Published Online
on December 5, 2005

A more recent version of this article appeared on December 13, 2005

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Submitted on April 15, 2005
Revised on August 8, 2005
Accepted on September 19, 2005

Nebivolol Reduces Nitroxidative Stress and Restores Nitric Oxide Bioavailability in Endothelium of Black Americans

R. Preston Mason PhD, Leszek Kalinowski MD, PhD, Robert F. Jacob PhD, Adam M. Jacoby BS, and Tadeusz Malinski PhD^*

From the Department of Biochemistry, Ohio University, Athens, Ohio (L.K., A.M.J., T.M.); Elucida Research, Beverly, Mass (R.P.M., R.F.J.); and Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (R.P.M.). Dr Kalinowski was on sabbatical leave from the University of Gdansk.

^* To whom correspondence should be addressed. E-mail: malinski{at}ohiou.edu.

Background--Alterations in endothelial function may contribute to increased susceptibility of black Americans to cardiovascular disease. The ability to pharmacologically reverse endothelial dysfunction in blacks was tested with nebivolol, a ₁-selective agent with vasodilating and antioxidant properties.

Methods and Results--The effects of nebivolol on endothelial nitric oxide (NO), superoxide (O₂^-), and peroxynitrite concentration (ONOO^-) release were studied in human umbilical vein endothelial cells and iliac artery endothelial cells isolated from age-matched black and white donors. Kinetics and concentrations of NO/O₂^-/ONOO^- were measured simultaneously with nanosensors from single cells and shown to have significant interracial differences. The rate of NO release was 5 times slower in blacks than in whites (94 versus 505 nmol · L^-1 · s^-1), whereas the rates of release were faster by 2 times for O₂^- and 4 times for ONOO^- (22.1 versus 9.4 nmol · L^-1 · s^-1 for O₂^- and 810 versus 209 nmol · L^-1 · s^-1 for ONOO^-). Pretreatment with 1.0 to 5.0 µmol/L nebivolol restored NO bioavailability in endothelial cells from black donors with concurrent reductions in O₂^- and ONOO^- release, similar to levels in the endothelium of whites. The effects of nebivolol were dose-dependent and not observed with atenolol; similar effects were observed with apocynin, an NAD(P)H oxidase inhibitor.

Conclusions--Reduced endothelial NO bioavailability in American blacks is mainly due to excessive O₂^- and ONOO^- generation by NAD(P)H and uncoupled endothelial NO synthase. Nebivolol decreased O₂^- and ONOO^- concentrations and restored NO bioavailability in blacks to the level recorded in cells from whites, independently of ₁-selective blockade.

Key words: cardiovascular diseases • endothelium • nitric oxide • beta-blockers • ethnic groups

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