Effects of simvastatin on endothelial function after chronic inhibition of nitric oxide synthase by L-NAME.
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.
Pérez-Guerrero
Concepción
C
Department of Pharmacology, Faculty of Pharmacy, University of Seville, C/Profesor Garcia-Gonzalez s/n, 41014 Seville, Spain.
Alvarez de Sotomayor
María
M
Jimenez
Luis
L
Herrera
María Dolores
MD
Marhuenda
Elisa
E
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014665:Vasodilator Agents; D019821:Simvastatin; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester