Effect of nebivolol on endothelial nitric oxide and peroxynitrite release in hypertensive animals: Role of antioxidant activity

被引:95
作者
Mason, R. Preston
Kubant, Ruslan
Jacob, Robert F.
Walter, Mary F.
Boychuk, Bohdan
Malinski, Tadeusz
机构
[1] Ohio Univ, Dept Biochem, Athens, OH 45701 USA
[2] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc,Dept Med, Boston, MA 02115 USA
[3] Elucida Res, Beverly, MA USA
关键词
D O I
10.1097/01.fjc.0000238593.67191.e2
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
We tested the activity of nebivolol, a beta(1)-selective blocker with respect to nitric oxide (NO) and peroxynitrite (ONOO-) generation in the endothelium of normotensive Wistar Kyoto (WKY rats) and spontaneously hypertensive rats (SHR). The endothelial effects of nebivolol and its 2 optical enantiomers were correlated with its antioxidant activity and compared to another beta-blocker, atenolol, and 2 agonists of nitric oxide synthase (eNOS), calcium ionophore (CI) and acetylcholine (ACh). The effects of nebivolol on the bioavailability of NO and ONOO-, indicators of endothelial function and dysfunction, respectively, were measured in vitro using nanosensors placed in mesenteric arteries. Compared with WKY rats, treatment of SHR vessels either with ACh (1 mu mol/L) or CI (1 mu mol/L) showed marked deficiencies (> 40%, P < 0.01) in bioavailable NO concomitant with increased ONOO- levels (> 50%, P < 0.01). The [NO]/[ONOO-] ratio measured after stimulation with CI was 2.77 +/- 0.05 in WKY rats and much lower (1.14 +/- 0.11) in SHR indicating significant eNOS uncoupling and endothelial dysfunction in hypertensive animals. Treatment with nebivolol (10 mu mol/L) inhibited eNOS uncoupling and reduced endothelial dysfunction in SHR, as evidenced by an increase in the [NO]/[ONOO-] ratio to 3.09 +/- 0.04. The basis for nebivolol activity is attributed to its unique membrane interactions as determined by small-angle x-ray diffraction, as well as its antioxidant activity at nanomolar to micromolar levels. The antioxidant effects of nebivolol and its enantionters were not reproduced by atenolol. These results demonstrate that nebivolol inhibits endothelial dysfunction through a potent antioxidant mechanism attributed to its physicochemical interactions with the membrane, independent of beta(1)-blockade activity.
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页码:862 / 869
页数:8
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