Treatment of chronic mountain sickness: Critical reappraisal of an old problem

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Respiratory Physiology & Neurobiology 158 (2007) 251–265

Treatment of chronic mountain sickness:Critical reappraisal of an old problem

Marıa Rivera-Ch a,∗, Fabiola Leon-Velarde a, Luis Huicho b,c,d

a Departamento de Ciencias Biologicas, Facultad de Ciencias y Filosofıa, Instituto de Investigaciones de Altura,Universidad Peruana Cayetano Heredia, Av. Honorio Delgado 430, Lima LI 31, Peru

b Departamento Academico de Pediatrıa, Universidad Nacional Mayor de San Marcos, Lima LI 5, Lima, Peruc Departamento Academico de Pediatrıa, Universidad Peruana Cayetano Heredia, LI 5, Lima Peru

d Instituto de Salud del Nino, LI 5, Lima, Peru

Accepted 1 May 2007

bstract

A review is made on the different treatment strategies essayed to date in the management of chronic mountain sickness (CMS). After a briefresentation of the epidemiology and of the pathophysiological mechanisms proposed for explaining the disease, the advantages and drawbacks ofhe different treatment approaches are discussed, along with their pathopysiological rationale. A particular emphasis is dedicated to the scientificoundations underlying the development of acetazolamide and angiotensin-converting enzyme inhibitors as promising therapeutic agents for CMS,
s well as the clinical evidence existing so far on their usefulness in the treatment of CMS. Various methodological issues that need to be addressedn future clinical studies on efficacy of therapies for CMS are discussed. There is also a brief discussion on potential treatment options for chronicigh altitude pulmonary hypertension. Closing remarks on the need of taking increasingly into account the development and implementation ofreventive measures are made.
2007 Elsevier B.V. All rights reserved.

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eywords: Chronic mountain sickness; High altitude; Treatment

. Introduction

When we were invited to write a paper for this special issuen honor of Dr. Carlos Monge Cassinelli, we recalled once againhe inspiring atmosphere prevailing at our laboratory. There heassionately discussed with us on almost every issue relevant tonderstanding how living organism function as integral systems,ncluding the fascinating area of oxygen cascade in biologicalystems. Of course, human exposure to chronic hypoxia andMS occupied a prominent place, following a tradition initi-ted decades before by Dr. Carlos Monge Medrano, who hadescribed the condition for the first time in 1925 (Monge-M,925). Albeit our main motivation was intellectual challenge, Dr.
onge Cassinelli was always aware on the importance of CMS
s a problem of countless underserved highland inhabitants, whoeserved higher priority in the development of national health

∗ Corresponding author. Tel.: +51 1 93488786; fax: +51 1 3190019.E-mail addresses: [email protected] (M. Rivera-Ch),

[email protected] (F. Leon-Velarde), [email protected] (L. Huicho).

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569-9048/$ – see front matter © 2007 Elsevier B.V. All rights reserved.oi:10.1016/j.resp.2007.05.003

olicies. He stubbornly taught us that basic science is funda-ental for building a prosperous nation. But he also believed in

ublic health as a respectable science with an enormous potentialor improving life quality of people. This is a humble and yet welleserved tribute to a man who taught us, with his own example,hat it is possible to perform sustained and high quality researchhile actively struggling for better scenarios in our own coun-

ry, and furthermore that we can pursue horizontal, relevant, androductive joint ventures with scientific colleagues throughouthe world.

Several publications have been devoted to various aspects ofMS including epidemiology, pathophysiological basis, clinical

eatures and treatment strategies (Leon-Velarde, 1993; Leon-elarde et al., 1993; Monge-C et al., 1992; Sime et al., 1975;inslow and Monge-C, 1987). We will focus in this review

n the quality of evidence supporting the different treatmentpproaches and on the rationale behind their use, after a brief
verview on the epidemiology and pathophysiology of CMS,n order to have a better idea of the burden that this diseaseepresents, and also for better understanding the rationale ofhe therapies investigated so far. Wherever relevant, we will
mailto:[email protected]



dx.doi.org/10.1016/j.resp.2007.05.003

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52 M. Rivera-Ch et al. / Respiratory Phys

lso address future potential research avenues on treatment andrevention.

.1. Definition, symptoms, and clinical diagnosis

CMS has been defined by a recent international consen-us as a clinical syndrome occurring to natives or long-lifeesidents above 2500 m, characterized by excessive erythro-ytosis, defined by excessive hemoglobin (Hb) concentrationfemales Hb ≥ 19 g/dL; males Hb ≥ 21 g/dL), severe hypoxemialow SaO2), and in some cases moderate or severe pulmonaryypertension, which may evolve to cor pulmonale, leadingo congestive heart failure (Leon-Velarde et al., 2005). Thisonsensus definition emphasizes that clinical manifestationsradually disappear after descent to lower altitudes and reap-ear after return to high altitude. It also proposes a CMS scoreased on clinical symptoms and Hb concentration for grad-ng the severity of the disease, which use should allow betteromparability of future studies. Subjects with chronic respira-ory diseases or those with any underlying chronic conditionhat worsens hypoxemia are excluded from this CMS defini-ion. Clinical features of CMS include dyspnea, palpitations,nsomnia, headache, confusion, loss of appetite, lack of mentaloncentration and memory impairment. Patients may also sufferrom decreased exercise tolerance, bone pain, acral paresthesiand occasionally hemoptysis. Clinical examination may revealyanosis, congestive conjunctivae, and dilatation of retinal ves-els. An accentuated second heart sound and cardiomegalyre frequently evidenced, due to right ventricle hypertrophy.ith the progression of the disease, overt heart failure occurs

ventually.

.2. Incidence, risk factors, and pathophysiology

Longitudinal studies on the incidence and the role of riskactors in the development of CMS are lacking. The esti-ated prevalence of this condition is 15.6% (Leon-Velarde andrregui, 1994; Leon-Velarde et al., 1994) on the basis of a cross-

ectional study performed in men resident in Cerro de Pasco, aeruvian mining city placed at 4300 m. Risk factors proposedy the authors included age, obesity, low arterial oxygen sat-ration (SaO2), and low peak expiratory flow. This study alsoevealed that chronic respiratory diseases may increase high alti-ude hypoxemia, contributing to increased symptoms of CMSLeon-Velarde et al., 1994). By contrast, prevalence of CMS inibetans has been estimated in 0.91% (Wu et al., 1998) in studiessing the same definition criteria of those in the Peruvian study.

CMS affects quality of life, mental and physical performancend very likely leads to premature death and accounts for a sub-tantial morbidity burden in high altitude settings. It has beenroposed therefore that, at least in the Andean region (Bolivia,olombia, Ecuador, Peru, Venezuela, and Chile), CMS shoulde considered a public health problem and that it should be
ncluded in the health policy priorities of those countries (Leon-elarde, 2003). Kyrgyzstan health authorities have also called
or an increased support to research related to CMS and under-cored the importance of paying more attention to pulmonary

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& Neurobiology 158 (2007) 251–265

ypertension and cor pulmonale in Kyrgyzstan and China (Leon-elarde, 2003).

Aging, worsened hypoventilation during sleep and periodicreathing are all been proposed as aggravating factors (Leon-elarde et al., 1993; Kryger et al., 1978; Normand et al., 1992;ernardi et al., 2003; Spicuzza et al., 2004; Sun et al., 1996). It

eems that lifestyle and environmental pollution can also accel-rate the development of CMS (Frisancho, 1988; Monge-C etl., 1992). In this regard, it is interesting that mean Hb concen-ration found in a mining city (Chuquicamata, Chile, 2800 m),s higher than that found in a non-mining city placed at 4100 mSantolaya et al., 1981, 1984/1985).

Issues needing further assessment in future studies includehe appropriate control of contextual and modifying factors.nvironmental pollution can increase frequency and severity ofhronic pulmonary conditions in high altitude settings, obesityelated to western lifestyles adopted by high altitude popula-ions is increasingly frequent, and genetic factors are proving toe critical in determining the degree of adaptation to life at highltitude (Beall et al., 2002).

.3. Hypoxic ventilatory response (HVR) and CMS

Like many other clinical conditions, CMS is multifactorialn its origin. Understandably, there is no unanimous agree-ent on its pathophysiology (Monge-C et al., 1992; Winslow

nd Monge-C, 1987; Leon-Velarde, 1993; Leon-Velarde etl., 1993). Hypoventilation has been proposed as one of thenderlying mechanisms leading to an abnormally enhancedrythropoiesis, increased red cell mass and blood viscosity, sys-emic and pulmonary hypertension and heart failure (Reeves and

eil, 2001; Severinghaus et al., 1966). A blunted HVR has beenhown in subjects with CMS (Sime et al., 1975). The authorsuggested this as the basic underlying cause. However, bluntedVR has also been demonstrated in some subjects without CMS

Bainton et al., 1964; Severinghaus et al., 1966). In addition, theunction of the peripheral chemoreceptors has been shown to bebnormal (Leon-Velarde et al., 2003a).

Studies were carried out to examine the plasticity of chemore-exes to both short- and long-term changes in blood gas tensionsf chronically hypoxic high altitude natives with blunted respira-ory responses to hypoxia. Natives who had moved to live at seaevel had ventilatory responses to acute hypoxia (few minutes)imilar to that of sea-level controls (Gamboa et al., 2003a,b).owever, responses to sustained hypoxia (20 min) remainedarkedly blunted. These results may explain the apparent dis-

repancy in previous studies with regard to HVR. The basicotion remaining is that chronic alveolar hypoventilation in sus-eptible high altitude natives plays a central role in the genesisf CMS, enhancing erythropoiesis that results in an abnormallyncreased red cell mass and blood viscosity.

.4. Erythropoiesis and CMS

Many of the clinical features of CMS may be attributed tohe excessive polycythemia, which leads to hyperviscosity ofhe blood and consequently impaired blood flow and impaired

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M. Rivera-Ch et al. / Respiratory Physi

xygen delivery to several organs including the brain. Paradox-cally, the increases in red blood cells aimed at increasing thexygen carrying capacity lead directly to hyperviscosity, whichventually worsens hypoxemia. From this pathophysiologicalerspective it follows that one therapeutic strategy for CMS ishe development of agents that decrease polycythemia actingirectly or indirectly on EPO-mediated erythropoiesis. Therere various pharmacological and non-pharmacological interven-ions that have been studied, and others that are being activelyssessed or need to be studied in the future. We offer later theeview of the existing literature on this therapeutic approach.

.5. The autonomic nervous system and CMS

There is a recent update of the pathopysiological basis ofMS with emphasis on changes occurring at the autonomicontrol level, including cardiovascular and cerebrovascular con-rol aspects in affected subjects (Hainsworth et al., 2007). Thiseview quotes studies performed in high altitude natives with andithout CMS. One of these studies showed that affected subjectsave impaired autonomic control of cardiovascular and cerebralunction, particularly in aspects related to peripheral vascularesistance and cerebral blood flow autoregulation (Claydon et al.,005). Peripheral vascular resistance, the major mechanism forhe control of blood pressure was studied through measurementf responses of forearm vascular resistance to carotid barorecep-or stimulation in high altitude residents with and without CMS,oth at their altitude of residence and shortly after descent toea level (Moore et al., 2006). Results showed that baroreflexensitivity was similar in both groups and at both locations. Atigh altitude the “set point” was higher in the CMS group but,ithin a day of exposure to normoxia, it was reset to a lowerressure which was similar to that of healthy subjects (Moore etl., 2006). In another study, cerebral autoregulation was assessedhrough the correlation between flow and pressure during ortho-tatic stress. The results showed impairment of cerebrovascularutoregulation in CMS patients (Claydon et al., 2005).

.6. High altitude pulmonary hypertension and CMS

Finally, it must be emphasized that CMS and high altitudeulmonary hypertension (HAPH) represent separate manifesta-ions of chronic hypoxia, that is, stimulation of erythropoiesisnd stimulation of pulmonary hypertension, respectively. Inany CMS patients, both manifestations are present simul-

aneously (Penaloza and Sime, 1971; Penaloza et al., 1971).owever, occasionally CMS patients may have little or no ele-ation of pulmonary artery pressure or resistance beyond theormal increase at high altitude (Antezana et al., 1998). Alterna-ively, particularly in children and young adults, life-threateningAPH may occur with little or no increase in Hb (Anand and Wu,004; Ge and Helun, 2001; Lin and Wu, 1974; Sui et al., 1988).herefore, two separate pathophysiologies have been proposed

or these altitude-related illnesses, with the recognition that in aiven patient they may or may not coexist (Leon-Velarde et al.,005). This separation has clinical implications. We need to payarticular emphasis to the development of separate treatment

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& Neurobiology 158 (2007) 251–265 253

trategies, one aimed at improving pulmonary hypertension andts clinical consequences, and the other at seeking effective treat-

ents for CMS with excessive polycythemia. Thus later in thiseview we will also discuss briefly the potential of various agentsn the treatment of HAPH.

.7. Genetic adaptations and CMS

Adding to the complexity of the pathophysiology of CMS,here are genetic differences in the response of high altitudeopulations to chronic hypoxia. Andeans display a pheno-ype characterized by enhanced erythrocytosis (Monge, 1978;

inslow and Monge, 1978) that may even lead to CMSWinslow and Monge, 1978), a condition whose hallmark isxcessive erythrocytosis and low SaO2. Tibetans show insteadormal erythropoiesis and low SaO2 (Beall, 2000, 2006).ecently, a third pattern of adaptation was described in Ethiopi-ns native to high altitude settings without evidence of ironeficient anemia, hemoglobinopathy, or chronic inflammatoryonditions. They showed Hb concentration and SaO2 valuesimilar to those found at sea level (Beall et al., 2002). It seemshat natural selection has favored the presence and persistencef genes for a low erythropoietic response and of genes forigher oxygen saturation (Beall et al., 1994, 1997, 2004), andonferred to Ethiopians a better degree of adaptation to highltitude hypoxia (Beall et al., 2004). It appears therefore thatigh-altitude hypoxia acts as an agent of natural selection con-erring greater reproductive success among women estimatedith high probability to have genotypes for high percent of oxy-en saturation (Beall et al., 2004). The implication is that if thisattern persists, then the frequency of the high saturation alleleill increase (Beall et al., 2004).Thus it seems that CMS is not always an unavoidable final

esult of the responses to chronic hypoxia. Better understandinghe role of genetic basis of such responses and of modifyingactors such as life style, environmental and indoor pollutionnd chronic respiratory conditions will pave the way for devel-ping future preventive and therapeutic interventions for CMS.ig. 1 shows the proposed pathophysiological events leading toMS and/or pulmonary artery hypertension and sites that can be

nfluenced by pharmacological agents. This conceptual modeloes not include the responses to chronic hypoxia occurring athe cellular and molecular level. These responses have been dis-ussed in detail elsewhere (Hochachka, 1986; Hochachka et al.,998) and are beyond the scope of this review.

. Therapeutic approaches proposed:athophysiological and clinical rationale

For a better understanding of the different therapeutic strate-ies proposed ever since the first description of CMS, we willry to offer the corresponding underlying pathophysiologicalationale. For assessing efficacy of treatments, we first need to
ave an agreement on a set of conditions allowing comparabil-ty of studies and a rigorous evaluation of study methodologies.uch conditions include a clear definition of CMS, an integratedathophysiological framework taking into account all relevant

254 M. Rivera-Ch et al. / Respiratory Physiology & Neurobiology 158 (2007) 251–265

Fig. 1. Proposed pathophysiology of CMS and HAPH. Determinant (genetic) and modifying/risk factors in the response to hypoxia are showed and sites for possibletherapeutic interventions are signaled by arrows denoting stimulatory (+) or inhibitory effects (−). Andean, Tibetan and Ethiopian populations are showed as examplesof different genetic patterns of adaptation, which determine the responses to chronic hypoxia that may de modulated by modifying/risk factors. Depending on geneticand modifying factors, high-altitude hypoxia raises different responses that involve regulatory actions of central and peripheral system nervous on the cardiovascularand respiratory systems, which in turn modify the oxygen transport that may be impaired in those predisposed, leading eventually to excessive erythrocytosis and CMS.A actorsi : higE eryl-a

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lternatively or simultaneously, hypoxia may lead to HAPH. Modifying/risk fncrease their severity. CNS: central nervous system; NS: nervous system; HAPHPO: erythropoietin; IGF-1: insulin-like growth factor 1; Ac-SDKP: N-acetyl-s

teps and factors in the development of CMS that are suscepti-le to intervention and modification, and finally explicit criteriaor a formal assessment of the validity and applicability of theifferent therapeutic studies.

We will use as reference for our analyses the definition ofMS agreed on the International Consensus Statement (Leon-elarde et al., 2005). In addition, we will consider whether

he evidence-base for each particular treatment comes fromystematic reviews of randomized controlled trials, from indi-idual randomized controlled trials, non-randomized controlledrials, case-series, case-reports, consensus/expert opinion, ani-al studies, or from basic studies addressing physiological and

athophysiological aspects. Systematic reviews of randomizedontrolled trials and well-designed individual randomized con-rolled trials will be ranked as those with the highest level ofvidence (Harbour and Miller, 2001), whereas basic studies wille considered as preliminary evidence waiting for appropriatelinical testing in humans. In addition to the quality of evidence,henever we make judgments about the strength of a recom-endation on CMS treatment, we will also consider the balance

etween benefits and harms, translation of the evidence intopecific circumstances, the certainty of the baseline risk, andesource utilization (Atkins et al., 2004). Clinical relevant out-omes taken into account for judging the quality of the studiesn treatment of CMS will include CMS score and quality of life.hanges in Hb concentration, SaO2, baseline ventilation, HVR,nd pulmonary artery pressure will be considered as relevant
urrogate outcomes.
We broadly classify the therapeutic approaches of CMSn those aimed at reducing pharmacologically or non-harmacologically the increased red blood cell mass and in

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hose directed to stimulate ventilation for increasing SaO2 andherefore to reduce the increased erythropoietic response thatharacterizes CMS.

.1. Non-pharmacologic reduction of erythremia:lood-letting

Blood-letting is used in patients with CMS for the purposef reducing red cell mass volume and Hb concentrations at leasto values considered normal for the altitude of residence. Weid not find randomized controlled trials on safety and effi-acy of this therapy. Performing such a clinical trial wouldace formidable practical challenges. Case-series and case-eports have shown that blood-letting with or without isovolemicemodilution reduces hematocrit values, improves oxygenationnd leads to improvement of symptoms (Cruz et al., 1979; Klein,983; Sedano et al., 1988; Sedano and Zaravia, 1988; Winslowt al., 1985; Wu, 1979). Blood-letting also decreases ventilation-erfusion mismatching and improves PaO2 (Manier et al., 1988).lthough adverse events such as severe iron deficiency in most

reated patients have been observed with the use of this therapeu-ic procedure in other conditions (Barenbrock et al., 1993), theyailed to be reported in a systematic way in the case-series andase-reports published to date in the treatment of CMS. Of note,n one study where before- and after-therapy measurements wereerformed in three subjects with CMS, hematocrit decreased inll, but no improvement of symptoms was observed 24 h after
leeding (Monge-C et al., 1966). It is a common observationhat if the patient stays at high altitude, hematocrit reaches againre-treatment values and symptoms reappear within a few dayso weeks. Measurements after treatment in the reported studies

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ere performed, but the authors did not report in a systematicay whether changes in quantitative measurements and in symp-

oms along specific periods of time after the institution of therapyere evaluated. Thus we do not know with certainty how long theeneficial effects last. It is claimed that blood-letting along withsovolemic hemodilution is safer than phlebotomy without vol-me replacement (Klein, 1983) and that it allows a long-lastingmprovement of symptoms (Sedano and Zaravia, 1988). How-ver, we did not find solid findings from well designed clinicaltudies supporting such statements.

High altitude residents, in particular those from the Andeanegion, frequently express concern on being deprived of part ofheir blood, and thus the acceptance of blood-letting may be quiteow, although this issue has not been systematically investigated.ue to its transient effects, to invasive nature of the therapy,

nd to acceptance problems, the conduction of future random-zed controlled trials with blood-letting, alone or in combinationith isovolemic hemodilution, seems unlikely. Currently, blood-

etting is practiced on a very limited scale.

.2. Pharmacologic reduction of erythremia

The main growth factor that promotes production of blood redells in hematopoietic organs is erythropoietin (EPO). Unequiv-cal evidence for the existence of EPO was provided by Erslev inhe middle of the 20th century (Erslev, 1953). Shortly afterwards,ioneer studies demonstrated erythropoietic activity in plasmand urine from anemic animals (Borsook et al., 1954; Gordont al., 1954; Hodgson and Toha, 1954). Human EPO was suc-essfully purified in 1977 (Miyake et al., 1977). The primaryite of EPO production has been localized in kidneys (Jacobsont al., 1957). More specifically EPO is produced mainly byeritubular cells of the kidney (Lacombe et al., 1988). It haseen documented that liver and other extra-renal cells such asacrophages are also able to produce EPO (Jelkmann, 1992).lowered oxygen capacity, a reduced oxygen partial pressure

nd an increased O2-Hb affinity are all factors that stimulate theroduction of erythropoietin (Jelkmann, 1992).

.2.1. Angiotensin-converting enzyme inhibitorsVarious findings preceded the essay of ACE inhibitors in the

reatment of CMS. First, a certain proportion of kidney trans-lanted patients developed post-transplant erythropoiesis (PTE)hrough enhanced erythropoiesis mediated by an altered regula-ion in EPO production (Thevenod et al., 1983), and transplantedatients receiving ACE inhibitors had anemia as a side-effectLamperi and Carozzi (1985)), suggesting that drugs able tonhibit erythropoiesis could be useful in the treatment of PTE.n addition, a positive association was found between renin-ngiotensin system activation and elevated red blood cell massn diverse clinical conditions (Bourgoignie et al., 1968; Hudgsont al., 1967; Labeeuw et al., 1992; Onoyama et al., 1989, 1995;olpe et al., 1994; Vlahakos et al., 1991, 1999). At least two
ystems participate in the pathogenesis of PTE in addition ofPO, namely, the renin-angiotensin system, and endogenousndrogens (Vlahakos et al., 2001, 2003). Furthermore, otherrythropoiesis-stimulating factors might play a contributing
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& Neurobiology 158 (2007) 251–265 255

ole, including the oligopeptide N-acetyl-seryl-aspartyl-lysyl-roline (Ac-SDKP), a natural inhibitor of the pluripotent stemell whose catabolism is increased by ACE inhibitors (Azizi etl., 1996), and the growth factor insulin-like growth factor 1IGF-1) (Blahakos et al., 2003; Congote et al., 1991; Glicklicht al., 2001).

ACE inhibitors or angiotensin II receptors antagonists haveroved to be effective in the treatment of PTE (Gaston et al.,994), very likely through increase of renal blood flow, inhi-ition of sodium reabsorption in renal tubular cells with aonsequent fall in oxygen consumption leading eventually ton enhanced erythropoietin production, and blockade of a directffect of angiotensin II on erythropoiesis (Cole et al., 2000; Mrugt al., 1997; Perazella and Bia, 1993), possibly mediated byn up-regulation of angiotensin type 1 receptors on erythroidrecursors.(Gupta et al., 2000). The accumulation of Ac-SDKPnduced by ACE inhibitors could also decrease directly the EPOroduction independently of effects mediated by angiotensin IIAzizi et al., 1996).

An excessively increased Hb concentration as a result ofnhanced erhythropoiesis as a hallmark of CMS (Morrone et al.,997; Dainiak et al., 1989; Leon-Velarde et al., 1991; Winslowt al., 1989) and the development of proteinuria and chronicenal disfunction in a proportion of affected patients (Monge-Mnd Monge-C, 1966; Rennie et al., 1971) led to the assessmentf possible beneficial effects of ACE inhibitors in high altitudeolycythemia.

The prophylactic and therapeutic effects of enalapril weressessed in experimental chronic hypobaric hypoxia in miceGamboa et al., 1997). Treated mice showed significantlyeduced hematocrit values compared with those of controls whennalapril was administered after exposure to hypoxia. In a pre-iminary non-controlled and non-randomized study, seven malesnd three females with CMS native to Cerro de Pasco werereated with enalapril during 30 days (Vargas et al., 1996). Hema-ocrit decreased after the second week of therapy and CMS scorelso decreased, but the results were not consistent in all par-icipants. This was the first clinical study on the therapeuticole of an ACE inhibitor in CMS, but definitive conclusions onafety and efficacy could not be derived due to its methodologicalrawbacks.

The main clinical evidence on efficacy of ACE inhibitors inhe treatment of CMS comes from the only randomized trialerformed to date (COMGAN, 2002). Twenty-six consecutiveatients with altitude polycythemia and persistent proteinuriaere randomly assigned to receive either enalapril (5 mg/day) oro treatment and were followed for 2 years. The study was openo doctors and patients. The primary endpoint was the effect ofnalapril on packed cell volume, Hb concentration, and urinaryrotein excretion rate. Secondary endpoints were the relationsetween packed cell volume and Hb concentration and urinaryrotein excretion rate at study entry, and between reduction inacked cell volume or Hb concentration and reduction in uri-
ary protein excretion rate during treatment. All patients weref mixed Indian and European, mostly Spanish, ethnic origin,ere born at altitudes of 3200–4000 m, and had lived in La Paz
3600 m) for at least 1 year. Diagnosis of altitude polycythemia

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nd persistent proteinuria was made on the basis of packed cellolume greater than or equal to 55%, and urinary protein excre-ion rate greater than or equal to 150 mg/24 h, measured on twor more occasions, 2 months apart, in otherwise healthy peo-le. Patients were advised to restrict their dietary sodium and toat 0.6–0.8 g protein per kg body weight daily. Other antihyper-ensive drugs but not ACE inhibitors or angiotensin II receptorntagonists were allowed. The sample size of the study was pow-red to detect a mean 6.74% decrease in packed cell volume inreated patients and none in controls.

In study patients but not in controls, mean packed cell volume,b concentration, and proteinuria fell significantly. At 12 and 24onths of follow-up, packed cell volume, Hb concentration, and

roteinuria differed significantly between the groups. In studyatients, follow-up changes in packed cell volume or Hb con-entration and proteinuria were strongly correlated. Enalaprilas well tolerated by all patients.In addition to the above discussed mechanisms, possible path-

ays accounting for the beneficial effect of enalapril observed inhis study include a direct and indirect effect on erythropoiesis.nalapril is known to increase renal blood flow and decreaseodium tubular reabsorption, which in turn lead to increasedxygen availability at the level of erythropoietin-producing cells.

The study hypothesis was that in altitude polycythemia,ncreased production of erythrocytes sustained by erythropoi-tin, being at least in part dependent on angiotensin II (Morronet al., 1997), could be limited by inhibition of production ofngiotensin II. The fact that the extent and temporal pattern ofeductions in packed cell volume and Hb concentration inducedy ACE inhibition were almost identical in these disordersPerazella and Bia, 1993; Montanaro et al., 2000) corroborateduch hypothesis. The decrease in packed cell volume and Hboncentration was progressive and linear, suggesting that com-lete recovery from polycythemia might just be a function ofime.

A progressive and time-dependent reduction of proteinuriaas also shown, that in some cases decreased to undetectable

evels. This reduction was clearly a specific effect of treatments controls showed progressive increase. Enalapril may haveecreased proteinuria by improving the sieving properties of thelomerular barrier (Remuzzi et al., 1990, 1991). But ameliora-ion of the effects of polycythemia might have partly contributedo reduction in proteinuria, as there was a positive correlationn the study patients between changes in packed cell volume (orb concentration) and proteinuria.Finally, the authors state that reductions in both packed

ell volume and proteinuria should have an additive effect inecreasing the cardiovascular and renal complications of alti-ude polycythemia, and in the long term, should substantiallyeduce morbidity and mortality. As baseline packed cell vol-me and Hb concentration were positively correlated with bloodressure, serum creatinine, blood urea nitrogen, and protein-ria, polycythemia is likely an independent risk factor for renal
nd cardiovascular disease in high altitude natives. In controlslood pressure and proteinuria increased throughout the studylong with Hb concentration and packed cell volume. This sug-ests that high altitude polycythemia could also contribute to the
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& Neurobiology 158 (2007) 251–265

evelopment and progression of chronic renal dysfunction, veryikely through increased blood pressure, blood viscosity or bothWinterborn et al., 1987), although chronic hypoxia might alsoirectly cause renal disease (Fine et al., 2000).

This open randomized controlled clinical trial was adequatelyowered to detect a clinically relevant decrease of primary out-omes in treated subjects. Clear inclusion and exclusion criteriaere also stated. The results are quite convincing, as packed

ell volume, Hb concentration, and particularly proteinuria fellignificantly in a sustained way along the treatment period. Theuthors acknowledge that economic constraints led them to use axed small dose of enalapril and that higher doses of enalapril orombination with other inhibitors of angiotensin activity, suchs angiotensin II receptor antagonists, might be more effectivend rapid in treatment of polycythemia. Other drawbacks of thetudy include lack of clinical data for defining whether study sub-ects suffered also from symptoms attributable to CMS, besidesryhtrocytosis and proteinuria. Lack of assessment of clinicalymptoms and of quality of life is an important limitation of thetudy, as CMS affects profoundly the performance of patientsn their daily routine. Subjects with packed cell volume greaterhan or equal to 55% were included in the study, but there is nonformation on male to female ratio, whereas gender differenti-ted thresholds of Hb ≥21 and ≥19 g/dL have been proposed inen and women, respectively, for determining the existence of

xcessive eryhtrocytosis as part of the definition of CMS (Leon-elarde et al., 2005). Thus the study could not assess the efficacyf enalapril in patients with defined clinical and laboratory cri-eria of CMS, particularly in those with higher red cell mass and

ore severe symptoms. Future larger studies are needed to assesshe safety and efficacy of enalapril and other ACE inhibitorsnd of angiotensin II receptor antagonists in the treatment ofMS with and without proteinuria. They should include clini-al improvement and quality of life as primary outcomes, andstandardized definition of CMS including clinical and labora-

ory data should be used to allow comparability (Leon-Velardet al., 2005).

.2.2. MethylxanthinesErythrocytosis occurs in 6.8–17.3% of kidney transplanted

atients (Oymak et al., 1995). The polycythemia arising afteridney transplant is associated with increased levels of ery-hropoietin (EPO) (Oymak et al., 1995; Thevenod et al., 1983;aciong et al., 1996). Increased serum levels of EPO have

lso been observed in patients with high altitude polycythemiaDainiak et al., 1989; Leon-Velarde et al., 1991; Winslow etl., 1989). Methylxanthines, including teophylline and pentoxi-ylline have been used for treating eryhtrocytosis associated withenal diseases such as in patients who developed polycythemiafter kidney transplant (Bakris et al., 1990; Ward and Clissold,987). It has also been reported that pentoxifylline reduces bloodiscosity and thus may improve blood flow and tissue oxy-enation (Bacher et al., 2005; Porter et al., 1982; Strano et al.,
984). Adenosine is a cellular messenger that exerts its actionhrough A1 and A2 adenosine receptors. A2 receptors stimu-ate adenylate cyclase, activated by micromolar concentrationsf adenosine (Ueno et al., 1988). Under hypoxic conditions,

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ncreased micromolar concentrations of adenosine stimulate A2eceptors resulting in an increase of cAMP, a second messengerhat is involved in renal EPO production (Fisher, 1988). Pen-oxifylline antagonizes the A2 receptors, so it may produce aeduction in the levels of cAMP and EPO. On the basis ofuch physiologic and pharmacologic evidence, animal studiesere conducted in order to assess the effects of methylxantinesn the polycythemia associated to chronic hypoxia exposure.entoxifylline blunted significantly the hematocrit increase inice when administered prior to exposure to chronic inter-ittent hypobaric hypoxia (Gamboa et al., 1997). The same

esults were not seen when the drug was administered afterice had developed hypoxic polycythemia. We were not able tond randomized clinical trials performed to assess the effects of

heophylline or pentoxifylline in patients with chronic mountainickness. Moreover, the beneficial effects of methylxantines andn particular of theophylline on polycythemia in kidney trans-lanted patients were not confirmed in a recent randomized,pen labeled, crossover trial study (Trivedi and Lal, 2003).

.2.3. Adrenergic blockers and dopaminergic antagonistsThe sympathetic nervous system plays an important role

n the regulation of EPO production in animals exposed toypoxia (Fink and Fisher, 1977). Renal nerve activity facilitatesPO secretion during hypobaric hypoxia through a mechanism

hat involves norepinephrine. Norepinephrine seems to exertts effects by activating either �-adrenergic or �-adrenergiceceptors. Based on this rationale, prazosin, an �-adrenergicntagonist used as an anti-hypertensive drug, was administeredor up to 28 days in mice with eryhtrocytosis resulting from expo-ure to hypobaric hypoxia and in controls, to assess its effects onoth EPO production and the rate of eryhthropoiesis (Izaguirret al., 1994). The drug inhibited the rate of erythropoiesis, aseasured by red blood cell iron59 uptake, with a decrease of

ematocrit from the third day. It also inhibited the oxygen-ependent secretion of EPO. The researchers postulated thathe drug may exert its modulating effects on erythropoiesis byeducing the peripheral vascular resistance seen during hypoxia,roducing an increase of renal blood flow, thus improving theenal oxygen supply, which drives erythropoietin formation. Weid not find any clinical trial in humans to assess prazosin safetynd efficacy in the treatment of CMS.

As it is known that hypoxia also activates the �-adrenergicystem, which stimulates red blood cell production, a non-ontrolled study was performed to assess the effect of adrenergic-receptor inhibition with propranolol on fuid volumes and

he polycythemic response (Grover et al., 1998). The studyas designed to test the hypothesis that altitude polycythemiaight be sustained by increased adrenergic activity. No reduc-

ion in hematocrit or Hb concentration occurred in response to-adrenergic blockade in 11 unacclimatized men exposed to300 m for 3 weeks (Grover et al., 1998). There are not publishedtudies with propranolol in high altitude natives with CMS.

Carotid bodies respond to hypoxia synthesizing and releas-ng several neuromodulators among them dopamine, whichhows an elevated concentration (Peguignot et al., 1987).

odulations of dopaminergic pathways may contribute to the

ipro

& Neurobiology 158 (2007) 251–265 257

ime-dependent changes in ventilation observed during acclima-ization to hypoxia (Tatsumi et al., 1995; Huey et al., 2000a;uey and Powell, 2000). Pre- and post-synaptic dopamine D2

eceptors in the carotid bodies and in the central nervous sys-em modulate the respiratory response to hypoxia (Huey etl., 2000b). Thus domperidone, a D2 dopaminergic antagonisteceptor has been tried in animal and human experiments tossess its effect on ventilation and to test the hypothesis thatlunting of the respiratory response to hypoxia may be due toncreased levels of dopamine (Gamboa et al., 2003a,b; Leon-elarde et al., 2003b).

In the animal experiment, 18 chronically hypoxic rats weretudied with and without domperidone treatment (Gamboa et al.,003a,b). Acute and prolonged treatment significantly increasedoikilocapnic ventilatory response to hypoxia and decreased Hboncentration from 21.6 to 18.9 g/dL. The results suggest that thetimulant effect of D2 receptor blockade on ventilatory responseo hypoxia may compensate the blunted peripheral chemosen-itvity after chronic exposure and this in turn may decrease Hboncentration.

In the human study, domperidone (single oral dose of 40 mg)as administered to five patients with CMS and to five con-

rols without CMS, all high altitude natives and living at 4300 mLeon-Velarde et al., 2003b). A control set of experiments waserformed on 5 native adults at sea level who also received theame single oral dose of domperidone. The slope of isocap-ic ventilation as function of SaO2 increased significantly afteromperidone administration in all three groups. These resultsonfirm the previous findings in chronically hypoxic rats anduggest that domperidone could be assessed in formal clinicalrials for determining its safety and efficacy in the treatment ofMS.

.3. Central or peripheral ventilation stimulants

Since hypoventilation seems to be a prominent pathophysio-ogic feature leading to hypoxemia and eryhtrocytosis in patientsith CMS, agents aimed to stimulate central or peripheral

ontrol of ventilation seem natural candidates for performinglinical studies on their efficacy in CMS.

.3.1. Central stimulants: medroxyprogesteroneKryger et al. performed a randomized-placebo con-

rolled study of the effects of medroxypogesterone acetate20–60 mg/day) in subjects with excessive polycythemia at highltitude (Kryger et al., 1978). Medroxypogesterone is a hormonehat exerts stimulant effects on central control of ventilation.ome patients were treated for up to 5 years. After 10 weeksf treatment, subjects showed improvement of tidal volume andinute ventilation, lowered PaCO2, and raised PaO2 and SaO2,

nd decreased hematocrit that reached values normal for 3100ltitude, as well as virtual elimination of CMS symptoms. Theajor adverse event reported by some patients was decrease of

nterest in sex that is probably related to a reduced androgenroduction. The small sample size of the study did not allow aeliable assessment of clinical outcomes. Although the resultsf this trial are encouraging, the decrease of libido is an impor-

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ant consideration that may have impaired medroxyprogesteronecceptance, as most affected patients are males.

.3.2. Peripheral stimulants: almitrineAlmitrine is a substance that stimulates the aortic and carotid

hemoreceptors (Laubie and Diot, 1972; Laubie and Schmitt,980) and thus a clinical assessment of its possible beneficialffects in patients with CMS was warranted. Two double-blind,lacebo controlled trials were conducted in 40 subjects withematocrit values over 57% living in La Paz (3600–4000 m).hey were reported in a single publication (Villena et al., 1985).he first one aimed at assessing the ventilatory response and

he variation in PaO2 immediately after the acute administra-ion of oral almitrine (3 mg/kg/day) or placebo. Twenty subjectsere randomly assigned to almitrine and 20 subjects to placebo.hree hours later there was a significant increase in PaO2, pHnd respiratory rate, although the increase in ventilation wasot significant. In the second protocol, patients were randomlyssigned to oral almitrine (1 mg/kg/day) for 4 weeks (n = 10) oro placebo (n = 10). Measurements were taken every week. Thereas a slight but significant reduction in hematocrit (−3.5%) in

reated patients, but all the remaining measurements (ventilation,aCO2, pH, oxygen consumption, CO2 production) remainedonstant. The authors implied therefore that the reduction ofematocrit was not due to an increase in diurnal PaO2 but insteado an improvement of pulmonary ventilation during sleep. Thereere not significant side-effects, except for one patient who

eported dyspnea. This complaint was related to a particularlytrong respiratory effect, as the ventilation increased from 7.5 to4.4 L/min in this subject. There is no information on inclusionnd exclusion criteria, on the power of sample size in each pro-ocol, on clinical features of included subjects, on concomitantreatment allowed, and whether or not subjects were randomlyssigned to active treatment or to placebo.

Additional and adequately designed studies of almitrine areeeded before reaching a definitive conclusion on its safety andfficacy in the treatment of CMS. In particular, longer therapeu-ic schemes are needed, including nocturnal assessments of SaO2nd ventilation, along with the evaluation of clinical featuresnd well-being perception of patients, as well as compliancessessment.

. Acetazolamide: a new promising therapeutic agent

.1. Physiological rationale

Carbonic anhydrase was discovered in 1932 (Meldrum andoughton, 1933). Maren defined it as a catalyst in the intercon-ersion between CO2 and H2CO3, or any of its ionic speciesMaren, 1967). Modulation of carbonic anhydrase activity pro-ides a mean to regulate the rate of HCO3

− transport (Sterlingt al., 2001). The family of mammalian carbonic anhydrasesonsists of at least 10 members with both cytosolic forms and
orms with catalytic site anchored to the extracellular surfacef the cell (Geers and Gros, 2000; Kivela et al., 2000). Thenzyme has many physiological roles, including CO2 transport,cid–base regulation, nitrogen metabolism, fluid secretion and
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& Neurobiology 158 (2007) 251–265

bsorption, and ventilatory control and thus when consideringhe physiological effects and clinical implication of the thera-eutic use of an inhibitor of carbonic anhydrase, the ubiquity ofhe enzyme in the body should always be considered (Swenson,998). In the red blood cells the enzyme is strictly cytoplas-ic and its primary role is the modulation of CO2 transport and

xcretion. The process of CO2 transport begins with molecu-ar CO2 diffusing out of the tissues and into the circulation andhen into the red blood cells along its partial pressure gradi-nt. In the red blood cells CO2 is hydrated into bicarbonate andproton; a process catalyzed by carbonic anhydrase (Esbaugh

nd Tufts, 2006). The bicarbonate ion is then shuttled out of theell, while the proton is buffered by either Hb or non-carboniccid buffers. These processes remove both end products of CO2ydration from the red blood cells, allowing a maximal amountf CO2 to be loaded into the blood (Esbaugh and Tufts, 2006).t the respiratory surface, these reactions are reversed and CO2

s eliminated from the body along its partial pressure gradientEsbaugh and Tufts, 2006).

Carbonic anhydrase stimulates the reabsorption of HCO3−

n the proximal tubules of the kidney, an effect that is inhibitedy agents such as acetazolamide (Clapp et al., 1963; Swenson,998). Acetazolamide also produces diuresis, increases cere-ral blood flow, and stimulates ventilation through metaboliccidosis (Swenson, 1998). Acetazolamide has been effective ineducing central apneas in high altitude mountaineers (Hackettt al., 1987; Sutton et al., 1979) or in patients with sleep-relatedreathing disorders at sea level (DeBacker et al., 1995). How-ver, it has never been evaluated in subjects chronically exposedo altitude hypoxia such as those suffering from CMS. More-ver, acetazolamide reduces EPO secretion (Miller et al., 1973;ckardt et al., 1989), either by its inhibitory action on reabsorp-

ion in the proximal tubule of the kidney (Eckardt et al., 1989)r through a rightward shift of the O2-Hb affinity curve dueo acidosis (Miller et al., 1973). For such inhibitory effects onarious biological actions of carbonic anhydrase acetazolamideas therefore a potential therapeutic agent in the treatment ofatients with CMS.

.2. Clinical studies

Acetazolamide has recently been studied in a clinical trial asnew pharmacologic therapy for CMS (Richalet et al., 2005).he working hypothesis of this study was that subjects whoevelop CMS have nocturnal hypoventilation, associated or notith sleep apneas, leading to prolonged or repetitive episodes of

rterial O2 desaturation responsible for an excessive nocturnalroduction of EPO and stimulation of erythropoiesis (Richalet etl., 2005). It was proposed that acetazolamide would reduce EPOroduction principally by stimulating ventilation and reducinghe level of nocturnal hypoxemia, and possibly by an indirectffect on the renal EPO production. This study also aimed atvaluating the efficiency of the treatment, not only by hemat-
crit or serum EPO, but also by serum ferritin, as an index ofvailable iron stores, and serum soluble transferrin receptors, asn index of overall bone marrow erythropoietic activity. It was aandomized, double-blind placebo-controlled study of acetazo-

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amide efficacy and safety in subjects with CMS from Cerroe Pasco, Peru (4300 m). Subjects were randomly assignedo receive daily during 3 weeks either oral placebo (n = 10),50 mg of oral acetazolamide (n = 10), or 500 mg of oral acetazo-amide (n = 10). Acetazolamide decreased hematocrit by 7.1%nd 6.7%, serum erythropoietin by 67% and 50%, and serumoluble transferrin receptors by 11.1% and 3.4%, and increasederum ferritin by 540% and 134%, for groups treated with50 and 500 mg of acetazolamide, respectively. Acetazolamide250 mg) increased nocturnal SaO2 by 5% and decreased meanocturnal heart rate by 11% and the number of apnea–hypopneapisodes during sleep by 74%. All the changes were significantlyifferent. The decrease in erythropoietin was attributed mainlyo the acetazolamide-induced increase in ventilation and SaO2.t was concluded that acetazolamide showed efficacy and safetyn the treatment of CMS. Acetazolamide reduced hypoventi-ation, which may be accentuated during sleep, and bluntedrythropoiesis.

According to the results of this study, it is proposed that theechanisms by which acetazolamide exert its beneficial effect

n subjects with CMS may include at least in part a ventilatorytimulant effect and in part an inhibitory renal effect on EPOroduction, independent of SaO2.

The finding of a decreased resting PETCO2 in CMS patientsho received acetazolamide in the clinical trial we are discussingere reinforce the possibility that the drug exerts a stimulatoryffect on ventilation and that this is the main mechanism, throughhich the drug, at the dose used, is beneficial in patients withMS (Rivera-Ch, M., unpublished). On the other hand, it isnown that EPO is produced by peritubular cells in the kid-ey (Lacombe et al., 1988) and that acetazolamide can inhibitPO production in humans (Miller et al., 1973) and in mice

Eckardt et al., 1989) exposed to hypoxia. It acts specifically onhe proximal tubule by inhibiting sodium reabsorption, whichs the main determinant of renal oxygen consumption. More-ver, serum EPO has been inversely correlated to the level ofenal tissue oxygenation at high altitude (Richalet et al., 1994).hus, by reducing reabsorption activity, acetazolamide would

ocally lower oxygen consumption and increase oxygen pres-ure within the tissue, thereby reducing the hypoxic signal thatriggers EPO production (Eckardt et al., 1989). The acid–basetatus of the subjects showed that acetazolamide had inducedetabolic acidosis that has certainly participated, not only in

he stimulation of ventilation but also in better oxygenation ofenal EPO-producing cells, through a rightward shift of the O2-b affinity curve. The acetazolamide-induced decrease in EPO

ound in the clinical trial could have been limited by a con-omitant decrease in blood volume (Richalet et al., 2005). Theositive effect of the drug on mean nocturnal SaO2 and frequencyistribution of nocturnal SaO2 suggests that nocturnal hypoven-ilation is an important factor contributing to the development ofxcessive erythropoiesis in CMS. Thus this study gives for therst time, not only the potential possibility of mass treatment of
MS but also a significant contribution to its pathophysiology.reathing disturbances during sleep, such as periodic breath-
ng, may contribute to nocturnal desaturation, but do not appearo be determining factors because they were not particularly

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& Neurobiology 158 (2007) 251–265 259

requent in patients with CMS and are not markedly modifiedy acetazolamide. Low ventilatory response to hypoxia in highltitude residents, and especially in patients with CMS, has beendvanced as responsible for this low ventilation (Kryger et al.,978; Severinghaus et al., 1966; Bernardi et al., 2003).

The results of this clinical trial are encouraging. It showseneficial effects in patients with CMS without important side-ffects. Its low cost may allow scaling-up the intervention withubstantial public health impact. There remain, however, severaloints to be addressed in future studies. Sample sizes adequatenough for inferring both primary and secondary endpoints willdd significantly to the strength of evidence. In addition, asMS is a lifelong condition, duration of treatment and follow-upfter discontinuation of the drug should be substantially longer,o as to define clearly whether the best treatment approach isn intermittent, periodic scheme, or a chronic, continuous one.n addition, clinical relevant outcomes need to be taken intoccount, including improvement of symptoms and perceiveduality of life.

. Treatment of chronic high altitude pulmonaryypertension (HAPH)

.1. Pathophysiology

As we pointed out before, chronic high altitude pulmonaryypertension is described in some but not all patients withxcessive polycythemia and CMS, and is characterized by rightentricular enlargement and pulmonary hypertension that canrogress to heart failure and premature death (Maggiorini andeon-Velarde, 2003). This observation suggests that pulmonaryypertension follows a pathophysiologic sequence quite differ-nt from CMS. In fact, there is evidence pointing to increasedulmonary vascular resistance secondary to hypoxia inducedulmonary vasoconstriction and vascular remodeling of pul-onary arterioles (Aldashev et al., 2002; Ge and Helun, 2001;eath, 1989; Heath et al., 1990). Treatment options for pul-onary hypertension are therefore not necessarily the same thatere described for CMS.The structural changes in the pulmonary vasculature that

ccur in subjects with HAPH may be explained at least in party hypoxia associated smooth muscle cell proliferation. Theseeatures along with the increased pulmonary vascular tone rep-esent potential targets for therapeutic intervention (Maggiorinind Leon-Velarde, 2003). The biochemical pathways underly-ng HAPH are poorly understood, but modifications of nitricxide synthesis, metabolism and effects may have a role. Innimal studies the absence of endothelial nitric oxide synthasencreases susceptibility to this condition (Fagan et al., 2000). Ofote, it has been shown that indigenous Tibetans acclimatisedo life at 3600 m have two-fold higher nitric oxide concentra-ions in exhaled breath than lowlanders (Beall et al., 2001), andnhaled nitric oxide has been shown to have beneficial effects
n pulmonary hemodynamics in HAPH (Anand et al., 1998).itric oxide is a potent vasorelaxant and has also antiprolif-
rative effects which are mediated by cyclic GMP (Ignarro etl., 1999). Cyclic GMP is hydrolysed by phosphodiesterases

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PDE). PDE5 is the major PDE subtype present in pulmonaryasculature and is more abundant in the lung than in other tissuesThomas et al., 1990). These observations offered the possibil-ty of relatively selective pulmonary vasodilatation with littleystemic hypotension. In fact, it was observed that agents withDE5 inhibitory activity reduce pulmonary artery pressure innimal models (Itoh et al., 2004; Sebkhi et al., 2003; Schermulyt al., 2004).

.2. Clinical studies

A randomized, double blind, placebo-controlled trial for eval-ating the effects of sildenafil in subjects living above 2500 mith HAPH has been published recently (Aldashev et al., 2005).ildenafil is a PDE5 inhibitor. In this study, eligible patientsere randomized to receive sildenafil, 25 or 100 mg, or match-

ng placebo every 8 h for 12 weeks. The primary endpoint was thehange in mean pulmonary arterial pressure (Ppa) from baselineweek 0) after 12 weeks of treatment. There was a statisticallyignificant difference between the three groups in changes fromaseline to week 12 in mean Ppa measured 8–10 h post-dose.lso, both doses of sildenafil improved exercise capacity andhysical symptom score. Sildenafil was well tolerated. Necro-copic lung specimens from three subjects with HAPH showedbundant PDE5 in the muscular coat of remodelled pulmonaryrterioles. The authors concluded that PDE5 is an attractive drugarget for the treatment of HAPH and a larger study of the long-erm effects of PDE5 inhibition in HAPH is warranted (Aldashevt al., 2005).

Eligible subjects for this study had to be transferred to theeferral facility located at 760 m to undergo cardiac catheteri-ation and thus one can wonder whether the Ppa measurementst this low altitude reflected accurately the high altitude values,lthough the authors argue that untreated increased pulmonaryrterial pressure remains high for several days after removal fromigh altitude setting, as it has been verified in animals (Sebkhi etl., 2003). In addition, only one in four subjects with electrocar-iographic evidence of right ventricular hyperthrophy acceptedr were able to travel the distance to the hospital for protocoltudies and only 22 patients were able to repeat the hospital vis-ts required for the sildenafil component of the study. Thus thetudy was underpowered to assess the full potential of sildenafiln HAPH and to explore the dose–response relationship. How-ver, sildenafil has several characteristics that make it attractiveor future larger clinical trials. It has a selective effect on pul-onary arteries, has little effect on systemic blood pressure, and

t is well tolerated.Nifedipine is a calcium channel-blocker that has been used

n subjects suffering from high altitude pulmonary edemaBartsch et al., 1991), primary pulmonary hypertension (Richnd Brundage, 1987) or pulmonary hypertension secondary tohronic obstructive pulmonary disease (Simoneau et al., 1981;ajkov et al., 1993).

There are no published randomized controlled studies ofalcium channel-blockers in patients with HAPH. In a non-andomized comparative study, systolic pulmonary arterialressure (Ppa) was studied by Doppler echocardiography, at rest

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& Neurobiology 158 (2007) 251–265

nd after sublingual nifedipine, in 31 asymptomatic residentst 3600 m (Antezana et al., 1998). Individuals were separatednto two groups with high and low Ppa. Individuals were alsoplit into two groups according to Hb concentration: those withormal Hb values for the altitude of residence and those withbnormally high Hb values (above 18 g/dL). No significant dif-erence in Ppa was observed between the low-Hb and high-Hbroups. Nifedipine induced a decrease of >20% in Ppa in two-hirds of the subjects. This response was correlated with higherevels of basal Ppa and was inversely correlated with age inhe low-Hb group. Also, pulmonary vasoreactivity to nifedipineas independent of the degree of Hb. The authors concluded

hat mild to moderate pulmonary hypertension secondary tohronic altitude hypoxia may be reversible, despite a possibleemodelling of the pulmonary arterioles. They suggest that thisntervention could possibly prevent the progression of the pul-onary hypertension to heart failure. Limiting factors for an

xtended use of calcium antagonists include the fact that theyave to be given in relatively high doses for obtaining an effectn pulmonary artery pressure, lack specificity for the pulmonaryascular bed and side effects such as ankle edema are quiterequent (Hackett and Roach, 2001; Rich et al., 1992).

Acetazolamide has been used for decades as the drug ofhoice for preventing and treating acute mountain sicknessAMS) and very recently has shown encouraging effects inatients with CMS, as it was discussed before. Preclinical animalnd human studies done in the 1950s had revealed that acetazo-amide was a moderate respiratory stimulant and that it exerts thisffect through the inhibition of renal carbonic anhydrase and theeneration of a mild metabolic acidosis secondary to an inhib-ted renal reabsorption of bicarbonate (Maren, 1967). The firsteport of hypoxic pulmonary vasoconstriction (HPV) inhibitiony acetazolamide was by Emery et al. (1977) in a study focusedn the effects of hypercapnia on hypoxia and the pulmonary cir-ulation. It was reported in this study that acetazolamide causedartial inhibition of HPV in the isolated perfused lung. Thisnding of a carbonic anhydrase inhibitor effect on a processot thought to involve acid–base exchange or a pH transductionignal went wholly unrecognized. As carbonic anhydrase wasiscovered in many other tissues beyond the red cell and kid-ey, this ventilatory stimulation was also demonstrated to be aonsequence of vascular endothelial and central chemoreceptorarbonic anhydrase inhibition (Swenson, 1998). In a comprehen-ive review on carbonic anhydrase inhibitors and HPV, evidences presented on the hypoxic response of the pulmonary circula-ion that may be useful in different conditions having HPV as

prominent pathogenic event (Swenson, 2006). Such condi-ions include high altitude pulmonary edema and high altitudeerebral edema, considered extremely severe forms or varia-ions of AMS, HAPH, and primary pulmonary hypertension.here are consistent data from pulmonary artery smooth muscleells, isolated perfused lungs, and live unanesthetized animalsll pointing to a potent reduction in HPV by acetazolamide. It is
xtremely interesting that the efficacy of acetazolamide as a HPVnhibitor does not appear to be related to carbonic anhydrasenhibition, since other potent carbonic anhydrase inhibitors haveo effect on HPV (Swenson, 2006). Thus, besides its established

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ffect in AMS and its potentially beneficial role in treatmentf CMS, the effects of acetazolamide on chronic HAPH alsoeserve to be assessed.

. Is it time for a shift to a preventive approach?

Obesity and chronic respiratory diseases seem to increasehe risk of developing CMS and the severity of the conditionLeon-Velarde and Arregui, 1994; Leon-Velarde et al., 1994).ddressing risk and aggravating factors for CMS seems a plau-

ible and potentially beneficial preventive approach for reducinghe burden of disease due to CMS. Although insufficientlytudied to date, factors amenable to preventive public healthnterventions include westernized lifestyles such as sedentaryife, unhealthy feeding habits, heavy alcohol consumption andmoking, as well as obesity, chronic respiratory conditions, andnvironmental and indoor pollution. Comparative studies tak-ng into account these and other contextual factors are neededo better define the burden of disease, time-course and sever-ty of CMS in different populations. In particular, comparisonsf populations living in areas relatively free of environmentalontamination such as mining activity with those living in highltitude settings relatively free of such contaminants are war-anted. Surveillance of health impact resulting from correctivenvironmental interventions in mining cities and other settingsith high prevalence of risk and modifying factors is neces-

ary, particularly for assessing changes in aspects related to highltitude related diseases such as CMS. Advocating intermittentxposure for high altitude residents susceptible of developingMS and particularly for those working in mining settlementsay reduce the negative effects of chronic hypoxia. Also, if

arly exposure to chronic hypoxia demonstrates to be associ-ted with an increased risk of CMS or other clinical expressionsf maladaptation later during adulthood, then there would be arospect for additional preventive measures during pregnancynd infancy.

. Conclusions

There is not yet a safe and effective therapeutic approach toMS for massive use. Descent to low altitudes is not accept-ble because of its disrupting effects on family life and on workpportunities. Blood-letting has been reported to decrease onlyransiently blood red cell mass, there are cultural barriers tots massive use, and it is unacceptably invasive. Pharmacologiclockade of erythropoiesis by agents such as methylxantines istill in an experimental phase, and �- and �-adrenergic agentsave been only preliminary tested. Medroxypogesterone coulde used in older affected women, but it is unacceptable for mostale patients. Stimulants of peripheral chemoreceptors such

s almitrine have been tried only in one limited randomizedontrolled study and thus they need further clinical trials. Aceta-olamide and ACE inhibitors are promising therapies, but before
dvocating their massive use there are remaining issues that needo be solved in future larger trials. Use of standard definitions ofMS such as the recent consensus definition (Leon-Velarde etl., 2005) will also improve comparability of studies.
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& Neurobiology 158 (2007) 251–265 261

Sildenafil and other agents whose effects are mediated inome way via modification of nitric oxide pathway are aimedainly to reduction of the pulmonary artery pressure, which will

ot necessarily have beneficial effects in patients with excessiveolycythemia and CMS.

Finally, the importance of changing the current paradigm tone that privileges preventive interventions cannot be overem-hasized. However, before health policy interventions based onound evidence are scaled-up, further systematic studies on theole of risk and modifying factors of CMS are needed.

cknowledgment

MSc. Adolfo Castillo polished up the grammar of formerersions of the manuscript and provided useful comments.

eferences

ldashev, A.A., Sarybaev, A.S., Sydykov, A.S., Kalmyrzaev, B.B., Kim, E.V.,Mamanova, L.B., Maripov, R., Kojonazarov, B.K., Mirrakhimov, M.M.,Wilkins, M.R., Morrell, N.W., 2002. Characterization of high altitudepulmonary hypertension in the Kyrgyz: association with angiotensincon-verting enzyme genotype. Am. J. Respir. Critl. Care. Med. 66, 396–402.

ldashev, A.A., Kojonazarov, B.K., Amatov, T.A., Sooronbaev, T.M., Mir-rakhimov, M.M., Morrell, N.W., Wharton, J., Wilkins, M.R., 2005.Phosphodiesterase type 5 and high altitude pulmonary hipertension. Thorax60, 683–687.

nand, I.S., Prasad, B.A.K., Chugh, S.S., Rao, K.R.M., Cornfield, D.N., Milla,C.E., Singh, N., Singh, S., Selvamurthy, W., 1998. Effects of inhalednitric oxide and oxygen in high-altitude pulmonary edema. Circulation 98,2441–2445.

nand, I.S., Wu, T., 2004. Syndromes of subacute mountain sickness. High Alt.Med. Biol. 5, 156–170.

ntezana, A.M., Antezana, G., Aparicio, O., Noriega, I., Velarde, F.L., Richalet,J.P., 1998. Pulmonary hypertension in high-altitude chronic hypoxia:response to nifedipine. Eur. Respir. J. 12, 1181–1185.

tkins, D., Best, D., Briss, P.A., Eccles, M., Falck-Ytter, Y., Flottorp, S., Guy-att, G.H., Harbour, R.T., Haugh, M.C., Henry, D., Hill, S., Jaeschke, R.,Leng, G., Liberati, A., Magrini, N., Mason, J., Middleton, P., Mrukowicz, J.,O’Connell, D., Oxman, A.D., Phillips, B., Schunemann, H.J., Edejer, T.T.,Varonen, H., Vist, G.E., Williams, J.W., Zaza, S., GRADE Working Group,2004. Grading quality of evidence and strength of recommendations. Br.Med. J. 328, 1490.

zizi, M., Rousseau, A., Ezan, E., Guyene, T.T., Michelet, S., Grognet, J.M.,Lenfant, M., Corvol, P., Menard, J., 1996. Acute angiotensin-convertingenzyme inhibition increases the plasma level of the natural stem cell regulatorN-acetyl-seryl-aspartyl-lysyl-proline. J. Clin. Invest. 97, 839–844.

acher, A., Eggensperger, E., Koppensteiner, R., Mayer, N., Klimscha, W.,2005. Pentoxifylline attenuates the increase in whole blood viscosity aftertransfusion. Acta Anaesthesiol. Scand. 49, 41–46.

akris, L., Sauter, E.R., Hussey, J.L., Fisher, J.W., Gaber, A.O., Winstt, R., 1990.Effects of theophylline on erythropoietin production in normal subjects andin patients with erythrocytosis after renal transplantation. N. Engl. J. Med.323, 86–90.

ainton, C.R., Carcelen, A., Severinghaus, J.W., 1964. Carotid chemoreceptorinsensitivity in Andean natives. J. Physiol. 177, 30–31.

arenbrock, M., Spieker, C., Rahn, K.H., Zidek, W., 1993. Therapeutic
efficiency of phlebotomy in posttransplant hypertension associated witherythrocytosis. Clin. Nephrol. 40, 241–243.
artsch, P., Maggiorini, M., Rittert, M., Noti, C., Vock, P., Oelz, O., 1991.Prevention of high pulmonary oedema by nifedipine. N. Engl. J. Med. 325,1284–1289.

2 iology

B

B

B

B

B

B

B

B

B

B

C

C

C

C

C

C

D

D

E

E

EE

F

F

F

F

F

G

G

G

G

G

G

G

G

G

G

G

H

H

H

H

HH


eall, C.M., 2000. Oxygen saturation increases during childhood anddecreases during adulthood among high altitude native Tibetans residingat 3800–4200 m. High Alt. Med. Biol. 1, 25–32.

eall, C.M., 2006. Andean, Tibetan, and Ethiopian patterns of adaptation tohigh-altitude hypoxia. Integr. Comp. Biol. 46, 18–24.

eall, C.M., Blangero, J., Williams-Blangero, S., Goldstein, M.C., 1994. Amajor gene for percent of oxygen saturation of arterial hemoglobin in Tibetanhighlanders. Am. J. Phys. Anthropol. 95, 271–276.

eall, C.M., Decker, M.J., Brittenham, G.M., Kushner, I., Gebremedhin, A.,Strohl, K.P., 2002. An Ethiopian pattern of human adaptation to high-altitudehypoxia. Proc. Nat. Acad. Sci. U.S.A. 99, 17215–17218.

eall, C.M., Laskowski, D., Strohl, K.P., Soria, R., Villena, M., Vargas, E.,Alarcon, A.M., Gonzales, C., Erzurum, S.C., 2001. Pulmonary nitric oxidein mountain dwellers. Nature 414, 411–412.

eall, C.M., Strohl, K., Blangero, J., Williams-Blangero, S., Brittenham, G.M.,Goldstein, M.C., 1997. Quantitative genetic analysis of arterial oxygen sat-uration in Tibetan highlanders. Hum. Biol. 69, 597–604.

eall, C.M., Song, K., Elston, R.C., Goldstein, M.C., 2004. Higher offspring sur-vival among Tibetan women with high oxygen saturation genotypes residingat 4000 m. Proc. Nat. Acad. Sci. 101, 14300–14304.

ernardi, L., Roach, R.C., Keyl, C., Spicuzza, L., Passino, C., Bonfichi, M.,Gamboa, A., Gamboa, J., Malcovati, L., Schneider, A., Casiraghi, N., Mori,A., Leon-Velarde, F., 2003. Ventilation, autonomic function, sleep and ery-thropoietin: chronic mountain sickness of Andean natives. Adv. Exp. Med.Biol. 543, 161–175.

orsook, H., Graybiel, A., Keighley, G., Windsor, E., 1954. Polycythemicresponse in normal adult rats to a non protein plasma extract from anemicrabbits. Blood 9, 734–742.

ourgoignie, J.J., Gallagher, N.I., Perry Jr., H.M., Kurz, L., Warnecke, M.A.,Donati, R.M., 1968. Renin and erythropoietin in normotensive and in hyper-tensive patients. J. Lab. Clin. Med. 71, 523–536.

lapp, J.R., Watson, J.F., Berliner, R.W., 1963. Effect of carbonic anhydraseinhibition on proximal tubular bicarbonate reabsorption. Am. J. Physiol.205, 693–696.

laydon, V.E., Norcliffe, L.J., Moore, J.P., Rivera, M., Leon-Velarde, F., Appen-zeller, O., Hainsworth, R., 2005. Cardiovascular responses to orthostaticstress in healthy altitude dwellers, and altitude residents with chronic moun-tain sickness. Exp. Physiol. 90, 103–110.

ole, J., Ertoy, D., Lin, H., Sutliff, R.L., Ezan, E., Guyene, T.T., Capecchi, M.,Corvol, P., Bernstein, K.E., 2000. Lack of angiotensin II-facilitated erythro-poiesis causes anemia in angiotensin converting enzyme-deficient mice. J.Clin. Invest. 106, 1391–1398.

ommission on Global Advancement of Nephrology (COMGAN), ResearchSubcommittee of the International Society of Nephrology, 2002.Angiotensin-converting-enzyme inhibition therapy in altitude poly-cythaemia: a prospective randomised trial. Lancet 359, 663–666.

ongote, L.F., Brox, A., Lin, F.K., Lu, H.S., Fauser, A.A., 1991. The N-terminalsequence of the major erythropoietic factor of an anephric patient is identicalto insulin-like growth factor 1. J. Clin. Endocrinol. Metab. 72, 727–729.

ruz, J.C., Diaz, C., Marticorena, E., Hilario, V., 1979. Phleobotomy improvespulmonary gas exchange in chronic mountain polycythemia. Respiration 38,305–313.

ainiak, N., Spielvogel, H., Sorba, S., Cudkowicz, L., 1989. Erythropoietinand the polycythemia of high-altitude dwellers. Adv. Exp. Med. Biol. 271,17–21.

eBacker, W.A., Verbraecken, J., Willemen, M., Wittesaele, W., DeCook,W., Van de Heyning, P., 1995. Central apnea index decreases after pro-longed treatment with acetazolamide. Am. J. Respir. Crit. Care Med. 151,87–91.

ckardt, K.U., Kurtz, A., Bauer, C., 1989. Regulation of erythropoietin produc-tion is related to proximal tubular function. Am. J. Physiol. 256, F942–F947.

mery, C.J., Sloan, P.J., Mohammed, F.H., Barer, G.R., 1977. The action ofhypercapnia during hypoxia on pulmonary vessels. Bull. Eur. Physiopath.
Respir. 13, 763–776.
rslev, A., 1953. Humoral regulation of red cell production. Blood 8, 349–357.sbaugh, A.J., Tufts, B.L., 2006. The structure and function of carbonic anhy-

drase isozymes in the respiratory system of vertebrates. Respir. Physiol.Neurobiol. 154, 185–198.

H

H

& Neurobiology 158 (2007) 251–265

agan, K.A., McMurtry, I., Rodman, D.M., 2000. Nitric oxide synthase inpulmonary hypertension: lessons from knockout mice. Physiol. Res. 49,539–548.

ine, L.G., Bandyopadhay, D., Norman, J.T., 2000. Is there a common mech-anism for the progression of different types of renal diseases other thanproteinuria? Towards the unifying theme of chronic hypoxia. Kidney Int. 75(Suppl.), S22–S26.

ink, G.D., Fisher, J.W., 1977. Role of the sympathetic nervous system in thecontrol of erythropoietin production. In: Fisher, J.W. (Ed.), Kidney Hor-mones, vol. II. Erythropoietin. Academic Press, London, pp. 387–413.

isher, J.W., 1988. Pharmacologic modulation of erythropoietin production.Annu. Rev. Pharmacol. Toxicol. 28, 101–122.

risancho, A.R., 1988. Origins of differences in hemoglobin concentrationbetween Himalayan and Andean populations. Respir. Physiol. 72, 13–18.

aciong, Z., Koziak, K., Jarzylo, I., Ludwicki, K., Malanowska, S., Paczek, L.,Szmidt, J., Walaszewski, J., Lao, M., 1996. Erythropoietin production afterkidney transplantation. Ann. Transplant. 1, 29–33.

amboa, A., Leon-Velarde, F., Rivera-Ch, M., Palacios, J.A., Pragnell, T.R.,O’Connor, D.F., Robbins, P.A., 2003a. Acute and sustained ventilatoryresponses to hypoxia in high-altitude natives living at sea level. J. Appl.Physiol. 94, 1255–1262.

amboa, J., Macarlupu, J.L., Rivera-Chira, M., Monge-C, C., Leon-Velarde, F.,2003b. Effect of domperidone on ventilation and polycythemia alter 5 weeksof chronic hypoxia in rats. Respir. Physiol. Neurobiol. 135, 1–8.

amboa, J., Rivera-Ch, M., Leon-Velarde, F., Salazar, M., Monge-C, C., 1997.Pentoxifillyne and enalapril and its effects on polycythemia induced byhypobaric hypoxia in mice. Acta Andina (Lima) 6, 5–10.

aston, R.S., Julian, B.A., Curtis, J.J., 1994. Post transplant erythrocytosis: anenigma revisited. Am. J. Kidney Dis. 24, 1–11.

eers, C., Gros, G., 2000. Carbon dioxide transport and carbonic anhydrase inblood and muscle. Physiol. Rev. 80, 681–715.

e, R.L., Helun, G., 2001. Current concept of chronic mountain sickness:pulmonary hypertension–related high-altitude heart disease. WildernessEnviron. Med. 12, 190–194.

licklich, D., Burris, L., Urban, A., Tellis, V., Greenstein, S., Schechner, R.,Devarajan, P., Croizat, H., 2001. Angiotensin-converting enzyme inhibitioninduces apoptosis in erythroid precursors and affects insulin-like growthfactor-1 in posttransplantation erythrocytosis. J. Am. Soc. Nephrol. 12,1958–1964.

ordon, A., Piliero, S.S.J., Kleinberg, W., Freedman, H.H., 1954. A plasmaextract with erythropoietic activity. Proc. Sot. Exp. Biol. Med. 86, 255–258.

rover, R.F., Selland, M.A., McCullough, R.G., Dahms, T.E., Wolfel, E.E.,Butterfield, G.E., Reeves, T.E., Greenleaf, J.E., 1998. �-adrenergic blockadedoes not prevent polycythaemia or decrease in plasma volume in men at4300 m altitude. Eur. J. Appl. Physiol. Occup. Physiol. 77, 264–270.

upta, M., Miller, B.A., Ahsan, N., Ulsh, P.J., Zhang, M.Y., Cheung, J.Y., Yang,H.C., 2000. Expression of angiotensin II type 1 receptor on erythroid pro-genitors of patients with post transplant erythrocytosis. Transplantation 70,1188–1194.

ackett, P.H., Roach, R.C., Harrison, G.L., Schoene, R.B., Mills Jr., W.J., 1987.Respiratory stimulants and sleep periodic breathing at high altitude. Am.Rev. Respir. Dis. 135, 896–898.

ackett, P.H., Roach, R.C., 2001. High-altitude illness. N. Engl. J. Med. 345,107–114.

ainsworth, R., Dirnkhill, M.J., Rivera-Ch, M., 2007. The autonomic nervoussystem at high altitude. Clin. Auton. Res. 17, 13–19.

arbour, R., Miller, J., 2001. A new system for grading recommendations inevidence based guidelines. BMJ 323, 334–336.

eath, D., 1989. Missing link from Tibet. Thorax 44, 981–983.eath, D., Williams, D., Rios-Dalenz, J., Calderon, M., Gosney, J., 1990. Small

pulmonary arterial vessels of Aymara Indians from the Bolivian Andes.Histopathology 6, 565–571.

ochachka, P.W., 1986. Defense strategies against hypoxia and hypothermia.Science 231, 234–241.

ochachka, P., Gunga, H.C., Kirsch, K., 1998. Our ancestral physiological phe-notype: and adaptation for hypoxia tolerance or for endurance performance?Proc. Natl. Acad. Sci. 95, 1915–1920.

ology

H

H

H

H

H

I

I

I

J

J

K

K

K

L

L

L

L

L

L

L

L

L

L

L

L

L

L

L

M

M

M

M

M

M

M

M

M

M

M

M

M

M

M

N

O


odgson, G., Toha, J., 1954. The eryhtropoietic effect of urine and plasma ofrepeatedly bled rabbits. Blood 9, 299–309.

udgson, P., Pearce, J.M., Yeates, W.K., 1967. Renal artery stenosis with hyper-tension and high haematocrit. Br. Med. J. 1, 18–21.

uey, K.A., Low, M.J., Kelly, M.A., Juarez, R., Szewezak, J.M., Powell, F.L.,2000a. Ventilatory responses to acute and chronic hypoxia in mice: effectsof dopamine D(2) receptors. J. Appl. Physiol. 89, 1142–1150.

uey, K.A., Brown, I.P., Jordan, M.C., Powell, F.L., 2000b. Changes in dopamineD2-receptor modulation of the hypoxic ventilatory response with chronichypoxia. Respir. Physiol. 123, 177–187.

uey, K.A., Powell, F.L., 2000. Time dependent changes in dopamine D2-mRNA in the arterial chemoreflex pathway with chronic hypoxia. BrainRes. Mol. 75, 264–270.

gnarro, L.J., Cirino, G., Casini, A., Napoli, C., 1999. Nitric oxide as a signalingmolecule in the vascular system: an overview. J. Cardiovasc. Pharmacol. 34,879–886.

toh, T., Nagaya, N., Fujii, T., Iwase, T., Nakanishi, N., Hamada, K., Kangawa,K., Kimura, H., 2004. A combination of oral sildenafil and beraprost ame-liorates pulmonary hypertension in rats. Am. J. Respir. Crit. Care Med. 169,34–38.

zaguirre, V., Vargas, M., Leon-Velarde, F., Huicho, L., Monge, C., Barcelo,A.C., Alippi, R.M., Bozzini, C.E., 1994. Inhibitory effect of an alpha 1-adrenergic antagonist on erythropoiesis in normoxic or hypoxic mice. Int. J.Clin. Lab. Res. 24, 213–216.

acobson, L.O., Goldwasser, E., Fried, W., Plzak, L., 1957. Role of the kidneyin erythropoiesis. Nature 79, 633–634.

elkmann, W., 1992. Erythropoietin, structure, control of production, and func-tion. Physiol. Rev. 72, 449–489.

ivela, A., Parkkila, S., Saarnio, J., Karttunen, T.J., Kivela, J., Parkkila, A.K.,Waheed, A., Sly, W.S., Grubb, J.H., Shah, G., Tureci, O., Rajaniemi, H.,2000. Expression of a novel transmembrane carbonic anhydrase isozyme XIIin normal human gut and colorectal tumors. Am. J. Pathol. 156, 577–584.

lein, H.G., 1983. Isovolemic hemodilution in high-altitude polycythemia. In:Proceedings of the International Symposium on Acclimatization, Adapta-tion, and Tolerance to High Altitude. US Department of Health and HumanServices, pp. 47–51.

ryger, M., McCullough, R.E., Collins, D., Scoggin, C.H., Weil, J.V., Grover,R.F., 1978. Treatment of excessive polycythemia of high altitude with res-piratory stimulant drugs. Am. Ver. Respir. Dis. 117, 455–464.

abeeuw, M., Prost, N.F., Daoud, S., Lapra, C., Zech, P., Pozet, N., 1992. Renalvenous erythropoietin concentrations in hypertensive patients with unilateralrenal disease. Nephrol. Dial. Transplant. 7, 1190–1193.

acombe, C., Da Silva, J.L., Bruneval, P., Fournier, J.G., Wendling, F., Casade-vall, N., Camilleri, J.P., Bariety, J., Varet, B., Tambourin, P., 1988. Peritubularcells are the site of erythropoietin synthesis in the murine hypoxic kidney.J. Clin. Invest. 81, 620–623.

amperi, S., Carozzi, S., 1985. Erythroid progenitor growth in erythrocytosictransplant patients. Artif. Organs 9, 200–204.

aubie, M., Diot, F., 1972. Etude pharmacologique de l’action stimulante duVectarion. Role des chemorecepteurs carotidiens et aortiques. J. Pharmacol.3, 363–374.

aubie, M., Schmitt, H., 1980. Long lasting hyperventilation induced byalmitrine: evidence for a specific effect on carotid and thoracic chemore-ceptors. Eur. J. Pharmacol. 61, 125–136.

eon-Velarde, F., Arregui, A., 1994. Desadaptacion a la Vida en lasGrandes Alturas. Instituto Frances de Estudios Andinos/Universidad Peru-ana Cayetano Heredia, Lima.

eon-Velarde, F., Arregui, A., Vargas, M., Huicho, L., Acosta, R., 1994. Chronicmountain sickness and chronic lower respiratory tract infections. Chest 106,151–155.

eon-Velarde, F., Arregui, A., Monge-C, C., Ruiz, H., 1993. Ageing at highaltitude and the risk of chronic mountain sickness. J. Wilderness Med. 4,183–188.

eon-Velarde, F., 1993. La enfermedad de Monge enfoque multifactorial. In:Leon-Velarde, F., Arregui, A. (Eds.), Hipoxia: Investigaciones Basicas yClinicas. IFEA, Lima, Peru, pp. 283–295.

eon-Velarde, F., 2003. Pursuing international recognition of chronic mountainsickness. High Alt. Med. Biol. 4, 256–259.

O

& Neurobiology 158 (2007) 251–265 263

eon-Velarde, F., Gamboa, A., Rivera-Ch, M., Palacios, J.A., Robbins, P.A.,2003a. Peripheral chemoreflex function in high-altitude natives and patientswith chronic mountain sickness. J. Appl. Physiol. 94, 1269–1278.

eon-Velarde, F., Gamboa, J., Gamboa, A., Rivera-Ch, M., Macarlupu, J.L.,Monge-C, C., 2003b. Domperidone: a possible strategy for chronic mountainsickness therapy. In: Viscor, G., Ricart, A., Leal, C. (Eds.), Health and Height.Publicacions de la Universitat de Barcelona, Barcelona, pp. 57–65.

eon-Velarde, F., Maggiorini, M., Reeves, J.T., Aldashev, A., Asmus, I.,Bernardi, L., Ge, R.L., Hackett, P., Kobayashi, T., Moore, L.G., Penaloza, D.,Richalet, J.P., Roach, R., Wu, T., Vargas, E., Zubieta-Castillo, G., Zubieta-Calleja, G., 2005. Consensus statement on chronic and subacute high altitudediseases. High Alt. Med. Biol. 6, 147–157.

eon-Velarde, F., Monge-C, C., Vidal, A., Carcagno, M., Criscuolo, M.,Bozzini, C.E., 1991. Serum immunoreactive erythropoietin in high altitudenatives with and without excessive erythrocytosis. Exp. Hematol. 19, 257–260.

in, C.P., Wu, T.Y., 1974. Clinical analysis of 286 cases of pediatric high altitudeheart diseases. Chin. Med. J. 54 (Eng. Suppl. to No. 6), 99–100.

aggiorini, M., Leon-Velarde, F., 2003. High-altitude pulmonary hyperten-sion: a pathophysiological entity to different diseases. Eur. Respir. J. 22,1019–1025.

anier, G., Guenard, H., Castaing, Y., Varene, N., Vargas, E., 1988. Pulmonarygas exchange in Andean natives with excessive polycythemia–effect ofhemodilution. J. Appl. Physiol. 65, 2107–2117.

aren, T.H., 1967. Carbonic anhydrase: chemistry, physiology, and inhibition.Physiol. Rev. 47, 595–781.

eldrum, N.U., Roughton, F.J.W., 1933. Carbonic anhydrase: Its preparationand properties. J. Physiol. (Lond.) 80, 113–142.

iller, M.E., Rorth, M., Parving, H.H., Howard, D., Reddington, I., Valeri, C.R.,Stohlman Jr., F., 1973. pH effect on erythropoietin response to hypoxia. N.Engl. J. Med. 288, 706–710.

iyake, T., Kung, C.K.I.I., Goldwasser, E., 1977. Purification of human ery-thropoietin. J. Biol. Chem. 252, 5558–5564.

onge-M, C., 1925. Sobre un caso de enfermedad de Vaques (Sındromeertitremico de altura). Comunicacion presentada a la Academia nacionalde Medicina. Sanmarti, Lima.

onge, C., 1978. Acclimatization in the Andes, Reissued 1948 edition. TheJohn Hopkins Press, Baltimore.

onge-C, C., Arregui, A., Leon-Velarde, F., 1992. Pathophysiology and epi-demiology of chronic mountain sickness. Int. J. Sports Med. 13, S79–S81.

onge-C, C., Lozano, R., Whittembury, J., 1966. Effect of blood-letting onchronic mountain sickness. Nature 207, 770.

onge-M, C., Monge-C, C., 1966. High altitude diseases: mechanism andmanagement. Charles C. Thomas, Sprienfield, II.

ontanaro, D., Gropuzzo, M., Boscutti, G., Risaliti, A., Bresadola, F., Mioni,G., 2000. Long-term therapy for postrenal transplant erythrocytosis withACE inhibitors: efficacy, safety and action mechanisms. Clin. Nephrol. 53,47–51.

oore, J.P., Claydon, V.E., Norcliffe, L.J., Rivera-Ch, M.C., Leon-Velarde, F.,Appenzeller, O., Hainsworth, R., 2006. Carotid baroreflex regulation of vas-cular resistance in high-altitude Andean natives with and without chronicmountain sickness. Exp. Physiol. 91, 907–913.

orrone, L.F., Di Paolo, S., Logoluso, F., Schena, A., Stallone, G., Giorgino, F.,Schena, F.P., 1997. Interference of angiotensin-converting enzyme inhibitorson erythropoiesis in kidney transplant recipients: role of growth factors andcytokines. Transplantation 64, 913–918.

rug, M., Stopka, T., Julian, B.A., Prchal, J.F., Prchal, J.T., 1997. Angiotensin IIstimulates proliferation of normal early erythroid progenitors. J. Clin. Invest.100, 2310–2314.

ormand, H., Vargas, E., Bordachar, J., Benoit, O., Raynaud, J., 1992. Sleepapneas in high altitude residents (3800 m). Int. J. Sports Med. 13, S40–S42.

noyama, K., Sanai, T., Motomura, K., Fujishima, M., 1989. Worsening ofanemia by angiotensin converting enzyme inhibitors and its prevention by
antiestrogenic steroid in chronic hemodialysis patients. J. Cardiovasc. Phar-macol. 13 (Suppl. 3), S27–S30.
noyama, K., Sanai, T., Motomura, K., Fujishima, M., 1995. Renin-angiotensinsystem stimulates erythropoietin secretion in chronic hemodialysis patients.Clin. Nephrol. 43, 53–59.

2 iology

O

P

P

P

P

P

R

R

R

R

R

R

R

R

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

T

T

T

T

U

V

V

V

V


ymak, O., Demiroglu, H., Akpolat, T., Erdem, Y., Yasavul, U., Turgan, C.,Caglar, S., Dundar, S., Kirazli, S., 1995. Increased erythropoietin responseto venesection in erythrocytosic renal transplant patients. Int. Urol. Nephrol.27, 223–227.

eguignot, J.M., Cottet-Emard, J.M., Dalmaz, Y., Peyrin, L., 1987. Dopamineand norepinephrine dynamics in rat carotid body during long-term hypoxia.J. Auton. Nerv. Syst. 21, 9–14.

enaloza, D., Sime, F., 1971. Chronic cor pulmonale due to loss of altitudeacclimatization (chronic mountain sickness). Am. J. Med. 50, 728–743.

enaloza, D., Sime, F., Ruiz, L., 1971. Cor pulmonale in chronic mountain sick-ness: present concept of Monge’s disease. In: Porter, R., Knight, J. (Eds.),High Altitude Physiology: Cardiac and Respiratory Aspects. Churchill Liv-ingstone, Edinburgh, pp. 41–60.

erazella, M.A., Bia, M.J., 1993. Posttransplant erythrocytosis: case reportand review of newer treatment modalities. J. Am. Soc. Nephrol. 3, 1653–1659.

orter, J.M., Cutler, B.S., Lee, B.Y., Reich, T., Reichle, F.A., Scogin, J.T.,Strandness, D.E., 1982. Pentoxifylline efficacy in the treatment of intermit-tent claudication: multicenter controlled double-blind trial with objectiveassessment of chronic occlusive arterial disease patients. Am. Heart J. 104,66–72.

eeves, J.T., Weil, J.V., 2001. Chronic mountain sickness: a view from the crow’snest. In: Roach, R.C., Wagner, P.D., Hackett, P.H. (Eds.), Hypoxia: FromGenes to the Bedside. Kluwer Academic/Plenum Publishers, New York, pp.419–437.

emuzzi, A., Puntorieri, S., Battaglia, C., Bertani, T., Remuzzi, G., 1990.Angiotensin-converting enzyme inhibition ameliorates glomerular filtrationof macromolecules and water and lessens glomerular injury in the rat. J.Clin. Invest. 85, 541–549.

emuzzi, A., Perticucci, E., Ruggenenti, P., Mosconi, L., Limonta, M., Remuzzi,G., 1991. Angiotensin-converting enzyme inhibition improves glomerularsize selectivity in IgA nephropathy. Kidney Int. 39, 1267–1273.

ennie, D., Marticorena, E., Monge-C, C., 1971. Renal oxygenation in malePeruvian natives living permanently at high altitude. J. Appl. Physiol. 30,450–456.

ichalet, J.P., Rivera, M., Bouchet, P., Chirinos, E., Onnen, I., Petitjean, O.,Bienvenu, A., Lasne, F., Moutereau, S., Leon-Velarde, F., 2005. Acetazo-lamide: a treatment for chronic mountain sickness. Am. Rev. Resp. Crit.Care Med. 172, 1427–1433.

ichalet, J.P., Souberbielle, J.C., Antezana, A.M., Dechaux, M., Le Trong, J.L.,Bienvenu, A., Daniel, F., Blanchot, C., Zittoun, J., 1994. Control of erythro-poiesis in humans during prolonged exposure to the altitude of 6542 m. Am.J. Physiol. 266, R756–R764.

ich, S., Brundage, B.H., 1987. High dose channel-blocking therapy for primarypulmonary hypertension: evidence for long term reduction in pulmonaryarterial pressure and regression of right ventricular hypertrophy. Circulation76, 135–141.

ich, S., Kaufmann, E., Levy, P.S., 1992. The effect of high doses of calcium-channel blockers on survival in primary pulmomary hypertension. N. Engl.J. Med. 327, 76–81.

ajkov, D., McEvoy, R.D., Cowie, R.J., 1993. Felodipine improves pul-monary hemodynamics in chronic obstructive pulmonary disease. Chest 103,1354–1361.

antolaya, R., Araya, J., Vecchiola, A., Prieto, R., Ramırez, R.M., Alcayata,R., 1981. Hematocrito, hemoglobina y presion de oxıgeno arterial en 270hombres y 266 mujeres sanas y residentes de altura (2800 m). Rev. Med.Hosp. Roy. H. Glover. 1, 17–29.

antolaya, R., Araya, J., Alfaro, R., Radmilovic, J., Fuenzalida, M., 1984/1985.Hematocrito en diferentes poblaciones residentes en distintos niveles dealtitud en los andes del norte de Chile. Arch. Biol. Andina 13, 152–173.

chermuly, R.T., Kreisselmeier, K.P., Ghofrani, H.A., Yilmaz, H., Butrous, G.,Ermert, L., Ermert, M., Weissmann, N., Rose, F., Guenther, A., Walmrath,D., Seeger, W., Grimminger, F., 2004. Chronic sildenafil treatment inhibits
monocrotaline-induced pulmonary hypertension in rats. Am. J. Respir. Crit.Care Med. 169, 39–45.
ebkhi, A., Strange, J.W., Phillips, S.C., Wharton, J., Wilkins, M.R., 2003.Phosphodiesterase type 5 as a target for the treatment of hypoxia-inducedpulmonary hypertension. Circulation 107, 3230–3235.

V

& Neurobiology 158 (2007) 251–265

edano, O., Pastorelli, J., Gomez, A., Flores, V., 1988. Sangrıa roja aislada vs.hemodilucion isovolemica inducida en mal de montana cronica [Resumen249]. In: Resumenes de trabajos libres. V Congreso Nacional. X CursoInternacional de Medicina Interna. Sociedad Peruana de Medicina Interna,Lima.

edano, O., Zaravia, A., 1988. Hemodilucion isovolemica inducida en malde montana cronica [Resumen 250]. In: Resumenes de trabajos libres. VCongreso Nacional. X Curso Internacional de Medicina Interna. SociedadPeruana de Medicina Interna, Lima.

everinghaus, J.W., Bainton, C.R., Carcelen, A., 1966. Respiratory insensitivityto hypoxia in chronically hypoxic men. Respir. Physiol. 1, 308–334.

ime, F., Monge-C, C., Whittembury, J., 1975. Age as a cause of chronic moun-tain sickness. Int. J. Biometeorol. 19, 93–98.

imoneau, G., Escourrou, P., Duroux, P., Lockhart, A., 1981. Inhibition ofhypoxic pulmonary vasoconstriction by nifedipine. N. Engl. J. Med. 304,1582–1585.

picuzza, L., Casiraghi, N., Gamboa, A., Keyl, C., Schneider, A., Mori, A., Leon-Velarde, F., Di Maria, G.U., Bernardi, L., 2004. Sleep-related hypoxaemiaand excessive erythrocytosis in Andean high-altitude natives. Eur. Respir. J.23, 41–46.

terling, D., Reithmeier, R.A.F., Casey, J.R., 2001. Carbonic anhydrase: in thedriver’s seat for bicarbonate transport. J. Pancreas 2 (Suppl.), 165–170.

trano, A., Davi, G., Avellone, G., Novo, S., Pinto, A., 1984. Double blind,crossover study of the clinical efficacy and the hemorheological effects ofpentoxifylline in patients with occlusive arterial disease of the lower limbs.Angiology 35, 459–466.

ui, G.J., Liu, Y.H., Cheng, X.S., Anand, I.S., Harris, E., Harris, P., Heath, D.,1988. Subacute infantile mountain sickness. J. Pathol. 155, 161–170.

un, S., Oliver-Pickett, C., Ping, Y., Micco, A.J., Droma, T., Zamudio, S.,Zhuang, J., Huang, S.Y., McCullough, R.G., Cymerman, A., Moore, L.G.,1996. Breathing and brain blood flow during sleep in patients with chronicmountain sickness. J. Appl. Physiol. 81, 611–618.

utton, J.R., Houston, C.S., Mansell, A.L., 1979. Effect of acetazolamide onhypoxemia during sleep at high altitude. N. Engl. J. Med. 301, 1329–1331.

wenson, E.R., 1998. Carbonic anhydrase inhibitors and ventilation: a complexinterplay of stimulation and suppression. Eur. Respir. J. 12, 1242–1247.

wenson, E.R., 2006. Carbonic anhydrase inhibitors and hypoxic pulmonaryvasoconstriction. Respir. Physiol. Neurobiol. 151, 209–216.

atsumi, K., Picket, C.K., Weil, J.V., 1995. Possible role of dopamine in venti-latory acclimatization to high altitude. Respir. Physiol. 99, 63–73.

hevenod, F., Radtke, H.W., Grutzmacher, P., Vincent, E., Koch, K.M.,Schoeppe, W., Fassbinder, W., 1983. Deficient feedback regulation of ery-thropoiesis in kidney transplant patients with polycythemia. Kidney Int. 24,227–232.

homas, M.K., Francis, S.H., Corbin, J.D., 1990. Characterisation of a purifiedbovine lung cGMP-binding cGMP phosphodiesterase. J. Biol. Chem. 265,14964–14970.

rivedi, H., Lal, S.M., 2003. A prospective, randomized, open labeled crossovertrial of fosinopril and theophylline in post renal transplant erythrocytosis.Ren. Fail. 25, 77–86.

eno, M., Brookings, J., Beckman, B., Fisher, J.W., 1988. A1 and A2 adenosinereceptor regulation of erythropoietin production. Life Sci. 43, 229–237.

argas, M., Leon-Velarde, F., Monge-C, C., Orozco, E., 1996. Enalapril inthe treatment of chronic mountain sickness. Wilderness Environ. Med. 2,193–194.

illena, M., Vargas, E., Guenard, H., Nallar, N., Tellez, W., Spielvogel, H., 1985.A double blind study of the effect of almitrine on chronic polycythaemia ofhigh altitude. Bull. Eur. Physiopathol. Respir. 21, 165–170.

lahakos, D.V., Canzanello, V.J., Madaio, M.P., Madias, N.E., 1991. Enalapril-associated anemia in renal transplant recipients treated for hypertension.Am. J. Kidney Dis. 17, 199–205.

lahakos, D.V., Kosmas, E.N., Dimopoulou, I., Ikonomou, E., Jullien, G.,Vassilakos, P., Marathias, K.P., 1999. Association between activation of
the renin-angiotensin system and secondary erythrocytosis in patients withchronic obstructive pulmonary disease. Am. J. Med. 106, 158–164.
lahakos, D.V., Marathias, K.P., Kosmas, E.N., 2001. Losartan reduces hemat-ocrit in patients with chronic obstructive pulmonary disease and secondaryerythrocytosis. Ann. Int. Med. 134, 426–427.

ology

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V

W

W

W

W

W

W

W

W


lahakos, D.V., Marathias, K.P., Agroyannis, B., Madias, N.E., 2003. Posttrans-plant erythrocytosis. Kidney Int. 63, 1187–1194.

olpe, M., Tritto, C., Testa, U., Rao, M.A.E., Martucci, R., Mirante, A., Enea,I., Russo, R., Rubattu, S., Condorelli, G., Cangianiello, S., Trimarco, B.,Peschle, S., Condorelli, M., 1994. Blood levels of erythropoietin in conges-tive heart failure and correlation with clinical, hemodynamic, and hormonalprofiles. Am. J. Cardiol. 74, 468–473.

ard, A., Clissold, S.P., 1987. Pentoxifylline: a review of its pharmacody-namic and pharmacokinetic properties, and its therapeutic efficacy. Drugs34, 50–97.

inslow, R.M., Monge-C, C., Brown, E.G., Klein, H.G., Sarnquist, F.,
Winslow, N.J., McKneally, S.S., 1985. Effects of hemodilution on O2transport in high-altitude polycythemia. J. Appl. Physiol. 59, 1495–1502.
inslow, R.M., Chapman, K.W., Gibson, C.C., Samaja, M., Monge-C, C.,Goldwasser, E., Sherpa, M., Blume, F.D., Santolaya, R., 1989. Different

& Neurobiology 158 (2007) 251–265 265

hematologic responses to hypoxia in Sherpas and Quechua Indians. J. Appl.Physiol. 66, 1561–1569.

inslow, R.M., Monge, C.C., 1978. Hypoxia, Polycythemia, and ChronicMountain Sickness. The John Hopkins Press, Baltimore.

inslow, R.M., Monge-C, C., 1987. Hypoxia, Polycythemia and Chronic Moun-tain Sickness. John Hopkins University Press, Baltimore, MD, pp. 19–30.

interborn, M.H., Bradwell, A.R., Chesner, I.M., Jones, G.T., 1987. The originof proteinuria at high altitude. Postgrad. Med. J. 63, 179–181.

u, T.Y., 1979. Excessive polycythemia of high altitude: an analysis of 82 cases[in Chinese]. Chin. J. Hematol. 3, 27–32.

u, T.Y., Li, W., Li, Y., Ge, R.-L., Cheng, Q., Wang, S., Zhao, G., Wei, L., Jin, Y.,
Don, G., 1998. Epidemiology of chronic mountain sickness: ten years’ studyin Qinghai -Tibet. In: Ohno, H., Kobayashi, T., Masuyama, S., Nakashima,M. (Eds.), Progress in Mountain Medicine and High Altitude Physiology.Press Committee of the 3rd World Congress on Mountain Medicine andHigh Altitude Physiology, Matsumoto, Japan, pp. 120–125.

Treatment of chronic mountain sickness: Critical reappraisal of an old problem

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