CLINICAL STUDIES
Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions
Wayne H. Kaesemeyer, MD*,
Ruth B. Caldwell, PhD ,
Jianzhong Huang, MD* and
R. William Caldwell, PhD*
* Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912, USA
Vascular Biology Center, Medical College of Georgia, Augusta, Georgia 30912, USA
Manuscript received September 18, 1997;
revised manuscript received August 17, 1998,
accepted September 17, 1998.
Address for correspondence: Dr. W. H. Kaesemeyer, Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912
wcaldwel{at}mail.mcg.edu
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.
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Abbreviations and Acronyms
| | ACH | = acetylcholine | | BAECs | = bovine aortic endothelial cells | | eNOS | = endothelial nitric oxide synthase | | L-ARG | = L-arginine | | LDL | = LDL cholesterol | | L-NAME | = nitro-L-arginine methyl ester | | MetHb | = methemoglobin | | NO | = nitric oxide | | PRA | = pravastatin | | SIM | = simvastatin |
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