Peroxynitrite induces both vasodilatation and impaired vascular relaxation in the isolated perfused rat heart

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 91; no. 26; pp. 12383 - 12387
• Main Authors: Villa, L M, Salas, E, Darley-Usmar, V M, Radomski, M W, Moncada, S
• Format: Journal Article
• Language: English
• Published: United States National Acad Sciences 20.12.1994; National Academy of Sciences
• Subjects: Acetylcholine - pharmacology; Animals; Cardiovascular disease; Coronary Circulation - drug effects; Epoprostenol - pharmacology; Isoproterenol - pharmacology; Male; Medical research; Nitrates - pharmacology; Nitric Oxide - chemistry; Penicillamine - analogs & derivatives; Penicillamine - pharmacology; Rats; Rats, Wistar; Rodents; S-Nitroso-N-Acetylpenicillamine; Vasodilation - drug effects
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.26.12383

The effects of the oxidant species peroxynitrite (ONOO-) on coronary perfusion pressure and vasodilatation elicited by acetylcholine, isoproterenol, and S-nitroso-N-acetyl-DL-penicillamine were investigated in the isolated perfused rat heart. ONOO- (0.3-1000 microM) caused a concentration-dependent vasodilatation of the coronary vasculature. This dilator response was inhibited by oxyhemoglobin, indicating that it was due to the generation of nitric oxide. Tachyphylaxis to ONOO- developed rapidly, so that the response disappeared after three or four applications of this compound. ONOO- not only induced tachyphylaxis but also inhibited the vasodilatation induced by the three vasodilators studied. This latter effect of ONOO- was critically dependent on its concentration, since it occurred at 3 microM, which was subthreshold as a dilator, and at 1000 microM, which was supramaximal, but not at 30 and 100 microM. These latter concentrations inhibited the responses to vasodilators only in the presence of oxyhemoglobin. Thus, a wide range of concentrations of ONOO- induce a vascular dysfunction, as evidenced by the tachyphylaxis to its own vasodilator actions and the long-lasting impairment of the responses to other vasodilators. However, at the same time ONOO- generates nitric oxide, which at certain concentrations of ONOO- is sufficient to counteract its deleterious action. Coinfusion of S-nitroso-N-acetyl-DL-penicillamine or prostacyclin at low concentrations that did not produce vasodilatation also protected against ONOO(-)-induced vascular dysfunction: these compounds may be protective through a common mechanism, as yet undefined.