α-MSH and other ACTH fragments improve cardiovascular function and survival in experimental hemorrhagic shock

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Abstract

Hypovolemic shock was produced in rats by withdrawing about 50% of the estimated total blood volume. Following mean arterial pressure stabilization in the range of 15–25 mm Hg, with a pulse pressure of 7–12 mm Hg, the rats were given intravenous bolus injections either of ACTH fragments or of saline. The following ACTH fragments or analogs were used: ACTH-(4–10), α-MSH, ACTH-(1–16), ACTH-(1–17), ACTH(1–18), [Nle4, D-Phe7]α-MSH, [β-Ala1,Lys17]ACTH-(1–17)-4-amino-n-butilamide (alsactide). ACTH-(1–24) and human synthetic ACTH-(1–39) were used for comparison. All animals treated with saline died in 22.51 ± 3.62 min. Treatment with ACTH fragments (160 μg/kg i.v.) increased blood pressure and pulse amplitude, the effect starting within a few minutes, gradually increasing, and reaching a maximum in 15–30 min. The blood and pulse pressure increases were sustained, remaining almost stable until the end of the 2 h recording. Two out of nine rats treated with alsactide, which was the least active, died within 2 h after treatment, while all rats treated with the other ACTH fragments or analogs were still surviving at that time. Both on a weight and on a molar basis, the most active was ACTH-(1–24), followed by ACTH-(1–16), by the α-MSH analog [Nle4,D-Phe7]ACTH-(1–13), by ACTH-(1–18) and by ACTH-(1–17). The present results show that melanocortins reverse otherwise fatal hypovolemic shock, and suggest a new therapeutic approach for shock treatment. Since endogenous opioids play a key role in the pathophysiology of shock, these data provide further experimental support to the hypothesis of a melanocortin-opioid homeostatic system, involved in many important body functions.

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      In addition, previous studies also showed that hemorrhagic shock reversal is mediated via CNS POMC-MC4Rs and may involve activation of efferent vagal cholinergic pathways [74]. For instance, microinjections of α-MSH in the nucleus ambiguus (nAMB) exerted excitatory effects on parasympathetic preganglionic neurons via activation of MC4R, resulting in increased vagal input to the heart and bradycardia responses [74–76]. These findings suggest that MC4R may play a role in mediating the parasympathetic component of baroreflex-induced bradycardia.

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      In these conditions, that in turn lead to the death of all saline-treated control animals within 30–35 min [15,16,18], conventional anti-shock drugs such as the glucocorticoid methylprednisolone, protease inhibitor aprotinin and sympathomimetic agent norepinephrine are ineffective [8]. Conversely, the intravenous bolus injection of nanomolar amounts of melanocortins [e.g., ACTH-(4–10), α-MSH, ACTH-(1–24), etc.] induces, within a few minutes, a dose-dependent restoration of arterial blood pressure and tissue blood flow, as well as a gradual normalization of blood gases, pH and lactate [12,15,16,18,89]. The melanocortin-induced shock reversal was found to be associated with a large increase in the volume of circulating blood, not due to hemodilution but as the consequence of the mobilization of the peripherally pooled residual blood that, in shock conditions, is trapped in capillaries and large blood reservoirs including liver and spleen [85,86,89].

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      The minimum active dose [20 μg/kg in the case of ACTH-(1–24)] produces a 40% survival at 2 h after treatment; the maximum active dose (160 μg/kg) practically restores arterial pressure, pulse amplitude and respiratory rate to pre-bleeding values (Bertolini et al., 1986c), and produces a 100% survival – without reinfusion of the shed blood or infusion of blood substitutes – for more than 24 h (Bertolini et al., 1989). Adrenal glands are not involved, because the effect is the same either in intact or in adrenalectomized animals (Bertolini et al., 1986a) and is independent of the corticotropic activity of the melanocortin injected (Bertolini et al., 1986c). The resuscitating effect of melanocortins has been confirmed also in other shock conditions: the hypovolemic shock produced in rabbits by the graded occlusion of the inferior vena cava (Ludbrook and Ventura, 1995) and the rat model of splanchnic ischemia/reperfusion-induced shock (splanchnic artery occlusion shock, SAO shock) (Squadrito et al., 1999), and also in a pre-terminal condition produced in rats by prolonged asphyxia (Guarini et al., 1997).

    • Brain effects of melanocortins

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      In normotensive, normovolemic rats, either conscious or under light urethane anesthesia (a condition where cardiovascular reflexes and sufficient sympathetic tone are maintained), the intravenous injection of the adrenocorticotropin fragment ACTH4–10 and of γ1- and γ2-MSH (10 times more potent than ACTH4–10) induce a dose-dependent, short-lasting increase in blood pressure, heart rate and pulse amplitude, with a maximal effect 25 s following administration (for reviews see: [363–365]). Melanocortin peptides with a longer C-terminal extension, including γ3-MSH, α-MSH, ACTH1–17, ACTH1–24, and the whole 1–39 sequence of ACTH, are on the other hand devoid of these cardiovascular effects in the normotensive, normovolemic animal [68,199,366], but have dramatic and long-lasting cardiovascular effects in severe hypotensive conditions (for a review see: [76]). α-Melanocyte-stimulating hormone (α-MSH) is considered a trophic factor for nerve tissue, both during fetal development and in adulthood [5,148,447].

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