Intermedin/adrenomedullin-2 dilates the rat pulmonary vascular bed: dependence on CGRP receptors and nitric oxide release.
Intermedin/adrenomedullin-2 (IMD/AM2) is a 47 amino acid peptide formed by enzymatic degradation of preprointermedin. The present study was undertaken to investigate the effects of rat IMD (rIMD) in the isolated buffer perfused rat lung (IBPR) under resting conditions and under conditions of elevated pulmonary vasoconstrictor tone (PVT). Under resting conditions in the IBPR, rIMD had little or no activity. When PVT was actively increased by infusion of U46619, bolus injection of IMD decreased pulmonary arterial pressure (PAP) in a dose-dependent manner. Since the pulmonary perfusion rate and left atrial pressure were constant, these reductions in PAP directly reflect reductions in pulmonary vascular resistance (PVR). The pulmonary vasodilator response to rIMD, when compared to calcitonin gene-related peptide (CGRP) on a molar basis, was greater at the lowest and midrange doses. The degree of inhibition by CGRP8-37 on pulmonary vasodilator response to rIMD was significantly less when compared to CGRP. Pretreatment with L-nitro-arginine-methyl ester (L-NAME), unlike meclofenamate and glybenclamide, significantly reduced the pulmonary vasodilator responses to rIMD. rIMD administration induced cross-tachyphylaxis to the pulmonary vasodilator response to CGRP whereas CGRP administration did not alter the ability of rIMD to dilate the IBPR. Pulmonary vasodilator responses to repeated injections of rIMD did not undergo tachyphylaxis. The present data demonstrate rIMD possesses direct vasodilator activity in the rat pulmonary vascular bed. The present data suggest activation of CGRP1 receptors and release of nitric oxide (NO*) mediate the pulmonary vasodilator response to rIMD whereas cyclooxygenase products and KATP channels do not contribute to the pulmonary vasodilator response to rIMD. The ability of rIMD to induce heterologous desensitization of CGRP1 receptor activation, to retain much of its pulmonary vasodilator activity after inhibition of CGRP1 receptors, and to lack homologous desensitization together suggests the pulmonary, unlike the systemic, vasodilator response to rIMD may depend on other vasodilator mechanisms including receptors in the calcitonin-receptor-like-receptor (CRLR) family.
Burak Kandilci
H
H
Department of Pharmacology, Hacettepe University, Faculty of Pharmacy, 06100 Ankara, Turkey.
Gumusel
Bulent
B
Wasserman
Anatolio
A
Witriol
Norman
N
Lippton
Howard
H
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D053607:Adrenomedullin; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D008297:Male; D008469:Meclofenamic Acid / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000378:metabolism / Q000494:pharmacology; D009479:Neuropeptides / Q000378:metabolism / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011651:Pulmonary Artery / Q000473:pathology; D011652:Pulmonary Circulation / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
C499411:Adm2 protein, rat; D004791:Enzyme Inhibitors; D009479:Neuropeptides; D018015:Receptors, Calcitonin Gene-Related Peptide; D014662:Vasoconstrictor Agents; D053607:Adrenomedullin; D009569:Nitric Oxide; D008469:Meclofenamic Acid; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011451:Prostaglandin-Endoperoxide Synthases; D005905:Glyburide; D019331:NG-Nitroarginine Methyl Ester