Effects of simvastatin on endothelial function after chronic inhibition of nitric oxide synthase by L-NAME.

Abstract

Blood pressure, plasma NO(2) and NO(3) level, heart weight index, antioxidant enzyme activity, and vascular reactivity in rat intact aortic rings were assessed to investigate the effects of 8-week treatment with the hydroxy-methyl-glutaryl coenzyme A reductase inhibitor simvastatin (1 mg/kg per day) on endothelial dysfunction induced by chronic Nomega-nitro-l-arginine methyl ester (l-NAME 70 mg/kg per day). Results were compared with those obtained in rats receiving l-NAME, simvastatin or control animals. Coadministration of simvastatin did not restore l-NAME-increased blood pressure but normalized heart weight index (P < 0.05), endothelium-dependent relaxation to acetylcholine (P < 0.001), and plasma NO(2) and NO(3) concentration (P < 0.001) without affecting relaxation to sodium nitroprusside. Endothelium-dependent relaxation in these animals was abolished by acute incubation with l-NAME, unaffected by thromboxane synthetase inhibitor and TXA(2)/PGH(2) receptor antagonist, ridogrel, and decreased by indomethacin. Simvastatin treatment also increased plasma NO(2)+NO(3) without affecting endothelial function, heart weight index, and blood pressure of control rats. The presence of superoxide dismutase (SOD) and catalase improved endothelial relaxation only in l-NAME-treated rats, but O(2)- generated by hypoxanthine and xanthine oxidase inhibited the relaxant effect in both l-NAME and simvastatin plus l-NAME-treated rats. SOD activity was increased in all groups receiving simvastatin. Long-term treatment with simvastatin restored l-NAME-induced endothelial dysfunction, probably by preventing nitric oxide decrease. Other effects of simvastatin, including release of compensating vasodilatory cyclo-oxygenase products and increased SOD activity, could also be involved.