Peroxynitrite induces both vasodilatation and impaired vascular relaxation in the isolated perfused rat heart.
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.
Villa
L M
LM
Wellcome Research Laboratories, Beckenham, Kent, United Kingdom.
Salas
E
E
Darley-Usmar
V M
VM
Radomski
M W
MW
Moncada
S
S
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects*; D011464:Epoprostenol / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009566:Nitrates / Q000494:pharmacology*; D009569:Nitric Oxide / Q000737:chemistry; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D026423:S-Nitroso-N-Acetylpenicillamine; D014664:Vasodilation / Q000187:drug effects*
D009566:Nitrates; C039642:peroxynitric acid; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D011464:Epoprostenol; D010396:Penicillamine; D007545:Isoproterenol; D000109:Acetylcholine