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

Wayne H. Kaesemeyer, Ruth B. Caldwell, Jianzhong Huang, R. William Caldwell

Research output: Contribution to journalArticle

335 Scopus citations

Abstract

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 plasma low density lipoprotein cholesterol (LDL). Both PRA and simvastatin (SIM) are equally effective in reducing LDL, but only PRA reduces platelet aggregation and is an effective vasodilator. Nitric oxide (NO) also inhibits platelet aggregation and vasodilates. Methods. We determined PRA and SIM effects on vasorelaxation in aortic rings and NO production by cultured bovine aortic endothelial cells. Nitric oxide was measured by using a 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 PRA (62.8%) and then SIM (37.1%). Direct measurement of NO confirmed that vasorelaxation is due to NO release and showed that PRA 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 PRA and SIM activate eNOS, but SIM is much less effective. Clinical benefits with PRA not explained by LDL reductions may be the result of an independent action of PRA on eNOS activation.

Original languageEnglish (US)
Pages (from-to)234-241
Number of pages8
JournalJournal of the American College of Cardiology
Volume33
Issue number1
DOIs
StatePublished - Jan 1 1999

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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