Central Action of Adrenomedullin to Inhibit Gastric Emptying in Rats*

Abstract

The central action of human adrenomedullin (AM) to influence gastric emptying and the peripheral mechanisms involved were studied in conscious rats. The 20-min rate of gastric emptying of a methylcellulose solution was assessed after intracisternal (i.c.) injection of AM or rat alpha-calcitonin gene-related peptide (alphaCGRP). AM and alphaCGRP dose-dependently inhibited gastric emptying with i.c. ED50 values of 120 and 100 pmol, respectively. Human proadrenomedullin N-terminal 20 peptide (150-600 pmol, i.c.) and AM (150 pmol, i.v.) had no effect. The inhibitory actions of AM and alphaCGRP (150 pmol, i.c.) were completely blocked by the CGRP antagonist, human CGRP-(8-37) injected i.c. at 30 microg, but not at 15 microg. The CRF antagonist, [D-Phe12,Nle(21,38),C(alpha)MeLeu37]CRF-(12-41) (10 microg/rat) injected i.c. prevented i.c. rat/human CRF (150 pmol)-induced 53% inhibition of gastric emptying while not modifying the effect of AM. The action of AM (150 pmol, i.c.) was abolished by bilateral adrenalectomy or the beta-adrenergic blocker, propranolol (1 mg/kg, i.p.), but was not altered by indomethacin (5 mg/kg, i.p.) or subdiaphragmatic vagotomy. These results indicate that i.c. AM and alphaCGRP equipotently inhibit gastric emptying through mechanisms similarly antagonized by a high dose of CGRP-(8-37). The central AM action is mediated through adrenal-dependent, beta-adrenergic pathways independently from activation of central CRF receptors.