DIFFERENT CARDIOVASCULAR PROFILES OF 3 MELANOCORTINS IN CONSCIOUS RATS - EVIDENCE FOR ANTAGONISM BETWEEN GAMMA(2)-MSH AND ACTH-(1-24)

1 We investigated the effects of [Nle(4),D-Phe(7)]alpha-melanocyte-sti mulating hormone (NDP-MSH), adrenocorticotropin-(1-24) (ACTH-(1-24)) a nd gamma(2)-MSH, three melanocortins with different agonist selectivit y for the five cloned melanocortin receptors, on blood pressure and he art rate in conscious, freely moving rats following intravenous admini stration. 2 As was previously found by other investigators as well as by us, gamma(2)-MSH, a peptide suggested to be an agonist with selecti vity for the melanocortin MC3 receptor, caused a dose-dependent, short lasting presser response in combination with a tachycardia. Despite t he fact that NDP-MSH is a potent agonist of various melanocortin recep tor subtypes, among which the melanocortin MC3 receptor, it did not af fect blood pressure or heart rate, when administered i.v. in doses of up to 1000 nmol kg(-1). 3 ACTH-(1-24) caused a dose-dependent decrease in blood pressure in combination with a dose-dependent increase in he art rate in a dose-range from 15 to 500 nmol kg(-1). The cardiovascula r effects of ACTH-(1-24) were independent of the presence of the adren als. 4 Pretreatment with ACTH-(1-24) caused a pronounced, dose-depende nt parallel shift to the right of the dose-response curve for the pres ser and tachycardiac effects of gamma(2)-MSH. The antagonistic effect of ACTH-(1-24) was already apparent following a dose of this peptide a s low as 10 nmol kg(-1), which when given alone had no intrinsic hypot ensive activity. 5 These results form further support for the notion t hat it is not via activation of one of the as yet cloned melanocortin receptors that gamma-MSH-like peptides increase blood pressure and hea rt rate. The cardiovascular effects of ACTH-(1-24) seem not to be medi ated by the adrenal melanocortin MC2 receptors, for which ACTH-(1-24) is a selective agonist, or by adrenal catecholamines. 6 There appears to be a functional antagonism between ACTH-(1-24) and gamma(2)-MSH, tw o melanocortins derived from a common precursor, with respect to their effect on blood pressure and heart rate. Whether this antagonism play s a (patho)physiological role remains to be shown.