cAMP signal transduction cascade, a novel pathway for the regulation of endothelial nitric oxide production in coronary blood vessels.
The aim of this study was to determine whether cAMP signal transduction plays a role in the regulation of endothelial nitric oxide (NO) production. Canine coronary blood vessels were isolated, and nitrite, the hydration product of NO, from these vessels was quantified by using the Griess reaction. Forskolin (10(-4) mol/L), 8-bromo-cAMP (10(-2) mol/L), or isoproterenol (10(-4) mol/L) significantly increased nitrite release to 168+/-10, 162+/-13, or 149+/-13 pmol/mg, respectively, from isolated coronary microvessels (all P<0.05; control, 86+/-3 pmol/mg). Adrenomedullin and calcitonin gene-related peptide (CGRP), both potent vasodilator peptides, also increased coronary microvascular nitrite production. N(omega)-nitro-L-arginine methyl ester, a competitive inhibitor of NO synthase, or Rp-cAMP, a protein kinase A inhibitor, markedly blocked the nitrite release induced by these agents. Forskolin and adrenomedullin also potentiated coronary NO production induced by bradykinin. In large coronary arteries, removal of the endothelium eliminated nitrite production to both forskolin and acetylcholine. Our data demonstrate that stimulation of cAMP signal transduction can substantially increase coronary NO production, indicating that there is a cAMP-mediated, endothelial NO-forming system in coronary blood vessels. Because the cAMP signal cascade can be activated by CGRP or adrenomedullin and enhance kinin-mediated nitrite production, the cAMP-NO pathway may play an important role in the regulation of cardiovascular function.
Zhang
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Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
Hintze
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D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D053607:Adrenomedullin; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism*; D046508:Culture Techniques; D000242:Cyclic AMP / Q000502:physiology*; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D010455:Peptides / Q000494:pharmacology; D015398:Signal Transduction
D010455:Peptides; D053607:Adrenomedullin; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D009569:Nitric Oxide; D000242:Cyclic AMP; D015740:Calcitonin Gene-Related Peptide; D007545:Isoproterenol; D000109:Acetylcholine; D001920:Bradykinin