Peroxynitrite-induced relaxation in isolated rat aortic rings and mechanisms of action.
The present study was designed to evaluate the effects of peroxynitrite (ONOO-), the product of superoxide and nitric oxide, on isolated segments of rat aorta. In the absence of any vasoactive agent, ONOO- (from 10(-8) to 10(-4) M) failed to alter the basal tension. In phenylephrine (PE; 5 x 10(-7) M)-precontracted rat aortic rings (RAR), ONOO- elicited concentration-dependent relaxation at concentrations of from 10(-8) to 10(-4) M. The effective concentrations producing approximately 50% of maximal relaxation (ED50) to ONOO- were 1.84 x 10(-5) M and 1.96 x 10(-5) M in intact and denuded RAR, respectively (P > 0.05). No significant differences in the relaxation responses were found between RAR with or without endothelium (P > 0.05). The presence of either 5 microM methylene blue (MB) or 5 microM 1H-[1,2,4]oxadiazolo-[4,3-alpha]quinoxalin-1-one (ODQ) significantly inhibited the relaxations induced by ONOO-. Sildenafil (10(-7) M), on the other hand, significantly potentiated the ONOO--induced relaxations. Tetraethylammonium chloride (T-2265) significantly decreased the ONOO--induced relaxations in a concentration-dependent manner. However, ONOO- had no effect on RAR precontracted by high KCL (40 mM, n = 6, P > 0.05). Addition of calyculin A also significantly decreased the ONOO--induced relaxation in a dose-dependent manner. Furthermore, ONOO- significantly inhibited calcium-induced contractions of K+-depolarized aortic rings in a concentration-related manner. Lastly, a variety of other pharmacological agents and antagonists including L-NMMA, L-arginine, indomethacin, atropine, naloxone, diphenhydramine, cimetine, glibenclamide, haloperidol, superoxide dismutase (SOD), and catalase did not influence the relaxant effects of ONOO- on RAR. Our new results suggest that ONOO--triggered relaxation on rat aortic rings is mediated by elevation of cGMP levels, membrane hyperpolarization via K+-channel activation, activation of myosin phosphatase activity, and interference with calcium movement and cellular membrane Ca2+ entry.
Li
Jianfeng
J
Department of Physiology and Pharmacology, State University of New York, Health Science Center at Brooklyn, Brooklyn, NY 11203, USA.
Li
Wenyan
W
Altura
Bella T
BT
Altura
Burton M
BM
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D002122:Calcium Chloride / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008387:Marine Toxins; D008751:Methylene Blue / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011687:Purines; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013450:Sulfones; D019789:Tetraethylammonium / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D008387:Marine Toxins; D010069:Oxadiazoles; D010080:Oxazoles; D010879:Piperazines; D011687:Purines; D011810:Quinoxalines; D013450:Sulfones; D014662:Vasoconstrictor Agents; D030421:Peroxynitrous Acid; D010656:Phenylephrine; D019789:Tetraethylammonium; C059041:calyculin A; D000068677:Sildenafil Citrate; D002122:Calcium Chloride; D011188:Potassium; D008751:Methylene Blue