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 carboxyterminal fragments of ADM, and calcitonin gene-related peptide (CGRP), a structurally related peptide, were investigated in the pulmo nary vascular bed of the rat. Under conditions of elevated tone and co ntrolled pulmonary blood flow in the isolated blood-perfused rat lung, injections of ADM, the 15-52 amino acid carboxy-terminal ADM analogue (ADM(15-52)), and CORP caused dose-related decreases in pulmonary art erial perfusion pressure. In contrast, the carboxy-terminal 22-52 and 40-52 amino acid fragments had no consistent vasodilator activity. Aft er administration of the nitric oxide synthase inhibitors, N-omega-nit ro-L-arginine benzyl ester or N-omega-nitro-L-arginine methyl ester (L -NAME), pulmonary vasodilator responses to ADM, to ADM(15-52), to CGRP , to acetylcholine, and to bradykinin were significantly decreased in the rat, whereas vasodilator responses to isoproterenol and nitroglyce rin were not changed. However, in the pulmonary vascular bed of the ca t, L-NAME had no significant effect on vasodilator responses to ADM in attenuated vasodilator responses to acetylcholine bradykinin. L-NAME had no effect on responses to isoproterenol or nitric oxide. When the relative vasodilator activity of the active peptides was compared, ADM (15-52) was approximately threefold less potent than ADM, and ADM was threefold less potent than CGRP in decreasing pulmonary vascular resis tance in the rat lung. When vasodilator responses were compared in the rat and cat, ADM was threefold more potent in decreasing pulmonary va scular resistance in the cat than in the rat, and vasodilator response s to ADM were independent of the intervention used to raise tone in th e rat. The present data demonstrate that ADM and ADM(15-52) have signi ficant vasodilator activity in the pulmonary vascular bed of the rat, and that responses to ADM, ADM(15-52), and CGRP are dependent on the r elease of nitric oxide in the rat. The present results indicate that p ulmonary 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.