Sympathetic nervous system mediation of acute cardiovascular actions of gamma 2-melanocyte-stimulating hormone.

Abstract

SUMMARY Peptides of the pro-opiocortin class produce pronounced cardiovascular and natriuretic actions. We have investigated the acute cardiovascular effects of one of the most potent members of this class, y 2 -melanocyte stimulating hormone (y 2 -MSH), in rats. Pressor actions of y 2 -MSH administered systemicaMy were eliminated by ganglionic blockade with chlorisondamine. Peripheral cholinergic blockade failed to affect either the pressor or cardioaccelerator responses to y 2 -MSH. Administration of y r MSH (2.0-10.0 /xg) produced vasoconstriction primarily in the mesenteric and hindlimb vascular beds, while the renal bed showed little response. Infusions of phenylephrine produced pressor responses similar to those found with y 2 -MSH, which were accompanied by a decrease in heart rate and vasoconstriction in the mesenteric and renal vascular beds. Hemodynamic changes produced by y 2 -MSH and phenylephrine were blocked or attenuated by a,-adrenergic receptor blockade with pra/.osin. Direct injection of y 2 -MSH into the renal artery produced an acute renal vasoconstriction that was not attenuated by a,-adrenergic or ganglionic blockade. These findings and the results of previous publications are consistent with the hypothesis that y 2 -MSH may produce a centrally mediated activation of the sympathetic nervous system, have direct vasoconstriction actions on the renal vasculature, and inhibit baroreceptor function to produce an increase in blood pressure without an accompanying bradycardia. -10 produce pressor, cardioaccelerator, and natriuretic actions. 4 The cardiovascular actions of the peptides appear to result from direct activation of the sympathetic nervous system, in that the pressor and cardioaccelerator actions From the

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

“…This suggests that the baroreceptor re¯ex-mediated reduction of tonic sympathetic activity due to pressor e ects is inhibited by these peptides. This agrees with ®ndings of Callahan et al (1985;, who reported that the pressor response to g 2 -MSH in conscious rats was blocked by the ganglionic blocking agent chlorisondamine or by blockade of the catecholamine release from sympathetic nerve terminals with bretylium tosylate. Others showed that pressor responses to Arg-Phe containing peptides in anaesthetized rats was reduced by the ganglionic blocking agent hexamethonium (Barnard & Dockray, 1984b).…”

“…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).…”

Melanocortin Antagonists Define Two Distinct Pathways of Cardiovascular Control by α- and γ-Melanocyte-Stimulating Hormones

“…SHU9005 is a novel, potent antagonist of the cloned, transfected rat MC3-R (pA 2 , 8.6) and a full agonist at the cloned human MC4-R (EC50, 4.7 ϫ 10 Ϫ10 M; Kesterson and Cone, unpublished observations). In agreement with published findings (Callahan et al, 1985), the ␣ 1 -adrenergic receptor antagonist prazosin, 0.1 mg/kg intravenously, inhibited the pressor response, whereas the ␤-blocker propranolol, 1 mg/kg intravenously, inhibited the tachycardia elicited by ␥-MSH (data not shown).…”

“…In contrast to the cardiovascular depressor effects elicited in the DVC, intravenous injection of higher doses of MSH peptides has been reported to cause pressor and tachycardic effects (Callahan et al, 1985;1988;Gruber and Callahan, 1989;Sun et al, 1992;De Wildt et al, 1993). Indeed, intravenous injection of melanocortins or some of their analogs was found to improve survival in experimental hemorrhagic shock (Bertolini et al, 1986).…”

“…Indeed, intravenous injection of melanocortins or some of their analogs was found to improve survival in experimental hemorrhagic shock (Bertolini et al, 1986). Findings to date also indicate that these effects are mediated indirectly via activation of sympathetic outflow to the heart and vasculature (Callahan et al, 1985) and therefore are likely to be of central origin. In the present experiments, ␥-MSH was both more potent and efficacious in increasing blood pressure and heart rate via intracarotid as compared with intravenous administration, whereas ␣-MSH was ineffective via either route.…”