Pulmonary vasodilator responses to adrenomedullin are reduced by
nitric oxide synthase inhibitors in the rat but not in the cat.
Nossaman, Bobby Dean, Chang Jian Feng, Alan David Kaye, Brecken
Dewitt, David H. Coy, William A. Murphy, and Philip J. Kadowitz.
Departments of Anesthesiology and Pharmacology, Tulane University
Medical Center, 1430 Tulane Avenue, New Orleans, LA 70112-2699
APStracts 3:0027L, 1996.
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 analog (ADM15-52), and CGRP caused dose-related
decreases in pulmonary arterial perfusion pressure. In contrast, the
carboxy-terminal 22-52 amino acid and the carboxy-terminal 40-52
amino acid fragments had no consistent vasodilator activity.
Following administration of the nitric oxide synthase inhibitors, Nw
-nitro-l-arginine benzyl ester or Nw-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, but 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 3
fold less potent than ADM and ADM was 3 fold 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 3
fold more potent in decreasing pulmonary 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 upon 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.
Received 13 January 1995; accepted in final form 9 November 1995.
APS Manuscript Number L11-5.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 8 February 96