Influence of blockade of α1-adrenoceptors, β1-adrenoceptors and vasopressin V1A receptors on the cardiovascular effects of γ2-melanocyte-stimulating hormone (γ2-MSH)

Abstract

gamma 2-Melanocyte-stimulating hormone (gamma 2-MSH) and related melanotropins have been shown to have various cardiovascular effects, including acute, short-lasting increases in blood pressure (MAP) and heart rate (HR). gamma 2-MSH, administered intravenously, dose-dependently increased MAP and HR with an ED50 of approximately 30 nmol/kg and a maximal effect on MAP of approximately 55 mm Hg and on HR of around 70 beats per minute. Intravenous (i.v.) pretreatment with the alpha 1-adrenoceptor antagonist, prazosin, caused the dose-response curve for the effect of gamma 2-MSH on MAP to shift to the right with a decrease in slope, whereas it had no effect on the dose-response curve for the effect on HR. I.v. pretreatment with the beta 1-adrenoceptor antagonist, metoprolol, had no effect on the dose-response curve for the effect of gamma 2-MSH on MAP, but it caused the dose-response curve for the effect of the peptide on HR to shift to the right with a decrease in slope. Neither i.v. nor intracerebroventricular (i.c.v.) administration of the vasopressin V1A receptor antagonist, SR 49059 ((2S) 1-[(2R 3S)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxy-benzene-sulfonyl)- 3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2-carboxamide), had significant effects on the dose-response curves for the effects of the peptide on either MAP or HR. The doses of prazosin, metoprolol and SR 49059 were found to be effective in counteracting the effects of agonists for these receptors (phenylephrine, isoprenaline and [Arg8]vasopressin, respectively). Taken together, these results support the postulate that the effects of gamma 2-MSH are, at least partially, due to an increase in sympathetic outflow to the periphery (Gruber and Callahan (1989), Am J Physiol 257: R681-R694), and that this increase leads to increased activation of vascular alpha 1-adrenoceptors and cardiac beta 1-adrenoceptors. If, as was suggested by these authors, gamma 2-MSH acts via activation of a central vasopressin system, it is via a vasopressin receptor subtype other than the vasopressin V1A receptor, since i.c.v. administration of a selective vasopressin V1A receptor antagonist failed to interfere with the pressor and cardioaccelerator effects of gamma 2-MSH.

γ-MSH, sodium metabolism, and salt-sensitive hypertension

“…Injections of ␥-MSH intravenously or into a carotid artery result in a transient pressor and cardioaccelerator response that is due to central activation of sympathetic outflow. This may involve a vasopressinergic pathway, because it is blunted in Brattleboro rats lacking vasopressin (45), although not all observations are consistent with this (119). It likely also involves a neural circuit in the anteroventral region of the third ventricle, because lesions of this region reduced the pressor response to intravenous ␥-MSH (11).…”

A study on possible modulating and direct effects of γ2-MSH and ACTH-(1–24) on the cardiovascular system of the rat

“…The absence of a direct effect on cardiovascular structures and the postulate of Gruber and Callahan (1989), which was further supported by the findings of others (Sun et al 1992;De Wildt et al 1993;Van Bergen et al 1997b) that the hemodynamic effects of γ 2 -MSH depend on an intact sympathetic nervous system led us to carry out a series of experiments to investigate possible modulating effects of the peptide at preganglionic or postganglionic level within the peripheral sympathetic nervous system. Previous studies have demonstrated that melanocortins structurally related to γ 2 -MSH, such as ACTH-(1-24), possess such a sympathetic nervous system-modulating property, which results, through activation of presynaptic ACTH (melanocortin) receptors, in a facilitation of noradrenaline release.…”

Relevance of the C‐terminal Arg‐Phe sequence in γ2‐melanocyte‐stimulating hormone (γ2‐MSH) for inducing cardiovascular effects in conscious rats

“…In addition to their e ects on the hormonal system, behaviour, temperature and feeding regulation, g-MSHs and in particular g 2 -MSH and its shorter fragment g 2 -MSH(6 ± 12) have strong e ects on the cardiovascular system (Callahan et al, 1985;Li et al, 1996;Sun et al, 1992;Van Bergen et al, 1995;1997a). Systemic administration of g 2 -MSH and g 2 -MSH(6 ± 12) to rats causes a dose-dependent increase in mean arterial pressure (MAP) and heart rate (HR).…”