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

Blood pressure, plasma NO2 and NO3 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 N-w-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, and NO, concentration (P < 6.001) 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 indometbacin. Simvastatin treatment also increased plasma NO2+NO3 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.