Nitroglycerin (exogenous nitric oxide) substitutes for endothelium-derived nitric oxide in potentiating vasorelaxations and cyclic AMP elevations induced by calcitonin gene-related peptide (CGRP) in rat aorta.
Rat calcitonin gene-related peptide (rCGRP) causes endothelium-dependent vasorelaxations via a dual signal transduction mechanism involving elevations of both cyclic AMP and cyclic GMP levels in rat aorta. These responses are all dependent on de novo synthesis of nitric oxide (NO) in endothelial cells and appear to involve a mechanistic link between cyclic GMP and cyclic AMP responses in smooth muscle cells. The present study determined whether NO from an exogenous source (i.e. added nitroglycerin) could substitute for endogenous NO in rCGRP-induced responses in endothelium-denuded aorta. Nitroglycerin (1 microM) significantly elevated cyclic GMP levels by 20-fold and 3.3-fold and cyclic AMP levels by 26% and 22% at 1 and 2 min, respectively. By itself, rCGRP (100 nM) did not significantly elevate cyclic AMP levels. In combination, however, nitroglycerin and rCGRP caused more-than-additive cyclic AMP elevations (41% above basal at 1 and 2 min). Nitroglycerin also potentiated rCGRP-induced vasorelaxations in endothelium-denuded rings, thus uncovering a direct (endothelium-independent) relaxant effect of rCGRP in rat aorta. The data indicate that exogenous NO can substitute for endogenous NO in rCGRP-induced relaxant and cyclic AMP responses in aorta. This nitroglycerin-induced potentiation of CGRP effects likely involves inhibition of cyclic-GMP-inhibited-phosphodiesterase in smooth muscle cells, thus allowing cyclic AMP to accumulate and mediate the direct vasodilator effects of rCGRP.
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Department of Physiology and Biophysics, University of Kentucky College of Medicine, Lexington 40536-0230.
Hao
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H
Wang
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X
Arden
W A
WA
Diana
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JN
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000502:physiology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D005996:Nitroglycerin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014664:Vasodilation / Q000187:drug effects*
D009569:Nitric Oxide; D000242:Cyclic AMP; D005996:Nitroglycerin; D006152:Cyclic GMP; D015740:Calcitonin Gene-Related Peptide