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 (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.
Martínez
V
V
CURE: Digestive Diseases Research Center, West Los Angeles Veterans Administration Medical Center, Department of Medicine and Brain Research Institute, University of California School of Medicine, 90073, USA. vmartine@ucla.edu
Cuttitta
F
F
Taché
Y
Y
D000315:Adrenalectomy; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D053607:Adrenomedullin; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005746:Gastric Emptying / Q000187:drug effects*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008747:Methylcellulose / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014628:Vagotomy
D000319:Adrenergic beta-Antagonists; D010446:Peptide Fragments; D010455:Peptides; C058636:calcitonin gene-related peptide (8-37); D053607:Adrenomedullin; D008747:Methylcellulose; D003346:Corticotropin-Releasing Hormone; D015740:Calcitonin Gene-Related Peptide; D007213:Indomethacin