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Central Action of Adrenomedullin to Inhibit Gastric Emptying in Rats¹

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, Los Angeles, California 90073; Biomarkers and Prevention Research Branch, Division of Cancer Prevention and Control, National Cancer Institute, National Institutes of Health (F.C.), Rockville, Maryland 20850-3300

Address all correspondence and requests for reprints to: Vicente Martínez, D.V.M., Ph.D., West Los Angeles Veterans Administration Medical Center, Building 115, Room 203, 11301 Wilshire Boulevard, Los Angeles, California 90073. E-mail: vmartine{at}ucla.edu

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 -calcitonin gene-related peptide (CGRP). AM and 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 CGRP (150 pmol, ic) were completely blocked by the CGRP antagonist, human CGRP-(8–37) injected ic at 30 µg, but not at 15 µg. The CRF antagonist, [D-Phe¹²,Nle^21,38,CMeLeu³⁷]CRF-(12–41) (10 µg/rat) injected ic 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 ß-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 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, ß-adrenergic pathways independently from activation of central CRF receptors.

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