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

Abstract

In conscious rats, gamma2-melanocyte-stimulating hormone (gamma2-MSH) dose-dependently increases blood pressure and heart rate, whereas adrenocorticotropin-(1-24) [ACTH-(1-24)] dose-dependently decreases blood pressure, an effect which was accompanied by a reflectory tachycardia. As the exact mechanism involved in these cardiovascular effects of the two melanocortins is as yet not known, we undertook a series of experiments to investigate the possibility that these peptides have modulating or direct effect on the cardiovascular system of the rat. In pithed rats gamma2-MSH, administered intravenously (i.v.) in doses of 5-200 nmol/kg, had no significant effect on systolic and diastolic blood pressure and on heart rate, whereas ACTH-(1-24), 5-500 nmol/kg, i.v., dose-dependently decreased blood pressure and increased heart rate. Infusion of gamma2-MSH, 10(-8) M, or ACTH-(1-24), 10(-6) M, in the isolated perfused rat heart did not significantly affect left ventricular pressure or coronary flow. Pretreatment with either gamma2-MSH or ACTH-(1-24) did not modify the responsiveness of the myocardium and coronary vasculature to salbutamol and phenylephrine. Neither gamma2-MSH nor ACTH-(1-24) did affect the vascular contractile machinery of skinned vascular smooth muscles of the rabbit with respect to Ca2+ handling in the cell, as measured by its sensitivity to exogenously applied Ca2+. Gamma2-MSH had no effect on blood pressure and heart rate in pithed rats in which postganglionic sympathetic outflow was stimulated by 1,1-dimethyl-4-phenylpiperazinium (DMPP), nor in pithed rats in which preganglionic sympathetic outflow was stimulated electrically. A dose of 15 nmol/kg ACTH-(1-24) had no significant influence on preganglionic outflow to the cardiac and vascular structures in pithed rats. These data show that gamma2-MSH does not exert its cardiovascular effects via a peripheral site of action at the level of the vascular system and the heart, nor directly on pre- or postganglionic sympathetic outflow. These results are in support for the notion that the peptide acts via a brain region localised outside the blood-brain barrier. The acute depressor effect of ACTH-(1-24), however, seems to be due to a direct effect on the vasculature in the periphery.

Central receptors mediating the cardiovascular actions of melanocyte stimulating hormones

“…Numerous earlier studies demonstrated that these cardiovascular responses occurred in conscious, unrestrained rats [15,17,18,[29][30][31][32]. Our study is the first we are aware of to demonstrate the effects of g 2 -MSH in mice, and the only one to show that the responses were almost identical in the same rodent whether anesthetized or conscious (Table 1).…”

“…pithing block the pressor and cardioaccelerator actions [3,13,29]. Numerous earlier studies demonstrated that these cardiovascular responses occurred in conscious, unrestrained rats [15,17,18,[29][30][31][32].…”

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

“…In addition, it is plausible that Arg-Phe containing peptides have direct positive chronotropic action on the heart, as application of FMRFa, MERFa and acFnLRFa on isolated molluscan heart preparations caused cardioacceleration (Painter et al, 1982). However, application of g-MSH on isolated molluscan (Greenberg et al, 1988) or rat (Van Bergen et al, 1998) heart preparations caused no cardiac e ects and in the pithed rat systemically administered g 2 -MSH (Sun et al, 1992;Van Bergen et al, 1998) or FMRFa (Thiemermann et al, 1991) does not exert cardiovascular e ects. These ®ndings suggest that g 2 -MSH does not induce cardiovascular action via a peripheral site of action.…”

“…So far, a most likely candidate receptor, involved in these cardiovascular e ects, is the melanocortin (MC) receptor. There are indications for a centrally located target for g-MSH (Sun et al, 1992;Van Bergen et al, 1998;Fodor et al, 1996). As the MC3-4 receptor subtypes are mainly expressed in the brain (Gantz et al, 1993;Mountjoy et al, 1994), these subtypes are most likely involved in g-MSH-induced cardiovascular actions.…”

Corticotropin-releasing hormone causes antidiuresis and antinatriuresis by stimulating vasopressin and inhibiting atrial natriuretic peptide release in male rats

“…To eliminate the possibility that the observed renal effects were due to CRH-induced secretion of ACTH, the peptide (10, 100, or 5,000 ng), in doses known to mimic the increase in plasma ACTH that follows the CRH administration and have been shown to affect blood pressure (17), was injected i.v. into conscious, normally hydrated animals, and their renal parameters were determined.…”