Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions

Objectives. We tested the hypothesis that pravastatin (PRA) activates endothelial nitric oxide synthase (eNOS). Background. Pravastatin has been found to have clinical benefits beyond those predicted by its actions in reducing plasm low density lipoprotein cholesterol (LDL). Both PR and simvastatin (SIM) are equally effective in reducing LDL, but only PR reduces platelet aggregation and is an effective vasodilator. Nitric oxide (NO) also inhibits platelet aggregation and vasodilates. Methods. We determined PR and SIM effects on vasorelaxation in aortic rings and NO production by cultured bovine aortic endothelial cells. Nitric oxide was measured by using NO electrode and by an assay for conversion of hemoglobin to methemoglobin. Specificity of NOS activation was tested by using the NOS inhibitor nitro-l-arginine methyl ester (l-NAME, 1 mmol/liter) in the presence or absence of excess l-arginine (l-ARG, 1 mmol/liter). Results. Endothelium-dependent vasorelaxation was maximal with acetylocholine (ACH, 100%), followed by PR (62.8%) and then SIM (37.1%). Direct measurement of NO confirmed that vasorelaxation is due to NO release and showed that PR and ACH had similar dose-dependent effects on NO production, while SIM was only 25% to 30% as effective. Methemoglobin assay confirmed these results and demonstrated their specificity for NOS activity. The l-NAME blunted the responses to 45% of initial values. Excess l-ARG reversed this effect and potentiated NO production to 133% of initial levels. Conclusions. Both PR and SIM activate eNOS, but SIM is much less effective. Clinical benefits with PR not explained by LDL reductions may be the result of an independent action of PR on eNOS activation.