The adrenocorticotropic hormone (ACTH)-induced reversal of hemorrhagic shock

Resuscitation, 18 (1989) 253-267 Elsevier Scientific Publishers Ireland Ltd.

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THE ADRENOCORTICOTROPIC HORMONE (ACTH)-INDUCED REVERSAL OF HEMORRHAGIC SHOCK

ALFIO BERTOLINI. WILLIAM FERRARI and SALVATORE GUARINI

Institute of Pharmacology, University of Modenq via G. Campi 287,411O Modena (Italy)

SUMMARY

Adrenocorticotropic hormone (ACTHI, while having negligible effects on cardiovascular function in the intact animal, induces a potent and sustained reversal of an otherwise invariably, rapidly fatal condition of hemorrhage- induced hypovolemic shock, in rats and dogs. The main site(s) of action are at the peripheral level; however, subsidiary site(s) of action in the CNS cannot be excluded. The studies on the mechanism of action indicate that the ACTH- induced reversal of hemorrhagic shock (a) is an extra-hormonal, adrenal- independent effect, because it is not affected by adrenalectomy and is shared by many ACTH-fragments practically devoid of corticotropic activity; (bl is antagonized by morphine in a surmontable way; (cl needs the functional integrity of the sympathetic nervous system (it is prevented by guanethidine, reserpine, and clonidinel and the availability of peripheral alpha-adrenoceptors (it is antagonized by dibenamine, prazosin and yohimbine, but not by practolol); (dl requires the integrity of afferent vagal fibers (it is almost completely abolished by vagotomyl; (el involves central cholinergic networks (it is antagonized by atropine sulphate, but not by atropine methyl bromide: and it is prevented by the intracerebroventricular injection of hemieholinium-31; (fl is associated with a massive increase in the volume of circulating blood, likely due to a mobilization from peripheral pooling sites (it is largely prevented by splenectomy or by suprahepatic veins ligature, and is associated with a restoration of the venous blood flow in peripheral vascular beds and with a normalization of venous PO,); (gl is associated with a restoration of heart and spleen adrenoceptors, whose number is significantly decreased during hemorrhagic shock. The survival time of hemorrhage-shocked animals, which is 26 r 3 min in controls, is greatly prolonged (44 + 18 hl by ACTH, provided that the treatment is made within 5 - 10 min after bleeding. Finally, in animals treated with ACTH within

5 - 10 min after bleeding, blood reinfusion retains its effectiveness and reverse shock even if performed 2 - 5 h later.

Key words: Shock - Hemorrhage - ACTH - Melanopeptides - Opioids

Printed and Published in Ireland

INTRODUCTION

Pursuing our efforts to produce pharmacological evidence in support of the idea that ACTH-MSH peptides (melanopeptidesl may play a prominent role as physiological antagonists of opioids in a general homeostatic system [l - 31, we recently discovered that ACTH and several of its fragments have a potent anti-shock effect [4 - 61.

The idea of an opioid-antiopioid homeostatic system is shared by others [7 - 111 and has been repeatedly proposed with ample supporting evidence by our group [12-181. It is corroborated by many cogent and largely consonant anatomical, neurochemical and functional data indicating that melanopeptides and opioid peptides influence autonomic, behavioral, sensory, endocrine, locomotor, gastrointestinal and immune functions in an usually mutually antagonistic, or at least complementary, highly integrated and versatile fashion (for review see Ref. 31.

Thus, when it became apparent that during shock there is a massive activation of opioid systems, and that opioid antagonists reverse hypotension and extend survival in several different shock conditions [lS-271, we decided to investigate the effect of melanopeptides on some typical hemodynamic parameters and on animal survival in an experimental model of hemorrhagic shock. Here we describe the main results so far obtained.

THE ANTI-SHOCK EFFECT OF MELANOPEPTIDES

Our experimental procedures have been repeatedly described in detail elsewhere [4-6, 28 -321. Briefly, the animals, previously anesthetized with ethylurethane (1.25 g/kg, i.p.1 and heparinized (heparin sodium, 600 I.U./kg, i.v.l, are stepwise bled to a Wiggers type of hemorrhagic shock without reinfusion (oligemic shock) [33-351 until their mean arterial blood pressure stabilizes at 18- 25 mmHg, and then are treated at various intervals.

Mean arterial pressure (MAP), pulse pressure (PP), heart rate (HR), respiratory rate (RR) and survival are continuously recorded for at least 2 h after treatment. In some cases, shocked animals have been sutured, allowed to recover from anesthesia, and then kept under observation up to the cut-off time of 15 days after treatment in order to determine the survival time.

Blood volume, complete blood count, blood gases, blood flow in selected vascular beds, influence of adrenalectomy, influence of splenectomy or of suprahepatic-vein ligature, characteristics of brain, spleen capsule and heart ventricle adrenoceptors have also been studied.

ACTH, alpha-MSH, and other ACTH-fragments have no [5] or scant [36] cardiovascular and respiratory effects in the intact animal.

On the other hand, in our extremely severe, pre-terminal condition of bleeding-induced hypovolemic shock, where all saline-treated animals die within 25 - 30 min, and where typical pressor agents (vasopressin, angiotensin

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II) have minor and transient (few minutes) ameliorating effects [37], the intravenous Lv.) injection of ACTH causes a dose-dependent reversal of hypotension (Fig. 1) and of respiratory depression [4-61. The effect starts a few minutes after injection, gradually increases, reaches a maximum in 15-20 min, and is sustained, remaining almost stable for at least 2 h (Fig. 2). Of all the ACTH- fragments studied, the tetracosactide ACTH-(l-24) is the one most active for

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Fig. 1. ACTH-induced reversal of hemorrhagic shock: dose-effect relationship. ::, percent survival 2 h after treatment; ??, pulse pressure; ::, mean arterial pressure; and ??, respiratory rate 15 min after treatment (percent of the respective pre-bleeding values). Twenty rats per dose, at least. P < 0.01, at least, vs. the corresponding values of saline-treated animals in all cases, except for the respiratory rate of rats treated with the dose of 20 pg/kg (ANOVA followed by Dunnett’s test).

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this anti-shock effect, much more active even than the complete sequence ACTH-(l-39) [5] (Fig. 3). Therefore, it has been the one we usually employed in our experiments, and from now on we will refer to it as ACTH. A dose of 40 pg/ kg i.v. assures a 100% survival for at least 2 h, and a dose of 160 rg/kg i.v. practically restores arterial pressure, pulse pressure and respiratory rate to the pre-bleeding values. This effect of ACTH has been observed in rats [4 - 51, dogs

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e 28 48 68 88 108 Fig. 3. Reversal of hemorrhagic shock induced by melanopeptides: structure-activity relationship. R, percent survival 2 h after treatment; 0, pulse pressure; and m, mean arterial pressure 15 min after treatment (percent of the respective pre-bleeding values). Groups of 12 animals, at least. Modif. a-MSH = (Nle’, D-PherIACTH-(l-13); alsactide = (3-Alai. Lys17)ACTH_(1-17Wamino+buti- lamide. P < 0.01, at least, vs. the corresponding values of saline-treated animals in all cases, except for pulse pressure (P < 0.05) and mean arterial pressure (P > 0.05) in alsactide-treated rats (ANOVA followed by Dunnett’s test).

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[S] and, so far anecdotically, in humans [38,39]. It is quite remarkable that such an effect, particularly on pulse amplitude, is obtained and maintained without the need for the infusion of blood or blood substitutes.

The time-lapse between bleeding and treatment is obviously of crucial importance (Table I); when ACTH is injected 5 min after bleeding termination, animals survive for approximately 2 days (44.17 f 17.84 h), without any other treatment; when the time-lapse is 15 min, the survival time is 2.79 f 1.07 h; and when animals are treated 25 min after bleeding, i.e. almost at the point of death, ACTH no longer has any effect. A similar trend is observed with the reinfusion of the withdrawn blood. If reinfusion is performed 5 min after bleeding, shock is reversed, survival lasting 307 f 52.80 h with 75% of the animals still alive 15 days after treatment; but when blood is reinfused 15 min after bleeding, the survival time is 6.57 2 4.38 h, and when reinfusion is made 25 min after bleeding it no longer has any effect at all.

However, and most important, when animals have been treated with ACTH

TABLE I

IMPORTANCE OF THE TIME-LAPSE BETWEEN SHOCK AND TREATMENT Effect of saline, ACTH, blood reinfusion, and ACTH followed by blood reinfusion at different intervals on the survival time of rats bled to hypovolemic shock (8- 12 rats per group). ACTH, ACTH-U- 241, 160 pg&g; Blood, reinfusion of the withdrawn blood. *P < 0.01 compared with saline-treated rats (ANOVA followed by Scbeffgs test). **P < 0.01 and *+*P < 0.05 compared with saline-treated rats (Fisher’s exact probability test).

Treatment, i.v.

Saline, equivolume to the withdrawn blood, 5 min after bleeding

ACTH, 5 min after bleeding ACTH, 15 min after bleeding ACTH, 25 min after bleeding Blood, 5 min after bleeding Blood, 15 min after bleeding Blood, 25 min after bleeding ACTH, 5 min after bleeding

+ Blood, 30 min later ACTH, 6 min after bleeding



+ Blood, 300 min later

Survival time % Survival (h,m f S.E.) 15 days after treatment

0.47 zt 0.06 0 44.17 f 17.84* 0

2.79 f 1.07+ 0 0.18 f 0.03 0

> 307.20 f 52.80* 75*+ 6.57 2 4.38+ 0 0.17 f 0.03 0

> 185.75 f 100.64* 50*+

> 122.59 f 46.68* 33***

> 157.25 f 57.34+ 36***

> 92.50 * 53.87* 12

within 5- 10 min after bleeding, blood reinfusion retains its effectiveness and reverses shock even if performed 2 - 5 h later.

The anti-shock effect of ACTH can be obtained also by intracerebroventricular (i.c.v.1 injection, and is quantitatively and qualitatively quite similar to that observed after i.v. injection [40].

MECHANISM OF THE ANTI-SHOCK EFFECT OF MELANOPEPTIDES

Adrenal glands are not involved, because the anti-shock effect is practically the same in intact and in adrenalectomized animals, and can be obtained also with ACTH-fragments and fragment analogs almost completely devoid of corticotropic activity: ACTH-(l-131 (a-MSH), the a-MSH analog (Nle*, D-Phe?-ACTH- (l-131, ACTH-(4-101[5].

The restoration of arterial pressure and pulse amplitude is associated with an impressive increase in the volume of circulating blood [29]. Such increase is not due to hemodilution: the number of red cells per volume unit is in fact the same as in the controls, and the sole significant difference is leukocytosis [29]. Capillary pooling and trapping of blood (“capillary paralysis”) [33], prolonged transit time, with consequent decreased venous return, and reduced cardiac output characterize the terminal, irreversible phase of shock [41].

The increase in circulating blood volume induced by ACTH in shocked animals seems to be the consequence of a mobilization of the peripherally pooled, “out of currency” blood. Indeed, the anti-shock effect of ACTH is greatly impaired in splenectomized animals [29] and in animals subjected to ligature of the suprahepatic veins [42] and is associated with a restoration of the venous blood flow in peripheral vascular beds, and with a normalization of venous PO,.

Morphine (2.5 mglkg, i.v., before starting bleeding) completely prevents the reversal of hemorrhagic shock induced by ACTH (160 pg/kg, i.v.l; however, this effect of morphine can be overcome by increasing the amount of ACTH [S]. This finding strongly supports the view that the anti-shock effect of pharmacological doses of ACTH is indeed the consequence of a functional antagonism towards endogenous opioids, which are massively released in such a condition [26,27]; the further increase of opioid tone caused by the injection of morphine requir- ing higher doses of ACTH.

As concerns the role of the autonomic nervous system, the so far available experimental data indicate that the ACTH-induced reversal of hemorrhagic shock is a complex phenomenon which involves afferent vagal fibers, a central cholinergic link and the activation of the sympathetic nervous system. Indeed, it is almost completely absent after bilateral vagotomy [28], it is prevented by atropine sulphate (hut not by atropine methylbromide) [28] and by the i.c.v. injection of hemicholinium-3, and it is completely prevented by guanethidine, reserpine and clonidine [32,43]. Moreover, it is mediated to a large extent through the activation of peripheral alpha-l- and alpha-2-adrenoceptors; it is in fact antagonized by dibenamine, prazosin and yohimbine, but not by practolol [32,43].

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Finally, the anti-shock effect of ACTH is associated with a restoration of heart ventricle and spleen capsule adrenoceptors, the number of which is significantly reduced in our experimental model of hemorrhagic shock [31].

DISCUSSION

There is increasing evidence to support the view that endogenous opioids, as well as several other neuropeptides [44,45], play a significant role in the regulation of the cardiovascular and respiratory functions (for review see Refs. 25 and 46) . In the CNS, chemoreceptor sensitivity at the bulbar level 1471, baroreflex activity at the level of the nucleus tractus solitarii [48], as well as somatosym- pathetic reflex at the level of the medulla oblongata [49] are influenced both by opioids and by their specific antagonists.

At the peripheral level, it has long been known that morphine and other opioids usually dilate resistance and capacitance vessels; characteristically, they produce venodilatation and move significant quantities of blood from the central to the peripheral circulation, with pooling of blood in peripheral, “storage” organs (“medical phlebotomy”) [25,50].

In shock conditions there is a massive activation of endogenous opioid systems and a sharp increase in circulating opioid peptides [26,27,51]; in particular, it has been shown that the plasma concentration of beta-endorphin rises to four times the basal level immediately after severe hemorrhage [52].

That opioid mechanisms are implicated in the pathophysiology of shock is further strongly suggested by the finding that opioid antagonists consistently raise blood pressure, increase cardiac output, and extend survival time in septic, hemorrhagic, anaphylactic and neurogenic models of shock in different animal species including primates [19,20,24,25,27] and, albeit not univocally [53 - 551, in humans as well [22,23,56]. However, recent animal and human data seem to question the assumption that the mechanism of action of naloxone in reversing the hemodynamic changes of shock is simply due to the blockade of opioid receptors, and make reference to a positive inotropic effect unrelated to opioid receptors. Thus, Sagy et al. have observed a positive inotropic response on isolated rat myocardium using ( + 1 naloxone, the non-opioid blocking isomer [57]. and the antiarrhythmic effect of naloxone [58] can similarly be obtained with the ( + ) stereoisomer as well [59]. Others have suggested that naloxone potentiates the effects of circulating catecholamines on the myocardium, resulting in improved contractility [60].

Finally, Roberts et al. have now reported in human cases of septic shock the unexpected finding of positive hemodynamic effects occurring only more than 4 h after the initial bolus of naloxone and the start of a continuous infusion of the drug; this is clearly not consistent with a displacement of endogenous opioids from their receptors, which should have produced a rapid effect [61].

Recent experimental data have further stressed and better defined the role of opioids in circulatory homeostasis. Schadt and coworkers [34,62] have shown, in conscious rabbits, that while rapid removal of approximately 15% of the

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total blood volume produced a sharp increase in plasma noradrenaline with maintenance of arterial pressure at control levels (non-hypotensive, compen- sated hemorrhage), a further bleeding of another 30% of the total volume produces a sudden fall in arterial pressure (hypotensive hemorrhage) and is not accompanied by any further increase in plasma noradrenaline. In the latter conditions, the injection of naloxone causes a prompt increase in plasma noradrenaline and arterial pressure, suggesting that during hemorrhagic hypotension there is an opiate-mediated inhibition of sympathetic outflow and of noradrenaline release [34]. More recently, Morita et al. have shown that in conscious rabbits hemorrhage elicits a biphasic effect on renal nerve activity, which rises initially during non-hypotensive hemorrhage and then falls during hypotensive hemorrhage, this decrease being reversed by naloxone [63].

Sandor et al. have recently shown that the bleeding volume required to induce hemorrhagic hypotension in rats is markedly reduced by the subcutaneous administration of morphine or by the i.c.v. injection of beta- endorphin, whereas it is significantly increased by the subcutaneous administration of naloxone or by the i.c.v. infusion of beta-endorphin antiserum 1641.

It is now well established that adrenergic neurons residing in a highly restricted zone (Cl area) of the rostra1 ventrolateral medulla play a critical role in the tonic and reflex regulation of arterial pressure and of respiratory function [65 - 681. Abundant pharmacological evidence demonstrates that these adrenergic neurons are tonically regulated by inhibitory gabaergic and opioid- ergic inputs and by excitatory cholinergic mechanisms [69,70].

Opioids inhibit the release of several neurotransmitters [10,71,72]. They inhibit noradrenergic and dopaminergic neurotransmission in the CNS [lo] and, in particular, inhibit the firing of locus coeruleus neurons [73], while naloxone enhances it [74]. It has long been known that a number of opioid actions in the CNS and in the periphery involve the inhibition of acetylcholine release (for review see Ref. 75); in particular, in the brain, opioid administration stereospe- cifically decreases the amount of liberated acetylcholine and the basal release of acetylcholine into lateral ventricular perfusates [76 - 781, an the i.c.v. administration of beta-endorphin in analgesic amounts causes a decrease in the turnover of acetylcholine in different brain areas, this effect being prevented by naltrexone [79]. So, opioids significantly depress, or abolish [80], the hyper- tensive response to a central cholinergic activation [81], most probably by inhi- biting acetylcholine release in the involved structures. Also while the injection of opioids into the rostra1 ventrolateral medulla produces cardiovascular and respiratory depression [69], the microinjection of cholinomimetic drugs in this same area reverses opioid-induced respiratory depression [82].

Conversely, melanopeptides increase noradrenaline synthesis and turnover in whole brain, as well as in more circumscribed areas (brain stem) of rats and mice (83,841 and selectively modulate restricted catecholaminergic neuronal systems [85]. In particular, ACTH increases by 97% the noradrenaline content of locus coeruleus [86], and the implantation of ACTH-(I-10) into the locus coeru-

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leus increases noradrenaline release [87]. Moreover, melanopeptides increase acetylcholine turnover in some brain areas [10,88] and stimulate sympatho- adrenomedullary activity at the peripheral level. Indeed, ACTH increases the activity of catecholamine-synthesizing enzymes, in particular that of phenylethanolamine-N-methyltransferase in the adrenal medulla [89]; and it increases the action potential-evoked release of noradrenaline from the post- ganglionic sympathetic terminals innervating the pulmonary artery of the rabbit, apparently by an effect at presynaptic ACTH receptors [go]. ACTH also raises the plasma noradrenaline level in vivo when injected into the right atrium of anesthetized rats [91], and potentiates the inotropic response of rat atria1 strip to noradrenaline [92].

Finally, Starke and coworkers have recently shown that the i.v. infusion of ACTH-(l-241(0.03- 1 pg/kg per mini increases the noradrenaline spillover rate and the plasma noradrenaline concentration in pithed rabbits with electrically stimulated sympathetic outflow [93].

Our present data, showing that melanopeptides are able to reverse an otherwise rapidly and invariably irreversible condition of hemorrhagic shock; that such effect involves the activation of a central choline@ pathway and occurs through an adequately restored responsivity of the sympathetic system; that it is associated with a mobilization of the peripherally pooled blood; and, finally, that it is antagonized by morphine, clearly suggest that such shock reversal induced by melanopeptides is due to their functional antagonism towards endogenous opioids, with opposite effects at all levels and on all structures involved in cardiovascular homeostasis.

This further corroborates and strengthens the idea of an opioid-antiopioid homeostatic system and suggests that irreversible shock is associated with, and probably to a large extent due to, a derangement of this balanced system resulting in a massive prevalence of the opioid component, which can only be neutralized through the administration of pharmacological doses of antiopioids.

CONCLUSION

Our data lead to both conceptual and practical conclusions. From a practical point of view, also on the basis of the preliminary human

data so far available, an unforeseen, simple and safe first-aid management of the hemodynamic and respiratory consequences of massive blood losses is envisaged. In fact, ACTH and the other ACTH-fragments active in reversing shock conditions are practically devoid of acute toxicity [94], and have no other pharmacological effect, even corticotropic activity being absent in the shortest effective fragments. It therefore seems possible to restore the hemodynamic and respiratory parameters to a level compatible with survival and to postpone by hours the infusion of blood without compromising its efficacy. The outstand- ing importance of such a possibility is self-evident.

From a conceptual point of view, our data demonstrate that (i) melanopeptides, which under normal conditions are almost inactive on

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cardiovascular function, have an extremely potent effect on blood mobilization, blood flow and arterial pressure in conditions of severe cardiovascular failure, such effect occurring through the activation of a complex mechanism that involves peripheral and central components; (ii) as a corollary, they further stress that pharmacological “activity” is a very relative concept and also depends, among many other things, on the functional condition of the consid- ered system: the case of melanopeptides is an extreme one, because they are inactive under normal conditions and extremely active and potent under path- ological conditions; (iii) our data also further stress that neuropeptides usually subserve multiple purposes in the organism, and that their sequence encodes many different messages, so that the traditional terminology is often mislead- ing or too limiting; (iv) finally, a “life-saving” mechanism may have been disclosed which, at least in mammals, is vestigial or anyhow functions only up to a limited degree and then fails, but which can be restored in a pharmacological way. Perhaps it is not out of place to remind that melanopeptides play a well known central role in the response of the organism to emergency situations, and that in some species they do in fact subserve the life-saving function of camouflage.

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The adrenocorticotropic hormone (ACTH)-induced reversal of hemorrhagic shock

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