Central action of adrenomedullin to inhibit gastric emptying in rats

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 (ic) injection of AM or rat alpha-calcitonin gene-related peptide (alpha CGRP). AM and alpha CGRP dose-dependently inhibited gastric emptying with ic ED50 values of 120 and 100 pmol, respectively. Human proadrenomedullin N-terminal 20 peptide (150-600 pmol, ic) and AM (150 pmol, iv) had no effect. The inhibitory actions of AM and alpha CGRP (150 pmol, ic) were completely blocked by the CGRP antagonist, human CGRP-(8-37) injected ic at 30 mu g, but not at 15 mu g. The CRF antagonist, [D-Phe(12),Nle(21,38),C(alpha)MeLeu(37)]CRF-(12-41)(10 mu g/rat) injected in prevented ic rat/human CRF (150 pmol)-induced 53% inhibition of gastric emptying while not modifying the effect of AM. The action of AM (150 pmol, ic) was abolished by bilateral adrenalectomy or the beta-adrenergic blocker, propranolol (1 mg/kg, ip), but was not altered by indomethacin (5 mg/kg, ip) or subdiaphragmatic vagotomy. These results indicate that ic AM and alpha CGRP 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.