and adult homeo-stasis. Biol Reprod 2003;68:423–38.

89 Podlasek CA, Meroz CL, Korolis H, Tang Y,McKenna KE, McVary KT. Sonic hedgehog, thepenis and erectile dysfunction: A review of sonichedgehog signaling in the penis. Curr Pharm Des2005;11:4011–27.

90 Manabe I, Nagai R. Regulation of smooth musclephenotype. Curr Atheroscler Rep 2003;5:214–22.

91 Shanahan CM, Weissberg PL. Smooth muscle cellheterogeneity: Patterns of gene expression in vas-cular smooth muscle cells in vitro and in vivo. Arte-rioscler Thromb Vasc Biol 1998;18:333–8.

92 Somlyo AP, Somlyo AV. Signal transduction andregulation in smooth muscle. Nature 1994;372:231–6.

93 Walsh MP. Regulation of vascular smooth muscletone. Can J Physiol Pharmacol 1994;72:919–36.

94 Somlyo AP, Somlyo AV, Kitazawa T, Bond M,Shuman H, Kowarski D. Ultrastructure, functionand composition of smooth muscle. Ann BiomedEng 1983;11:579–88.

95 Fukata Y, Mutsuki A, Kaibuchi K. Rho-Rho-kinasepathway in smooth muscle contraction and cytosk-eletal reorganization of non-muscle cells. TrendsPharmacol Sci 2001;22:32–9.

96 Somlyo AP, Somlyo AV. Signal transduction byG-proteins, Rho-kinase and protein phosphataseto smooth muscle and non-muscle myosin II.J Physiol 2000;522:177–85.

97 Wettschurek N, Offermanns S. Rho/Rho-kinasemediated signaling in physiology and pathophysi-ology. J Mol Med 2002;80:629–38.

98 Mills TM, Lewis RW, Wingard CJ, Linder AE, JinL, Webb RC. Vasoconstriction, RhoA/Rho-kinase

466 Gratzke et al.

J Sex Med 2010;7:445–475

and the erectile response. Int J Impot Res 2003;15(5 suppl):S20–4.

99 Park JK, Lee SO, Kim YG, Kim SH, Koh GY, ChoKW. Role of rho-kinase activity in angiotensinII-induced contraction of rabbit clitoral caverno-sum smooth muscle. Int J Impot Res 2002;14:472–7.

100 Cellek S. The Rho-kinase inhibitor Y-27632 andthe soluble guanylyl cyclase activator BAY41-2272relax rabbit vaginal wall and clitoral corpus caver-nosum. Br J Pharmacol 2003;138:287–90.

101 Wang H, Eto M, Steers WD, Somlyo AP, SomlyoAV. RhoA-mediated Ca2+ sensitization in erectilefunction. J Biol Chem 2002;277:30614–21.

102 Berridge MJ. The endoplasmic reticulum: A mul-tifunctional signaling organelle. Cell Calcium2002;32:235–49.

103 Lee MW, Severson DL. Signal transduction invascular smooth muscle: Diacylglycerol secondmessengers and PKC action. Am J Physiol 1994;267:C659–78.

104 Lincoln M, Cornwell TL. Intracellular cyclicGMP receptor proteins. FASEB J 1993;7:328–38.

105 Sausbier M, Schubert R, Voigt V, Hirneiss C,Pfeifer A, Korth M, Kleppisch T, Ruth P, HofmanF. Mechanisms of NO/cGMP-dependent vasore-laxation. Circ Res 2000;87:825–30.

106 Münzel T, Feil R, Mülsch A, Lohmann SM,Hofmann F, Walter U. Physiology and pathophysi-ology of vascular signaling controlled by cyclicguanosine 3,5-cyclic monophosphate-dependentprotein kinase. Circulation 2003;108:2172–83.

107 Lincoln TM, Thompson M, Cornwell TL. Purifi-cation and characterization of two forms of cyclicGMP-dependent protein kinase from bovine aorta.J Biol Chem 1988;263:17632–7.

108 Feil R, Gappa N, Rutz M, Schlossmann J, RoseCR, Konnerth A, Brummer S, Kuhbandner S,Hofman F. Functional reconstitution of vascularsmooth muscle cells with cGMP-dependentprotein kinase I isoforms. Circ Res 2002;90:1080–6.

109 Surks HK, Mochizuki N, Kasai Y, Georgescu SP,Tang KM, Ito M, Lincoln TM, Mendelsohn ME.Regulation of myosin phosphatase by a specificinteraction with cGMP-dependent protein kinaseIa. Science 1999;286:1583–7.

110 Schlossmann J, Ammendola A, Ashman K, ZongX, Huber A, Neubauer G, Wang GX, AllescherHD, Korth M, Wilm M, Hofmann F, Ruth P.Regulation of intracellular calcium by a signallingcomplex of IRAG, IP3 receptor and cGMP kinaseI beta. Nature 2000;404:197–201.

111 Geiselhöringer A, Werner M, Sigl K, Smital P,Wörner R, Acheo L, Stieber J, Weinmeister P, FeilR, Feil S, Wegener J, Hofmann F, Schlossmann J.IRAG is essential for relaxation of receptor-triggered smooth muscle contraction by cGMPkinase. EMBO J 2004;23:4222–31.

112 Raeymaekers L, Hofmann F, Casteels R. CyclicGMP-dependent protein kinase phosphorylatesphospholamban in isolated sarcoplasmic reticulumfrom cardiac and smooth muscle. Biochem J 1988;252:269–73.

113 Lincoln TM, Dey N, Sellak H. cGMP-dependentprotein kinase signaling mechanisms in smoothmuscle: From the regulation of tone to geneexpression. J Appl Physiol 2001;91:1421–30.

114 Waldkirch E, Ückert S, Sigl K, Imkamp F, Lang-naese K, Richter K, Jonas U, Sohn M, Stief CG,Wolf G, Hedlund P. Expression and distribution ofcyclic GMP-dependent protein kinase-1 (cGK1)isoforms in human penile erectile tissue. J Sex Med2008;5:536–43.

115 Ückert S, Hedlund P, Waldkirch E, Sohn M, JonasU, Andersson KE, Stief CG. Interactions betweencGMP- and cAMP-pathways are involved in theregulation of penile smooth muscle tone. World JUrol 2004;22:261–6.

116 Ückert S, Truss MC, Stief CG, Becker AJ, Jonas U.Effects of various cyclic nucleotide analogues onpharmacologically induced contractions of humancavernous smooth muscle. (Abstract) Int J ImpotRes 1994;6(1 suppl):A9.

117 Conti M, Jin SL. The molecular biology of cyclicnucleotide phosphodiesterases. Prog Nucleic AcidRes Mol Biol 1999;63:1–38.

118 Essayan DM. Cyclic nucleotide phosphodi-esterases. J Allergy Clin Immunol 2001;108:671–80.

119 Rybulkin SD, Yan C, Bornfeld KE, Beavo JA.Cyclic GMP phosphodiesterase and smoothmuscle function. Circ Res 2003;93:280–91.

120 Taher A, Stief CG, Raida M, Jonas U, ForssmannWG. Cyclic nucleotide phosphodiesterase activityin human cavernous smooth muscle and the effectof various selective inhibitors. (Abstract) Int JImpot Res 1992;4(2 suppl):11.

121 Küthe A, Wiedenroth A, Mägert HJ, Ückert S,Forssmann WG, Stief CG, Jonas U. Expression ofdifferent phosphodiesterase genes in human cav-ernous smooth muscle. J Urol 2001;165:280–3.

122 Stief CG, Taher A, Truss MC, Ückert S, Meyer M,Schulz-Knappe P, Forssmann WG, Jonas U. Diephosphodiesterase-isoenzyme des humanen corpuscavernosum penis und deren funktionelle Bedeu-tung. Akt Urol 1995;26(suppl):22–4.

123 Le Blanc C, Mironneau C, Barbot C, Henaff M,Bondeva T, Wetzker R, Macrez N. Regulation ofvascular L-types Ca2+ channels by phosphatidyli-nositol 3,4,5-trisphosphate. Circ Res 2004;95:300–7.

124 Callera GE, Bendhack LM. Mechanisms underly-ing the contractile response to endothelin-1 in therat renal artery. Pharmacology 2003;68:131–9.

125 Remillard CV, Lupien MA, Crepeau V, LeblancN. Role of Ca2+- and swelling-activated Cl- chan-nels in alpha1-adrenoceptor-mediated tone in


J Sex Med 2010;7:445–475

pressurized rabbit mesenteric arterioles. Cardio-vasc Res 2000;46:557–68.

126 Archer SL. Potassium channels and erectile dys-function. Vascul Pharmacol 2002;38:61–71.

127 Ruiz Rubio JL, Hernandez M, Rivera de los ArcosL, Benedito S, Recio P, García P, García-SacristánA, Prieto D. Role of ATP-sensitive K+ channels inrelaxation of penile resistance arteries. Urology2004;63:800–5.

128 Insuk SO, Chae MR, Choi JW, Yang DK, Sim JH,Lee SW. Molecular basis and characteristics ofKATP channel inhuman corporal smooth musclecells. Int J Impot Res 2003;15:258–66.

129 Bolotina VM, Najibi S, Palacino JJ, Pagano PJ,Cohen RA. Nitric oxide directly activates calcium-dependent potassium channels in vascular smoothmuscle. Nature 1994;368:850–3.

130 Förstermann U, Closs EI, Pollack JS, Nakane M,Schwarz P, Gath I, Kleinert H. Nitric oxide syn-thase isoenzymes: Characterization, purification,molecular cloning and functions. Hypertension1994;23:1112–31.

131 Denninger JW, Marletta MA. Guanylate cyclaseand the NO/cGMP signalling pathway. BiochimBiophys Acta 1999;1411:334–50.

132 Lee YC, Martin E, Murad F. Human recombinantsoluble guanylyl cyclase: Expression, purification,and regulation. Proc Natl Acad Sci USA 2000;97:10763–8.

133 Hata AN, Breyer RM. Pharmacology and signalingof prostaglandin receptors: Multiple roles ininflammation and immune modulation. PharmacolTher 2004;103:147–66.

134 Sugimoto Y, Narumiya S. Prostaglandin E recep-tors. J Biol Chem 2007;282:11613–7.

135 Negishi M, Sugimoto Y, Ichikawa A. Molecularmechanisms of diverse actions of prostanoid recep-tors. Biochim Biophys Acta 1995;1259:109–19.

136 Pierce KL, Regan JW. Prostanoid receptor hetero-geneity through alternative mRNA splicing. LifeSci 1998;62:1479–83.

137 Takuwa Y, Yanagisawa M, Takuwa N, Masaki T.Endothelin, its diverse biological activities andmechanisms of action. Prog Growth Factor Res1989;1:195–206.

138 Anggård EE, Botting RM, Vane JR. Endothelins.Blood Vessels 1990;27:269–81.

139 Holmquist F, Andersson KE, Hedlund H. Actionsof endothelin on isolated corpus cavernosum fromrabbit and man. Acta Physiol Scand 1990;139:113–22.

140 Saenz de Tejada I, Carson MP, de las Morenas A,Goldstein I, Traish AM. Endothelin: Localization,synthesis, activity, and receptor types in humanpenile corpus cavernosum. Am J Physiol 1991;261:H1078–85.

141 Traish AM, Moran E, Saenz de Tejada I. Physico-chemical characterization and solubilization ofendothelin receptors. Receptor 1991;1:229–42.

142 Ari G, Vardi Y, Hoffman A, Finberg JP. Possiblerole for endothelins in penile erection. Eur J Phar-macol 1996;307:69–74.

143 Komalavilas P, Shah PK, Jo H, Lincoln TM. Acti-vation of mitogen-activated protein kinase path-ways by cyclic GMP and cyclic GMP-dependentprotein kinase in contractile vascular smoothmuscle cells. J Biol Chem 1999;274:34301–9.

144 Hidalgo-Tamola J, Chitaley K. Type 2 diabetesmellitus and erectile dysfunction. J Sex Med 2009;6:916–26.

145 Moore CR, Wang R. Pathophysiology and treat-ment of diabetic erectile dysfunction. Asian JAndrol 2006;8:675–84.

146 Vrentzos GE, Paraskevas KI, Mikhailidis DP. Dys-lipidemia as a risk factor for erectile dysfunction.Curr Med Chem 2007;14:1765–70.

147 Musicki B, Burnett AL. Endothelial dysfunction indiabetic erectile dysfunction. Int J Impot Res2007;19:129–38.

148 Disanto ME. Contractile mechanisms in diabetes-related erectile dysfunction. Curr Pharm Des2005;11:3995–4010.

149 Guay AT, Velasquez E, Perez JB. Characterizationof patients in a medical endocrine-based center formale sexual dysfunction. Endocr Pract 1999;5:314–21.

150 Sairam K, Kulinskaya E, Boustead GB, HanburyDC, McNicholas TA. Prevalence of undiagnoseddiabetes mellitus in male erectile dysfunction. BJUInt 2001;88:68–71.

151 Lehman TP, Jacobs JA. Etiology of diabetic impo-tence. J Urol 1983;129:291–4.

152 Feldman HA, Goldstein I, Hatzichristou DG,Krane RJ, Mckinlay JB. Impotence and its medicaland psychosocial correlates: Results of the Massa-chusetts Male Aging Study. J Urol 1994;151:54–61.

153 Sarica K, Arikan N, Serel A, Arikan Z, Aytac S,Culcuoglu A, Bayram F, Yaman LS, Kupeli S. Mul-tidisciplinary evaluation of diabetic impotence. EurUrol 1994;26:314–8.

154 Metro MJ, Broderick GA. Diabetes and vascularimpotence: Does insulin dependence increase therelative severity? Int J Impot Res 1999;11:87–9.

155 Whitehead ED, Klyde BJ. Diabetes-related impo-tence in the elderly. Clin Geriatr Med 1990;6:771–95.

156 Grover SA, Lowensteyn I, Kaouache M, MarchandS, Coupal L, DeCarolis E, Zoccoli J, Defoy I. Theprevalence of erectile dysfunction in the primarycare setting: Importance of risk factors for diabetesand vascular disease. Arch Intern Med 2006;166:213–9.

157 Koncz L, Balodimos MC. Impotence in diabetesmellitus. Med Times 1970;98:159–70.

158 Chitaley K, Webb RC. Microtubule depolymeriza-tion facilitates contraction of vascular smoothmuscle via increased activation of RhoA/Rho-kinase. Med Hypotheses 2001;56:381–5.

468 Gratzke et al.

J Sex Med 2010;7:445–475

159 Mersdorf A, Goldsmith PC, Diederichs W, PadulaCA, Lue TF, Fishman IJ, Tanagho EA. Ultrastruc-tural changes in impotent penile tissue: A compari-son of 65 patients. J Urol 1991;145:749–58.

160 Saenz de Tejada I, Goldstein I, Azadzoi K, KraneRJ, Cohen RA. Impaired neurogenic andendothelium-mediated relaxation of penile smoothmuscle from diabetic men with impotence. N EnglJ Med 1989;320:1025–30.

161 Gazzaruso C, Giordanetti S, De Amici E, BertoneG, Falcone C, Geroldi D, Fratino P, Solerte SB,Garzaniti A. Relationship between erectile dys-function and silent myocardial ischemia in appar-ently uncomplicated type 2 diabetic patients.Circulation 2004;110:22–6.

162 Rhoden EL, Ribeiro EP, Teloken C, Souto CA.Diabetes mellitus is associated with subnormalserum levels of free testosterone in men. BJU Int2005;96:867–70.

163 Rhoden EL, Ribeiro EP, Riedner CE, Teloken C,Souto CA. Glycosylated haemoglobin levels andthe severity of erectile function in diabetic men.BJU Int 2005;95:615–7.

164 Romeo JH, Seftel AD, Madhun ZT, Aron DC.Sexual function in men with diabetes type 2: Asso-ciation with glycemic control. J Urol 2000;163:788–91.

165 Lu CC, Jiann BP, Sun CC, Lam HC, Chu CH,Lee JK. Association of glycemic control with riskof erectile dysfunction in men with type 2 diabetes.J Sex Med 2009;6:1719–28.

166 Yaman O, Akand M, Gursoy A, Erdogan MF, Ana-farta K. The effect of diabetes mellitus treatmentand good glycemic control on the erectile functionin men with diabetes mellitus-induced erectiledysfunction: A pilot study. J Sex Med 2006;3:344–8.

167 Corona G, Mannucci E, Mansani R, Petrone L,Bartolini M, Giommi R, Forti G, Maggi M.Organic, relational and psychological factors inerectile dysfunction in men with diabetes mellitus.Eur Urol 2004;46:222–8.

168 Kalinchenko SY, Kozlov GI, Gontcharov NP,Katsiya GV. Oral testosterone undecanoatereverses erectile dysfunction associated with diabe-tes mellitus in patients failing on sildenafil citratetherapy alone. Aging Male 2003;6:94–9.

169 Heidler S, Temml C, Broessner C, Mock K,Rauchenwald M, Madersbacher S, Ponholzer A. Isthe metabolic syndrome an independent risk factorfor erectile dysfunction? J Urol 2007;177:651–4.

170 Kupelian V, Shabsigh R, Araujo AB, O’DonnellAB, McKinlay JB. Erectile dysfunction as a predic-tor of the metabolic syndrome in aging men:Results from the Massachusetts Male Aging Study.J Urol 2006;176:222–6.

171 Esposito K, Giugliano F, Martedi E, Feola G,Marfella R, D’Armiento M, Giugliano D. Highproportions of erectile dysfunction in men with

the metabolic syndrome. Diabetes Care 2005;28:1201–3.

172 Giugliano F, Esposito K, Di PC, Ciotola M,Giugliano G, Marfella R, D’Armiento M,Giugliano D. Erectile dysfunction associates withendothelial dysfunction and raised proinflamma-tory cytokine levels in obese men. J EndocrinolInvest 2004;27:665–9.

173 Zohdy W, Kamal EE, Ibrahim Y. Androgen defi-ciency and abnormal penile duplex parameters inobese men with erectile dysfunction. J Sex Med2007;4:797–808.

174 Esposito K, Giugliano F, Di Palo C, Giugliano G,Marfella R, D’Andrea, F, D’Armiento M,Giugliano D. Effect of lifestyle changes on erectiledysfunction in obese men: A randomized con-trolled trial. JAMA 2004;291:2978–84.

175 Nangle MR, Cotter MA, Cameron NE. IkappaBkinase 2 inhibition corrects defective nitrergicerectile mechanisms in diabetic mouse corpus cav-ernosum. Urology 2006;68:214–8.

176 Nangle MR, Cotter MA, Cameron NE. Thecalpain inhibitor, A-705253, corrects penile nitrer-gic nerve dysfunction in diabetic mice. Eur J Phar-macol 2006;538:148–53.

177 Nangle MR, Cotter MA, Cameron NE. Correc-tion of nitrergic neurovascular dysfunction in dia-betic mouse corpus cavernosum by p38 mitogen-activated protein kinase inhibition. Int J Impot Res2006;18:258–63.

178 Christ GJ, Hsieh Y, Zhao W, Schenk G, Ven-kateswarlu K, Wang HZ, Tar MT, Melman A.Effects of streptozotocin-induced diabetes onbladder and erectile (dys)function in the same rat invivo. BJU Int 2006;97:1076–82.

179 Bozkurt NB, Pekiner C. Impairment ofendothelium- and nerve-mediated relaxationresponses in the cavernosal smooth muscle ofexperimentally diabetic rabbits: Role of weight lossand duration of diabetes. Naunyn SchmiedebergsArch Pharmacol 2006;373:71–8.

180 Gur S, Karahan ST, Ozturk B, Badilli M. Effectof ascorbic acid treatment on endothelium-dependent and neurogenic relaxation of corpuscavernosum from middle-aged non-insulin depen-dent diabetic rats. Int J Urol 2005;12:821–8.

181 Chitaley K, Luttrell I. Strain differences in suscep-tibility to in vivo erectile dysfunction following 6weeks of induced hyperglycemia in the mouse.J Sex Med 2008;5:1149–55.

182 Vernet D, Cai L, Garban H, Babbitt ML, MurrayFT, Rajfer J, Gonzalez-Cadavid NF. Reduction ofpenile nitric oxide synthase in diabetic BB/WORdp (type I) and BBZ/WORdp (type II) ratswith erectile dysfunction. Endocrinology 1995;136:5709–17.

183 Kawano K, Hirashima T, Mori S, Saitoh Y, Kuro-sumi M, Natori T. Spontaneous long-term hyper-glycemic rat with diabetic complications. Otsuka


J Sex Med 2010;7:445–475

Long-Evans Tokushima Fatty (OLETF) strain.Diabetes 1992;41:1422–8.

184 Xie D, Odronic SI, Wu F, Pippen A, DonatucciCF, Annex BH. Mouse model of erectile dysfunc-tion due to diet-induced diabetes mellitus. Urology2007;70:196–201.

185 Luttrell IP, Swee M, Starcher B, Parks WC, Chi-taley K. Erectile dysfunction in the type II diabeticdb/db mouse: Impaired venoocclusion with alteredcavernosal vasoreactivity and matrix. Am J PhysiolHeart Circ Physiol 2008;294:H2204–11.

186 Wingard C, Fulton D, Husain S. Altered penilevascular reactivity and erection in the Zuckerobese-diabetic rat. J Sex Med 2007;4:348–62.

187 Hurt KJ, Musicki B, Palese MA, Crone JK, BeckerRE, Moriarity JL, Snyder SH, Burnett AL. Akt-dependent phosphorylation of endothelial nitric-oxide synthase mediates penile erection. Proc NatlAcad Sci USA 2002;99:4061–6.

188 Newsholme P, Haber EP, Hirabara SM, RebelatoEL, Procopio J, Morgan D, Oliveira-Emilio HC,Carpinelli AR, Curi R. Diabetes associated cellstress and dysfunction: Role of mitochondrial andnon-mitochondrial ROS production and activity.J Physiol 2007;583:9–24.

189 Usta MF, Kendirci M, Gur S, Foxwell NA, Bival-acqua TJ, Cellek S, Hellstrom WJ. The breakdownof preformed advanced glycation end productsreverses erectile dysfunction in streptozotocin-induced diabetic rats: Preventive versus curativetreatment. J Sex Med 2006;3:242–50.

190 Cartledge JJ, Eardley I, Morrison JF. Advancedglycation end-products are responsible for theimpairment of corpus cavernosal smooth musclerelaxation seen in diabetes. BJU Int 2001;87:402–7.

191 Bivalacqua TJ, Usta MF, Kendirci M, Pradhan L,Alvarez X, Champion HC, Kadowitz PJ, Hell-strom WJ. Superoxide anion production in the ratpenis impairs erectile function in diabetes: Influ-ence of in vivo extracellular superoxide dismutasegene therapy. J Sex Med 2005;2:187–98.

192 Nangle MR, Cotter MA, Cameron NE. Effectsof the peroxynitrite decomposition catalyst,FeTMPyP, on function of corpus cavernosum fromdiabetic mice. Eur J Pharmacol 2004;502:143–8.

193 Khan MA, Thompson CS, Jeremy JY, MumtazFH, Mikhailidis P, Morgan RJ. The effect ofsuperoxide dismutase on nitric oxide-mediated andelectrical field-stimulated diabetic rabbit cavern-osal smooth muscle relaxation. BJU Int 2001;87:98–103.

194 Kovanecz I, Ferrini MG, Vernet D, Nolazco G,Rajfer J, Gonzalez-Cadavid NF. Pioglitazone pre-vents corporal veno-occlusive dysfunction in a ratmodel of type 2 diabetes mellitus. BJU Int 2006;98:116–24.

195 Carneiro FS, Giachini FR, Lima VV, CarneiroZN, Leite R, Inscho EW, Tostes RC, Webb RC.Adenosine actions are preserved in corpus caver-

nosum from obese and type II diabetic db/dbmouse. J Sex Med 2008;5:1156–66.

196 Martín-Morales A, Sanchez-Cruz JJ, Sáenz deTejada I, Rodríguez-Vela L, Jimenez-Cruz JF,Burgos-Rodríguez R. Prevalence and independentrisk factors for erectile dysfunction in Spain:Results of the Epidemiologia de la DisfuncionErectil Masculina study. J Urol 2001;166:569–74.

197 Montorsi F, Briganti A, Salonia A, Rigatti P, Mar-gonato A, Macchi A, Galli S, Ravagnani PM, Mon-torsi P. Erectile dysfunction prevalence, time ofonset and association with risk factors in 300 con-secutive patients with acute chest pain and angio-graphically documented coronary artery disease.Eur Urol 2003;44:360–5.

198 Solomon H, Man JW, Wierzbicki AS, Jackson G.Relation of erectile dysfunction to angiographiccoronary artery disease. Am J Cardiol 2003;91:230–1.

199 Chai SJ, Barrett-Connor E, Gamst A. Small-vessellower extremity arterial disease and erectile dys-function: The Rancho Bernardo study. Atheroscle-rosis 2009;203:620–5.

200 Bener A, Al-Hamaq AOAA, Kamran S, Al-AnsariA. Prevalence of erectile dysfunction in male strokepatients, and associated co-morbidities and riskfactors. Int Urol Nephrol 2008;40:701–8.

201 Montorsi P, Ravagnani PM, Galli S, Rotatori F,Veglia F, Briganti A, Salonia A, Deho F, Rigatti P,Montorsi F, Fiorentini C. Association betweenerectile dysfunction and coronary artery disease.Role of coronary clinical presentation and extent ofcoronary vessels involvement: The COBRA trial.Eur Heart J 2006;27:2632–9.

202 Akilli H, Gok H, Soylu A, Kayrak M. Severity ofcoronary artery disease and symptoms of erectiledysfunction in males with a positive exercise tread-mill test. Int J Urol 2007;14:733–7.

203 Vlachopoulos C, Rokkas K, Ioakeimidis N,Aggeli C, Michaelides A, Roussakis G, FassoulakisC, Askitis A, Stefanidis C. Prevalence of asymp-tomatic coronary artery disease in men withvasculogenic erectile dysfunction: A prospectiveangiographic study. Eur Urol 2005;48:996–1003.

204 Foresta C, Palego P, Schipilliti M, Selice R,Ferlin A, Caretta N. Asymmetric development ofperipheral atherosclerosis in patients with erectiledysfunction: An ultrasonographic study. Athero-sclerosis 2008;197:889–95.

205 Jackson G. Prevention of cardiovascular disease bythe early identification of erectile dysfunction. Int JImpot Res 2008;20(2 suppl):S9–14.

206 Azadzoi KM, Krane RJ, Sáenz de Tejada I, Gold-stein I, Siroky MB. Relative roles of cyclooxyge-nase and nitric oxide synthase pathways inischemia-induced increased contraction of cavern-osal smooth muscle. J Urol 1999;161:1324–8.

207 Azadzoi KM, Goldstein I, Siroky MB, Traish AM,Krane RJ, Saenz de Tejada I. Mechanisms of

470 Gratzke et al.

J Sex Med 2010;7:445–475

ischemia-induced cavernosal smooth muscle relax-ation impairment in a rabbit model of vasculogenicerectile dysfunction. J Urol 1998;160:2216–22.

208 Azadzoi KM, Master TA, Siroky MB. Effect ofchronic ischemia on constitutive and induciblenitric oxide synthase expression in erectile tissue.J Androl 2004;25:382–8.

209 Masuda H, Tsujii T, Okuno T, Kihara K, Goto M,Azuma H. Accumulated endogenous NOS inhibi-tors, decreased NOS activity, and impaired caver-nosal relaxation with ischemia. Am J Physiol RegulIntegr Comp Physiol 2002;282:R1730–8.

210 Behr-Roussel D, Darblade B, Oudot A, Compag-nie S, Bernabe J, Alexandre L, Giuliano F. Erectiledysfunction in hypercholesterolemic atheroscle-rotic apolipoprotein E knockout mice. J Sex Med2006;3:596–603.

211 Xie D, Odronic Si, Wu F, Pippen AM, Dona-tucci CF, Annex BH. A mouse model ofhypercholesterolemia-induced erectile dysfunc-tion. J Sex Med 2007;4:898–907.

212 Nikoobakht M, Nasseh H, Pourkasmaee M. Therelationship between lipid profile and erectile dys-function. Int J Impot Res 2005;17:523–6.

213 Roumeguere T, Wespes E, Carpentier Y, Hoff-mann P, Schulman CC. Erectile dysfunction isassociated with a high prevalence of hyperlipi-demia and coronary heart disease risk. Eur Urol2003;44:355–9.

214 Fung MM, Bettencourt R, Barrett-Connor E.Heart disease risk factors predict erectile dysfunc-tion 25 years later: The Rancho Bernardo Study.J Am Coll Cardiol 2004;43:1405–11.

215 Hall SA, Kupelian V, Rosen RC, Travison TG,Link CL, Miner MM, Ganz P, McKinlay JB. Ishyperlipidemia or its treatment associated witherectile dysfunction? Results from the Boston AreaCommunity Health (BACH) Survey. J Sex Med2009;6:1402–13.

216 Azadzoi KM, Saenz de Tejada I. Hypercholester-olemia impairs endothelium-dependent relaxationof rabbit corpus cavernosum smooth muscle.J Urol 1991;146:238–40.

217 Kim SC, Kim IK, Seo KK, Baek KJ, Lee MY.Involvement of superoxide radical in the impairedendothelium-dependent relaxation of cavernoussmooth muscle in hypercholesterolemic rabbits.Urol Res 1997;25:341–6.

218 Shukla N, Jones R, Persad R, Angelini GD, JeremyJY. Effect of sildenafil citrate and a nitric oxidedonating sildenafil derivative, NCX 911, on caver-nosal relaxation and superoxide formation inhypercholesterolemic rabbits. Eur J Pharmacol2005;517:224–31.

219 Kang KK, Yu JY, Yoo M, Kwon JW. The effect ofDA-8159, a novel PDE5 inhibitor, on erectilefunction in the rat model of hypercholesterolemicerectile dysfunction. Int J Impot Res 2005;17:409–16.

220 Ryu JK, Shin HY, Song SU, Oh SM, Piao S, HanJY, Park KW, Suh JK. Downregulation of angio-genic factors and their downstream target mol-ecules affects the deterioration of erectile functionin a rat model of hypercholesterolemia. Urology2006;67:1329–34.

221 Henry GD, Byrne R, Hunyh TT, Abraham V,Annex BH, Hagen PO, Donatucci CF. Intracaver-nosal injections of vascular endothelial growthfactor protects endothelial dependent corpora cav-ernosal smooth muscle relaxation in the hypercho-lesterolemic rabbit: A preliminary study. Int JImpot Res 2000;12:334–9.

222 Xie D, Pippen AM, Odronic SI, Annex BH,Donatucci CF. Intracavernosal basic fibroblastgrowth factor improves vasoreactivity in the hyper-cholesterolemic rabbit. J Sex Med 2006;3:223–32.

223 Seftel AD, Sun P, Swindle R. The prevalence ofhypertension, hyperlipidemia, diabetes mellitusand depression in men with erectile dysfunction.J Urol 2004;171:2341–5.

224 Giuliano FA, Leriche A, Jaudinot EO, Solesse deGendre A. Prevalence of erectile dysfunctionamong 7,689 patients with diabetes or hyperten-sion, or both. Urology 2004;64:1196–201.

225 Doumas M, Tsakiris A, Douma S, Grigorakis A,Papadopoulos A, Hounta A, Tsiodras S, DimitriouD, Giamarellou H. Factors affecting the increasedprevalence of erectile dysfunction in Greek hyper-tensive compared with normotensive subjects.J Androl 2006;27:469–77.

226 Selvin E, Burnett AL, Platz EA. Prevalence andrisk factors for erectile dysfunction in the US. AmJ Med 2007;120:151–7.

227 Johannes CB, Araujo AB, Feldman HA, Derby CA,Kleinman KP, McKinlay JB. Incidence of erectiledysfunction in men 40 to 69 years old: Longitudi-nal results from the Massachusetts Male AgingStudy. J Urol 2000;163:460–3.

228 Jaffe A, Chen Y, Kisch ES, Fischel B, Alon M,Stern N. Erectile dysfunction in hypertensivesubjects. Assessment of potential determinants.Hypertension 1996;28:859–62.

229 Fogari R, Preti P, Zoppi A, Fogari E, Rinaldi A,Corradi L, Mugellini A. Serum testosterone levelsand arterial blood pressure in the elderly. Hyper-tens Res 2005;28:625–30.

230 Behr-Roussel D, Chamiot-Clerc P, Bernabe J,Mevel K, Alexandre L, Safar ME, Giuliano F.Erectile dysfunction in spontaneously hypertensiverats: Pathophysiological mechanisms. Am J PhysiolRegul Integr Comp Physiol 2003;284:R682–8.

231 Behr-Roussel D, Gorny D, Mevel K, CompagnieS, Kern P, Sivan V, Bernabe J, Bedigian MP, Alex-andre L, Giuliano F. Erectile dysfunction: An earlymarked for hypertension? A longitudinal study inspontaneously hypertensive rats. Am J PhysiolRegul Integr Comp Physiol 2005;288:R276–83.


J Sex Med 2010;7:445–475

232 Jin L, Lagoda G, Leite R, Webb RC, Burnett AL.NADPH oxidase activation: A mechanism ofhypertension-associated erectile dysfunction. J SexMed 2008;5:544–51.

233 Feldman HA, Johannes CB, Derby CA, KleinmanKP, Mohr BA, Araujo AB, Mc Kinlay JB. Erectiledysfunction and coronary risk factors: Prospectiveresults from the Massachusetts Male Aging Study.Prev Med 2000;30:328–38.

234 Kupelian V, Link CL, McKinlay JB. Associationbetween smoking, passive smoking, and erectiledysfunction: Results from the Boston Area Com-munity Health (BACH) Survey. Eur Urol 2007;52:416–22.

235 Chew KK, Bremner A, Stuckey B, Earle C, Jam-rozik K. Is the relationship between cigarettesmoking and male erectile dysfunction indepen-dent of cardiovascular disease? Findings from apopulation-based cross-sectional study. J Sex Med2009;6:222–31.

236 He J, Reynolds K, Chen J, Chen CS, Wu X, DuanX, Reynolds R, Bazzano LA, Whelton PK, Gu D.Cigarette smoking and erectile dysfunction amongChinese men without clinical vascular disease. AmJ Epidemiol 2007;166:803–9.

237 Gades NM, Nehra A, Jacobson DJ, McGree ME,Girman CJ, Rhodes T, Roberts RO, Lieber MM,Jacobsen SJ. Association between smoking anderectile dysfunction: A population-based study. AmJ Epidemiol 2005;161:346–51.

238 Pourmand G, Alidaee MR, Rasuli S, Maleki A,Mehrsai A. Do cigarette smokers with erectile dys-function benefit from stopping?: A prospectivestudy. BJU Int 2004;94:1310–3.

239 Sighinolfi MC, Mofferdin A, De Stefani S, Micali S,Cicero AF, Bianchi G. Immediate improvement inpenile hemodynamics after cessation of smoking:Previous results. Urology 2007;69:163–5.

240 Xie Y, Garban H, Ng C, Rajfer J, Gonzalez-Cadavid NF. Effect of long-term passive smokingon erectile function and penile nitric oxide syn-thase in the rat. J Urol 1997;157:1121–6.

241 Imamura M, Waseda Y, Marinova GV, IshibashiT, Obayashi S, Sasaki A, Nagai A, Azuma H. Alter-ations of NOS, arginase, and DDAH proteinexpression in rabbit cavernous tissue after admin-istration of cigarette smoke extract. Am J PhysiolRegul Integr Comp Physiol 2007;293:R2081–9.

242 Tostes RC, Carneiro FS, Lee AJ, Giachini FR,Leite R, Osawa Y, Webb RC. Cigarette smokingand erectile dysfunction: Focus on NO bioavail-ability and ROS generation. J Sex Med 2008;5:1284–95.

243 Bivalacqua TJ, Sussan TE, Gebska MA, StrongTD, Berkowitz DE, Biswal S, Burnett AL, Cham-pion HC. Sildenafil inhibits superoxide formationand prevents endothelial dysfunction in a mousemodel of secondhand smoke induced erectile dys-function. J Urol 2009;181:899–906.

244 Harte CB, Meston CM. Acute effects of nicotineon physiological and subjective sexual arousal innonsmoking men: A randomized, double-blind,placebo-controlled trial. J Sex Med 2008;5:110–21.

245 Hirooka Y, Shimokawa H. Therapeutic potentialof rho-kinase inhibitors in cardiovascular diseases.Am J Cardiovasc Drugs 2005;5:31–9.

246 Fibbi B, Morelli A, Marini M, Zhang X-H,Mancina R, Vignozzi L, Filippi S, Chavalmane A,Silvestrini E, Colli E, Adorini L, Vannelli GB,Maggi M. Atorvastatin but not elocalcitol increasessildenafil responsiveness in spontaneously hyper-tensive rats by regulating the RhoA/ROCKpathway. J Androl 2008;29:70–84.

247 Schneider MP, Hilgers KF, Klingbeil AU, John S,Veelken R, Schmieder RE. Plasma endothelin isincreased in early essential hypertension. Am JHypertens 2000;13:579–85.

248 Mangiafico RA, Malatino LS, Santonocito M,Spada RS, Polizzi G, Tamburino G. Raised plasmaendothelin-1 concentrations in patients withprimary hypercholesterolemia without evidence ofatherosclerosis. Int Angiol 1996;15:240–4.

249 El Melegy NT, Ali ME, Awad EM. Plasma levelsof endothelin-1, angiotensin II, nitric oxide andprostaglandin E in the venous and cavernosalblood of patients with erectile dysfunction. BJU Int2005;96:1079–86.

250 Carneiro FS, Nunes KP, Giachini FR, Lima VV,Carneiro ZN, Nogueira EF, Leite R, Ergul A,Rainey WE, Webb RC, Tostes RC. Activation ofET-1/ETA pathway contributes to erectile dys-function associated with mineralocorticoid hyper-tension. J Sex Med 2008;5:2793–807.

251 Sullivan ME, Dashwood MR, Thompson CS,Mikhailidis DP, Morgan RJ. Down-regulation ofendothelin-B receptor sites in cavernosal tissue ofhypercholesterolemic rabbits. Br J Urol 1998;81:128–34.

252 Kifor I, Williams GH, Vickers MA, Sullivan MP,Jodbert P, Dluhy RG. Tissue angiotensin II as amodulator of erectile function. I. Angiotensinpeptide content, secretion and effects in the corpuscavernosum. J Urol 1997;157:1920–5.

253 Becker AJ, Uckert S, Stief CG, Truss MC,Machtens S, Scheller F, Knapp WH, Hartmann U,Jonas U. Possible role of bradykinin and angio-tensin II in the regulation of penile erection anddetumescence. Urology 2001;57:193–8.

254 Lin C-S, Ho H-C, Gholami S, Chen K-C, Jad A,Lue TF. Gene expression profiling of an arterio-genic impotence model. Biochem Biophys ResCommun 2001;285:565–9.

255 Baumhakel M, Schlimmer N, Bohm M, DO-ITInvestigators. Effect of irbesartan on erectile func-tion in patients with hypertension and metabolicsyndrome. Int J Impot Res 2008;20:493–500.

256 Ushiyama M, Morita T, Kuramochi T, Yagi S,Katayama S. Erectile dysfunction in hypertensive

472 Gratzke et al.

J Sex Med 2010;7:445–475

rats results from impairment of the relaxationevoked by neurogenic carbon monoxide and nitricoxide. Hypertens Res 2004;27:253–61.

257 Elesber AA, Solomon H, Lennon RJ, Mathew V,Prasad A, Pumper G, Nelson RE, McConnell JP,Lerman LO, Lerman A. Coronary endothelial dys-function is associated with erectile dysfunction andelevated asymmetric dimethylarginine in patientswith early atherosclerosis. Eur Heart J 2006;27:824–31.

258 Kaiser DR, Billups K, Mason C, Wetterling R,Lundberg JL, Bank AJ. Impaired brachial arteryendothelium-dependent vasodilation in men witherectile dysfunction and no other clinical cardiovas-cular disease. J Am Coll Cardiol 2004;43:179–84.

259 Yavuzgil O, Altay B, Zoghi M, Gurgun C, Kayik-cioglu M, Kultursay H. Endothelial function inpatients with vasculogenic erectile dysfunction. IntJ Cardiol 2005;103:19–26.

260 Kovacs I, Csaszar A, Toth J, Siller G, Farkas A,Tarjan J, Horvath J, Koller A. Correlation betweenflow-mediated dilation and erectile dysfunction.J Cardiovasc Pharmacol 2008;51:148–53.

261 Vardi Y, Dayan L, Apple B, Gruenwald I, Ofer Y,Jacob G. Penile and systemic endothelial functionin men with and without erectile dysfunction. EurUrol 2009;55:979–85.

262 Wespes E, Goes PM, Schiffmann S, Depierreux M,Vanderhaeghen JJ, Schulman CC. Computerizedanalysis of smooth muscle fibers in potent andimpotent patients. J Urol 1991;146:1015–7.

263 Sáenz de Tejada I, Moroukian P, Tessier J, Kim JJ,Goldstein I, Frohrib D. The trabecular smoothmuscle modulates the capacitor function of thepenis. Studies on a rabbit model. Am J Physiol1991;260:H1590–5.

264 Wespes E, Moreira De Goes P, Schulman C. Vas-cular impotence: Focal or diffuse penile disease. JUrol 1992;148:1435–6.

265 Toblli JE, Stella I, Inserra F, Ferder L, Zeller F,Mazza ON. Morphological changes in cavernoustissue in spontaneously hypertensive rats. Am JHypertens 2000;13:686–92.

266 Toblli JE, Stella I, Mazza ON, Ferder L, Inserra F.Protection of cavernous tissue in male spontane-ously hypertensive rats. Beyond blood pressurecontrol. Am J Hypertens 2004;17:516–22.

267 Clayton A, Ramamurthy S. The impact of physicalillness on sexual dysfunction. Adv Psychosom Med2008;29:70–88.

268 Derby CA, Barbour MM, Hume AL, McKinlay JB.Drug therapy and prevalence of erectile dysfunc-tion in the Massachusetts Male Aging Studycohort. Pharmacotherapy 2001;21:676–83.

269 Chobanian AV, Bakris GL, Black HR, CushmanWC, Green LA, Izzo JL Jr, Jones DW, MatersonBJ, Oparil S, Wright JT Jr, Roccella EJ, JointNational Committee on Prevention, Detection,Evaluation, and Treatment of High Blood Pres-

sure; National Heart, Lung, and Blood Institute,National High Blood Pressure Education ProgramCoordinating Committee. Seventh Report of theJoint National Committee on Prevention, Detec-tion, Evaluation, and Treatment of High BloodPressure. Hypertension 2003;42:1206–52.

270 Simonsen U. Interactions between drugs for erec-tile dysfunction and drugs for cardiovasculardisease. Int J Impot Res 2002;14:178–88.

271 Andersson KE. Erectile physiological and patho-physiological pathways involved in erectile dys-function. J Urol 2003;170:S6–13.

272 Grimm RH Jr, Grandits GA, Prineas RJ,McDonald RH, Lewis CE, Flack JM, Yunis C,Svendsen K, Liebson PR, Elmer PJ. Long-termeffects on sexual function of five antihypertensivedrugs and nutritional hygienic treatment in hyper-tensive men and women. Treatment of MildHypertension Study (TOMHS). Hypertension1997;29:8–14.

273 Simonsen U, Prieto D, Hernandez M, Sáenz deTejada I, Garcia-Sacristan A. Adrenoceptor-mediated regulation of the contractility in horsepenile resistance arteries. J Vasc Res 1997;34:90–102.

274 Srilatha B, Adaikan PG, Arulkumaran S, Ng SC.Sexual dysfunction related to antihypertensiveagents: Results from the animal model. Int J ImpotRes 1999;11:107–13.

275 Suzuki H, Tominaga T, Kumagai H, Saruta T.Effects of first-line antihypertensive agents onsexual function and sex hormones. J HypertensSuppl 1988;6:S649–51.

276 Croog SH, Levine S, Testa MA, Brown B, BulpittCJ, Jenkins CD, Klerman GL, Williams GH. Theeffects of antihypertensive therapy on the quality oflife. N Engl J Med 1986;314:1657–64.

277 [No authors listed]. Adverse reactions to bendrof-luazide and propranolol for the treatment of mildhypertension. Report of Medical Research CouncilWorking Party on Mild to Moderate Hyperten-sion. Lancet 1981;2:539–43.

278 Franzen D, Metha A, Seifert N, Braun M, HoppHW. Effects of beta-blockers on sexual perfor-mance in men with coronary heart disease. A pro-spective, randomized and double blinded study. IntJ Impot Res 2001;13:348–51.

279 Fogari R, Zoppi A, Poletti L, Marasi G, MugelliniA, Corradi L. Sexual activity in hypertensive mentreated with valsartan or carvedilol: A crossoverstudy. Am J Hypertens 2001;14:27–31.

280 Boydak B, Nalbantgil S, Fici F, Nalbantgil I, ZoghiM, Ozerkan F, Tengiz I, Ercan E, Yilmaz H, YoketU, Onder R. A randomised comparison of theeffects of nebivolol and atenolol with and withoutchlorthalidone on the sexual function of hyperten-sive men. Clin Drug Investig 2005;25:409–16.

281 Brixius K, Middeke M, Lichtenthal A, Jahn E,Schwinger RH. Nitric oxide, erectile dysfunction


J Sex Med 2010;7:445–475

and beta-blocker treatment (MR NOED study):Benefit of nebivolol versus metoprolol in hyper-tensive men. Clin Exp Pharmacol Physiol 2007;34:327–31.

282 Flack JM. The effect of doxazosin on sexual func-tion in patients with benign prostatic hyperplasia,hypertension, or both. Int J Clin Pract 2002;56:527–30.

283 Andersson KE. Pharmacology of penile erection.Pharmacol Rev 2001;53:417–50.

284 Becker AJ, Uckert S, Stief CG, Scheller F, KnappWH, Hartmann U, Jonas U. Plasma levels ofangiotensin II during different penile conditions inthe cavernous and systemic blood of healthy menand patients with erectile dysfunction. Urology2001;58:805–10.

285 Hale TM, Okabe H, Bushfield TL, Heaton JP,Adams MA. Recovery of erectile function afterbrief aggressive antihypertensive therapy. J Urol2002;168:348–54.

286 Fogari R, Zoppi A, Corradi L, Mugellini A, PolettiL, Lusardi P. Sexual function in hypertensivemales treated with lisinopril or atenolol: A cross-over study. Am J Hypertens 1998;11:1244–7.

287 Hale TM, Okabe H, Heaton JP, Adams MA. Anti-hypertensive drugs induce structural remodeling ofthe penile vasculature. J Urol 2001;166:739–45.

288 Hannan JL, Smallegange C, Hale TM, Heaton JP,Adams MA. Impact of antihypertensive treatmentson erectile responses in aging spontaneouslyhypertensive rats. J Hypertens 2006;24:159–68.

289 Park K, Shin JW, Oh JK, Ryu KS, Kim SW, PaickJS. Restoration of erectile capacity in normotensiveaged rats by modulation of angiotensin receptortype 1. J Androl 2005;26:123–8.

290 Llisterri JL, Lozano Vidal JV, Aznar VJ, ArgayaRM, Pol BC, Sanchez Zamorano MA, FerrarioCM. Sexual dysfunction in hypertensive patientstreated with losartan. Am J Med Sci 2001;321:336–41.

291 Villalba N, Stankevicius E, Simonsen U, Prieto D.Rho kinase is involved in Ca2+ entry of rat penilesmall arteries. Am J Physiol Heart Circ Physiol2008;294:H1923–32.

292 Cushman WC, Cohen JD, Jones RP, MarburyTC, Rhoades RB, Smith LK. Comparison of thefixed combination of enalapril/diltiazem ER andtheir monotherapies in stage 1 to 3 essential hyper-tension. Am J Hypertens 1998;11:23–30.

293 Palmer A, Fletcher A, Hamilton G, Muriss S,Bulpitt C. A comparison of verapamil and nife-dipine on quality of life. Br J Clin Pharmacol1990;30:365–70.

294 Schwarz ER, Rastogi S, Kapur V, SulemanjeeN, Rodriguez JJ. Erectile dysfunction in heartfailure patients. J Am Coll Cardiol 2006;48:1111–9.

295 Packer M, Bristow MR, Cohn JN, Colucci WS,Fowler MB, Gilbert EM, Shusterman NH. The

effect of carvedilol on morbidity and mortality inpatients with chronic heart failure. U.S. CarvedilolHeart Failure Study Group. N Engl J Med 1996;334:1349–55.

296 Pitt B, Zannad F, Remme WJ, Cody R, CastaigneA, Perez A, Palensky J, Wittes J. The effect ofspironolactone on morbidity and mortality inpatients with severe heart failure. RandomizedAldactone Evaluation Study Investigators. N EnglJ Med 1999;341:709–17.

297 Squire IB, Barnett DB. The rational use of beta-adrenoceptor blockers in the treatment of heartfailure. The changing face of an old therapy. Br JClin Pharmacol 2000;49:1–9.

298 Schneider J, Kaffarnik H. Impotence in patientstreated with clofibrate. Atherosclerosis 1975;21:455–7.

299 Bain SC, Lemon M, Jones AF. Gemfibrozil-induced impotence. Lancet 1990;336:1389.

300 Bruckert E, Giral P, Heshmati HM, Turpin G.Men treated with hypolipidaemic drugs complainmore frequently of erectile dysfunction. J ClinPharm Ther 1996;21:89–94.

301 Kersten S, Wahli W. Peroxisome proliferatoractivated receptor agonists. EXS 2000;89:141–51.

302 Xu S, Zhu BT, Turan V, Rusyn I, Thurman R,Peters JM, Gonzalez FJ, Conney AH. PPARalpha-dependent induction of liver microsomal esterifi-cation of estradiol and testosterone by aprototypical peroxisome proliferator. Endocrinol-ogy 2001;142:3554–7.

303 Do C, Huyghe E, Lapeyre-Mestre M, MontastrucJL, Bagheri H. Statins and erectile dysfunction:Results of a case/non-case study using the FrenchPharmacovigilance System Database. Drug Saf2009;32:591–7.

304 Jackson G. Simvastatin and impotence. BMJ1997;315:31.

305 Kostis JB, Rosen RC, Wilson AC. Central nervoussystem effects of HMG CoA reductase inhibitors:Lovastatin and pravastatin on sleep and cognitiveperformance in patients with hypercholester-olemia. J Clin Pharmacol 1994;34:989–96.

306 Pedersen TR, Faergemann O. Simvastatinseems unlikely to cause impotence. BMJ 1999;318:192.

307 Saltzman EA, Guay AT, Jacobson J. Improvementin erectile function in men with organic erectiledysfunction by correction of elevated cholesterollevels: A clinical observation. J Urol 2004;172:255–8.

308 Bank AJ, Kelly AS, Kaiser DR, Crawford WW,Waxman B, Schow DA, Billups KL. The effects ofquinapril and atorvastatin on the responsiveness tosildenafil in men with erectile dysfunction. VascMed 2006;11:251–7.

309 Hong SK, Han BK, Jeong SJ, Byun SS, Lee SE.Effect of statin therapy on early return of potency

474 Gratzke et al.

J Sex Med 2010;7:445–475

after nerve sparing radical retropubic prostatec-tomy. J Urol 2007;178:613–6.

310 Dogru MT, Basar MM, Simsek A, Yuvanc E,Guneri M, Ebinc H, Batislam E. Effects of statintreatment on serum sex steroids levels and auto-nomic and erectile function. Urology 2008;71:703–7.

311 Solomon H, Samarasinghe YP, Feher MD, Man J,Rivas-Toro H, Lumb PJ, Wierzbicki AS, JacksonG. Erectile dysfunction and statin treatment inhigh cardiovascular risk patients. Int J Clin Pract2006;60:141–5.

312 Gryglewski RJ, Uracz W, Swies J, Chlopicki S,Marcinkiewicz E, Lomnicka M, Madej J. Compari-son of endothelial pleiotropic actions of angio-tensin converting enzyme inhibitors and statins.Ann N Y Acad Sci 2001;947:229–45.

313 Morelli A, Chavalmane AK, Filippi S, Fibbi B,Silvestrini E, Sarchielli E, Zhang XH, Vignozzi L,Vannelli GB, Forti G, Maggi M. Atorvastatin ame-liorates sildenafil-induced penile erections inexperimental diabetes by inhibiting diabetes-induced RhoA/Rho-kinase signaling hyperactiva-tion. J Sex Med 2009;6:91–106.

314 Taylor MJ, Rudkin L, Hawton K. Strategiesfor managing antidepressant-induced sexual

dysfunction: Systematic review of randomisedcontrolled trials. J Affect Disord 2005;88:241–54.

315 Coleman CC, King BR, Bolden-Watson C, BookMJ, Segraves RT, Richard N, Ascher J, Batey S,Jamerson B, Metz A. A placebo-controlled com-parison of the effects on sexual functioning ofbupropion sustained release and fluoxetine. ClinTher 2001;23:1040–58.

316 Gitlin MJ, Suri R, Altshuler L, Zuckerbrow-MillerJ, Fairbanks L. Bupropion-sustained release as atreatment for SSRI-induced sexual side effects.J Sex Marital Ther 2002;28:131–8.

317 Abs R, Verhelst J, Maeyaert J, Van Buyten JP,Opsomer F, Adriaensen H, Verlooy J, Van Haven-bergh T, Smet M, Van Acker K. Endocrine conse-quences of long-term intrathecal administration ofopioids. J Clin Endocrinol Metab 2000;85:2215–22.

318 Billington CJ, Shafer RB, Morley JE. Effects ofopioid blockade with nalmefene in older impotentmen. Life Sci 1990;47:799–805.

319 Eri LM, Tveter KJ. Safety, side effects and patientacceptance of the antiandrogen Casodex in thetreatment of benign prostatic hyperplasia. EurUrol 1994;26:219–26.


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Anatomy, Physiology, and Pathophysiology of Erectile Dysfunction

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