Loss of K⁺_ATP-channel-mediated vasodilation after induction of tachyphylaxis to peroxynitrite

Systemic injections of peroxynitrite elicit pronounced vasodilator responses in rats by activation of ATP-dependent K⁺ channels (K ⁺ _ATP-channels). The aim of this study was to determine whether development of tachyphylaxis to the vasodilator actions of peroxynitrite involves the loss of K⁺_ATP-channel function. The falls in mean arterial blood pressure (MAP) and mesenteric and hindquarter vascular resistances produced by the K⁺_ATP-channel agonist, cromakalim (3-18 μg/kg, iv), and the nitric oxide (NO) donor, sodium nitroprusside (SNP; 1-4 μg/kg, iv), were determined in pentobarbital- anesthetized rats before and after induction of tachyphylaxis to peroxynitrite induced by the administration of 10 injections of peroxynitrite (10 μmol/kg, iv). The first dose of peroxynitrite elicited pronounced falls in MAP and vascular resistances whereas the tenth injection elicited much smaller responses that were equivalent to those of decomposed peroxynitrite. Before induction of tachyphylaxis to peroxynitrite, cromakalim and SNP produced dose-dependent reductions in MAP and vascular resistances. The hemodynamic actions of cromakalim were markedly attenuated after induction of tachyphylaxis to peroxynitrite whereas the SNP-induced responses were only slightly attenuated. These results suggest that tachyphylaxis to the vasodilator actions of peroxynitrite involves the loss of K⁺_ATP-channel function whereas tachyphylaxis to peroxynitrite minimally affects NO-mediated vasodilation. Taken together, these findings raise the possibility that peroxynitrite inhibits K⁺_ATP-channel function by oxidation and/or nitration of amino acids in these channels.