Wh. Kaesemeyer et al., Pravastatin sodium activates endothelial nitric oxide synthase independentof its cholesterol-lowering actions, J AM COL C, 33(1), 1999, pp. 234-241
Citations number
36
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Objectives. We tested the hypothesis that pravastatin (PRA) activates endot
helial nitric oxide synthase (eNOS).
Background. Pravastatin has been found to have clinical benefits beyond tho
se predicted by its actions in reducing plasma low density lipoprotein chol
esterol (LDL). Both PRA and simvastatin (SIM) are equally effective in redu
cing LDL, but only PRA reduces platelet aggregation and is an effective vas
odilator. Nitric oxide (NO) also inhibits platelet aggregation and vasodila
tes.
Methods. We determined PRA and SIM effects on vasorelaxation in aortic ring
s and NO production by cultured bovine? aortic endothelial cells. Nitric ox
ide was measured by using a NO electrode and by an assay for conversion of
hemoglobin to methemoglobin. Specificity of NOS activation was tested by us
ing 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 acetylocholi
ne (ACH, 100%), followed by PRA (62.8%) and then SIM (37.1%). Direct measur
ement of NO confirmed that vasorelaxation is due to NO release and showed t
hat PRA and ACH had similar dose dependent effects on NO production, while
SIM was only 25% to 30% as effective. Methemoglobin assay confirmed these r
esults and demonstrated their specificity for NOS activity. The L-NAME blun
ted the responses to 45% of initial values. Excess L-ARG reversed this effe
ct 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 res
ult of an independent action of PRA on eNOS activation. (C) 1998 by the Ame
rican College of Cardiology.