Nebivolol reduces nitroxidative stress and restores nitric oxide bioavailability in endothelium of black Americans

Abstract

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 β 1-selective agent with vasodilating and antioxidant properties. Methods and Results - The effects of nebivolol on endothelial nitric oxide (NO), superoxide (O 2-), 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/O 2-/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 O 2- and ≈4 times for ONOO - (22.1 versus 9.4 nmol·L -1·s -1 for O 2- 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 O 2- 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 O 2- and ONOO - generation by NAD(P)H and uncoupled endothelial NO synthase. Nebivolol decreased O 2- and ONOO - concentrations and restored NO bioavailability in blacks to the level recorded in cells from whites, independently of β 1-selective blockade. © 2005 American Heart Association, Inc.