S-nitrosothiols such as the putative endothelium-derived relaxing factor, L–S-nitrosocysteine, possess biological activity that is independent of their decomposition to nitric oxide (NO). Peroxynitrite is a powerful oxidant of protein and non-protein sulfhydryls and readily nitrates free and protein-associated tyrosine residues. Systemic injections of peroxynitrite elicit pronounced vasodilator responses in anaesthetized rats, which are subject to tachyphylaxis (Benkusky et al. 1998; Graves et al. 1998). Interestingly, the haemodynamic responses elicited by a variety of G protein-coupled receptor agonists are diminished after induction of tachyphylaxis to peroxynitrite. We have provided evidence that L–S-nitrosocysteine recognition sites may contain cysteine residues that are subject to oxidation (i.e. disulphide-bond formation) (Hoque et al. 1999, 2000). Accordingly, the aim of this study was to determine whether the vasodilator actions of L–S-nitrosocysteine are modified after induction of tachyphylaxis to peroxynitrite.

This study determined whether induction of tachyphylaxis to peroxynitrite (induced by giving ten I.V. injections of a 10 mmol kg^-1 dose) alters the haemodynamic actions of L–S-nitrosocysteine (12.5-100 nmol kg^-1, I.V.), in pentobarbitone-anaesthetized rats. Animals were humanley killed at the end of each experiment. L–S-nitrosocysteine elicited dose-dependent reductions in mean arterial blood pressure and in hindquarter and mesenteric vascular resistances. These responses were substantially attenuated after administration of peroxynitrite. For example, maximum fall in blood pressure to L–S-nitrosocysteine changed from -40 ± 5 % (control) to -13 ± 3 % (peroxynitrite treated; P < 0.05) and maximum fall in hindquarter resistance changed from -55 ± 7 % (control) versus 19 ± 3 % (peroxynitrite treated; P < 0.05, t test, n = 6). We have previously reported that the hypotensive and, and vasodilator actions of the NO donor (Z)-1-(N-methyl-N-(6(N-methylammoniohexyl)amino))diazen-1-ium-1,2-diolate (MAHMA NONOate) are not attenuated by induction of tachyphylaxis to peroxynitrite (Benkusky et al. 1998).

This study demonstrates that peroxynitrite diminishes L–S-nitrosocysteine-induced hypotension and vasodilatation although peroxynitrite does not impair NO-mediated hypotension and vasodilatation. These data support the concept that peroxynitrite reduces the vasodilator actions of L–S-nitrosocysteine via oxidation and/or nitration of S-nitrosothiol recognition sites.