Attenuation of vascular relaxation after development of tachyphylaxis to peroxynitrite in vivo.

Peroxynitrite, formed endogenously by the near diffusion-limited reaction of nitric oxide with superoxide anion, induces vascular relaxation. This effect is subject to rapid tachyphylaxis, suggesting that peroxynitrite may alter subsequent vasorelaxant responses. The present study examined the effects of peroxynitrite on mean arterial pressure and hindquarter, renal, and mesenteric vascular resistances in pentobarbital-anesthetized rats. Peroxynitrite induced dose-dependent decreases in mean arterial pressure and hindquarter and mesenteric vascular resistances. The repetitive administration of peroxynitrite resulted in the rapid development of tachyphylaxis, with subsequent doses producing progressively smaller effects. After the development of tachyphylaxis to peroxynitrite, the hemodynamic effects produced by the systemic administration of acetylcholine and prostacyclin were significantly attenuated, whereas the hemodynamic responses to bradykinin and the nitric oxide donor ( Z)-1-{ N-methyl- N-[6( N-methylammoniohexyl)amino]}diazen-1-ium-1,2-diolate (MAHMA NONOate) remained unchanged. These results demonstrate that 1) peroxynitrite is a potent vasorelaxant in vivo, 2) peroxynitrite-mediated vasodilatation is subject to the development of rapid tachyphylaxis, and 3) peroxynitrite alters the vascular smooth muscle response to prostacyclin, perhaps via inactivation of vascular smooth muscle ATP-sensitive potassium channel function.