Analysis of responses to adrenomedullin-(13---52) in the pulmonary vascular bed of rats

• Published in: American journal of physiology. Heart and circulatory physiology 1998-04, Vol.274 (4), p.H1255-H1263
• Main Authors: Gumusel, Bulent, Hao, Quingzhong, Hyman, Albert L, Kadowitz, Philip J, Champion, Hunter C, Chang, Jaw K, Mehta, Jawahar L, Lippton, Howard
• Format: Article
• Language: English
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.1998.274.4.H1255

1  Department of Pharmacology, Hacettepe University, Sihhiye, Ankara 06100, Turkey; 2  H. L. Laboratories, Incorporated, 3  Department of Surgery, Cardiopulmonary Research Lab and 4  Department of Pharmacology, Tulane University School of Medicine, and 7  Department of Pharmacology, Louisiana State University School of Medicine, New Orleans, Louisiana 70112; 5  Phoenix Pharmaceuticals, Incorporated, Mountain View, California 94043; and 6  Department of Medicine, University of Florida College of Medicine, Gainesville, Florida 32610 The effects of human adrenomedullin-(13 52) [hADM-(13 52)] were investigated in the rat pulmonary vascular bed and in isolated rings from the rat pulmonary artery (PA). Under conditions of controlled blood flow and constant left atrial pressure when tone was increased with U-46619, injections of hADM-(13 52) produced dose-related decreases in lobar arterial pressure. Pulmonary vasodilator responses in the intact rat and vasorelaxant responses to hADM-(13 52) in rat PA rings were inhibited by N G -nitro- L -arginine methyl ester ( L -NAME) and L - N 5 -(1-iminoethyl)ornithine hydrochloride ( L -NIO). Vasorelaxant responses to hADM-(13 52) were also inhibited by methylene blue, endothelium removal, hADM-(26 52), and iberiotoxin, whereas meclofenamate, calcitonin gene-related peptide-(8 37) [CGRP-(8 37)], glibenclamide, and apamin were without effect. Because vasorelaxant responses to NS-1619, a large-conductance Ca 2+ -activated K + channel agonist, were not altered by L -NAME and vasorelaxant responses to acetylcholine and CGRP were not altered by hADM-(26 52), the present data suggest that ADM-(13 52) acts on a receptor in the pulmonary vascular bed that is coupled to endothelial nitric oxide release. These data suggest that this nitric oxide release may lead to guanosine 3',5'-cyclic monophosphate-dependent K + channel activation, which produces a pulmonary vasorelaxant response through hyperpolarization of vascular smooth muscle cells. The present data suggest that ADM-(13 52) modulates receptor-mediated, but not voltage-dependent, pulmonary vascular contraction by influencing Ca 2+ influx. These results suggest that the ADM fragment, hADM-(13 52), acts as an endothelium-dependent vasodilator agent in the pulmonary vascular bed of the rat. nitric oxide; endothelium; blood vessels; rat pulmonary circulation; potassium channels; adrenomedullin receptor antagonist