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(Circulation. 2002;105:933.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Increased Nitric Oxide Bioavailability in Endothelial Cells Contributes to the Pleiotropic Effect of Cerivastatin

Leszek Kalinowski, MD; Lawrence W. Dobrucki, MS; Viktor Brovkovych, PhD; Tadeusz Malinski, PhD

From the Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio.

Correspondence to Dr Tadeusz Malinski, Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701. E-mail malinski{at}ohio.edu

Background— Although statins preserve endothelial function by reducing serum cholesterol levels, it has been suggested they may also stimulate nitric oxide (NO) synthase in endothelium with concurrent increase in superoxide (O₂^-) generation, leading to impairment of NO activity. Therefore, measurements of biologically active NO and O₂^- in endothelium after exposure to the HMG-CoA reductase inhibitor cerivastatin were undertaken to evaluate its potential effect on NO biological activity.

Methods and Results— Highly sensitive electrochemical NO and O₂^- microsensors were placed near the surface of a single human umbilical vein endothelial cell, and the kinetics of NO and O₂^- release were recorded in vitro. Cerivastatin demonstrated a time-dependent effect on NO release in endothelial cells. The initial release (approximately the first 3 minutes) was concentration-dependent (0.01 to 10 µmol/L) and was similar to that observed for typical NO synthase agonists calcium ionophore or acetylcholine. Cerivastatin stimulated NO release at a favorable rate and scavenged O₂^-, which led to the preservation of the active concentration of NO. The sustained effect (after 6 hours) of cerivastatin on endothelium was associated with an 35% increase in NO release as compared with the initial effect. In contrast to the initial effect, the sustained effect of cerivastatin was shown at concentrations 100-fold lower and was dependent on inhibition of endothelial HMG-CoA reductase.

Conclusions— These data provide direct evidence to prove that in the presence of cerivastatin, the NOS system in endothelium operates with high efficiency toward increasing NO activity by activation of NO release and by concurrent inactivation of O₂^-.

Key Words: nitric oxide • nitric oxide synthase • endothelium • cholesterol • atherosclerosis

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