Pulmonary vasodilator responses to adrenomedullin are reduced by NOS inhibitors in rats but not in cats.
Responses to and the mechanism of action of adrenomedullin (ADM), the carboxy-terminal fragments of ADM, and calcitonin gene-related peptide (CGRP), a structurally related peptide, were investigated in the pulmonary vascular bed of the rat. Under conditions of elevated tone and controlled pulmonary blood flow in the isolated blood-perfused rat lung, injections of ADM, the 15-52 amino acid carboxy-terminal ADM analogue (ADM15-52), and CGRP caused dose-related decreases in pulmonary arterial perfusion pressure. In contrast, the carboxy-terminal 22-52 and 40-52 amino acid fragments had no consistent vasodilator activity. After administration of the nitric oxide synthase inhibitors, N omega-nitro-L-arginine benzyl ester or N omega-nitro-L-arginine methyl ester (L-NAME), pulmonary vasodilator responses to ADM, to ADM15-52, to CGRP, to acetylcholine, and to bradykinin were significantly decreased in the rat, whereas vasodilator responses to isoproterenol and nitroglycerin were not changed. However, in the pulmonary vascular bed of the cat, L-NAME had no significant effect on vasodilator responses to ADM in doses that attenuated vasodilator responses to acetylcholine and bradykinin. L-NAME had no effect on responses to isoproterenol or nitric oxide. When the relative vasodilator activity of the active peptides was compared, ADM15-52 was approximately three-fold less potent than ADM, and ADM was threefold less potent than CGRP in decreasing pulmonary vascular resistance in the rat lung. When vasodilator responses were compared in the rat and cat, ADM was threefold more potent in decreasing pulmonary vascular vascular resistance in the cat than in the rat, and vasodilator responses to ADM were independent of the intervention used to raise tone in the rat. The present data demonstrate that ADM and ADM15-52 have significant vasodilator activity in the pulmonary vascular bed of the rat, and that responses to ADM, ADM15-52, and CGRP are dependent on the release of nitric oxide in the rat. The present results indicate that pulmonary vasodilator responses to ADM are not dependent on the release of nitric oxide in the cat and suggest that responses to the peptide are mediated by different mechanisms in the pulmonary vascular bed of the rat and cat.
Nossaman
B D
BD
Department of Anesthesiology, Tulane University Medical Center, New Orelans, Louisiana 70112-2699, USA.
Feng
C J
CJ
Kaye
A D
AD
DeWitt
B
B
Coy
D H
DH
Murphy
W A
WA
Kadowitz
P J
PJ
D053607:Adrenomedullin; D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000737:chemistry / Q000494:pharmacology; D002415:Cats; D005260:Female; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D005996:Nitroglycerin / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D010455:Peptides; D014665:Vasodilator Agents; D053607:Adrenomedullin; C071057:N(w)-nitroarginine benzyl ester; D001120:Arginine; D019001:Nitric Oxide Synthase; D005996:Nitroglycerin; D015740:Calcitonin Gene-Related Peptide; D007545:Isoproterenol; D019331:NG-Nitroarginine Methyl Ester