nitroarginine and cerivastatin

Increasing evidence suggests that statins may have pleiotropic effects on vascular wall independent of their cholesterol lowering properties. In the present study, we investigated the acute vascular effects of pravastatin, atorvastatin and cerivastatin on rat isolated aortic rings. Statins effectively and comparably relaxed the aortic rings precontracted submaximally with noradrenaline, in a concentration-dependent manner, in which a high potency was observed with cerivastatin. Endothelium removal or incubation of the aortic rings with nitric oxide synthase inhibitor L-NOARG (10(-4) M) and/or cyclooxygenase inhibitor indomethacin (10(-5) M) significantly attenuated the acute vasorelaxation induced by either of statin. Additionally, different from the other two statins, a significant reduction was observed in response to cerivastatin in the presence of KATP channel inhibitor, glibenclamide (10(-5) M) and Na+- K+ ATPase inhibitor, ouabain (10(-4) M). Furthermore, pretreatment of the rings with the cholesterol precursor mevalonate (10(-3) M) significantly inhibited the endothelium-mediated relaxant effects of the statins. Our findings suggest that statins could acutely modulate vascular tone importantly by endothelium-dependent and mevalonate-related pathways.

Topics: Animals; Aorta, Thoracic; Atorvastatin; Endothelium, Vascular; Glyburide; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Vitro Techniques; Male; Nitroarginine; Ouabain; Pravastatin; Pyridines; Pyrroles; Rats; Rats, Wistar; Vasodilation

Recent studies suggest that some of the beneficial effects of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may be due to their cholesterol-lowering independent effects on the blood vessels. Chronic inhibition of endothelial nitric oxide (NO) synthesis by oral administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) to rats induces early vascular inflammation as well as subsequent arteriosclerosis. The aim of the study is to test whether treatment with statins attenuates such arteriosclerotic changes through their cholesterol-lowering independent effects. We investigated the effect of statins (pravastatin and cerivastatin) on the arteriosclerotic changes in the rat model. We found that treatment with statins did not affect serum lipid levels but markedly inhibited the L-NAME-induced vascular inflammation and arteriosclerosis. Treatment with statins augmented endothelial NO synthase activity in L-NAME-treated rats. We also found the L-NAME induced increase in Rho membrane translocation in hearts and its prevention by statins. Such vasculoprotective effects of statins were suppressed by the higher dose of L-NAME. In summary, in this study, we found that statins such as pravastatin and cerivastatin inhibited vascular inflammation and arteriosclerosis through their lipid-lowering independent actions in this model. Such antiarteriosclerotic effects may involve the increase in endothelial NO synthase activity and the inhibition of Rho activity.

Topics: Animals; Anti-Inflammatory Agents; Arteriosclerosis; Blood Pressure; Chemokine CCL2; Coronary Vessels; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Lipids; Macrophages; Male; Monocytes; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide Synthase; Nitrites; Nitroarginine; Peptidyl-Dipeptidase A; Pravastatin; Proliferating Cell Nuclear Antigen; Pyridines; Rats; Rats, Inbred WKY; rhoA GTP-Binding Protein; RNA, Messenger; Systole; Transforming Growth Factor beta; Transforming Growth Factor beta1