Mechanism of vasodilating action of nebivolol

Abstract

A decrease in endothelium-derived relaxing factor or nitric oxide has been proposed as a potential mechanism of increased vascular resistance in hypertension. An increase in the generation of superoxide anions, which degrade nitric oxide and induce platelet aggregation, may also compromise regional blood flow in hypertension. Recent studies show that human neutrophils generate nitric oxide, which has a similar biologic profile to the endothelium-derived relaxing factor. This study measured nitric oxide synthase activity and superoxide generation in human neutrophils and platelet aggregation in patients with essential hypertension. Nitric oxide synthase activity, measured as conversion of 3H-L-arginine to 3H-L-citrulline, in peripheral blood neutrophils was decreased in hypertensive subjects (percent conversion of 3H-L-arginine: 4.2 ± 0.5 vs 9.0 ± 3.0 in control subjects; p < 0.01). Neirtrophil superoxide anion generation, measured as conversion of ferricytochrome C to ferrocytochrome C, in response to phorbol-12-myristate 13-acetate (100 ng/ml) was higher in hypertensive subjects (17.5 ± 8.1 vs 13.2 ± 3.0 nmoles/106 cells/10 minutes in control subjects; p < 0.05). Patients were treated with a selective β blocker, celiprolol, for 8 weeks. Supine blood pressure decreased from 177/103 mm Hg (mean ± SD 18/7) to 160/92 mm Hg (mean ± 10/5; p < 0.02), while heart rate was unchanged (73 ± 11 vs 69 ± 10 beats/min). Epinephrine and adenosine diphosphate-induced platelet aggregation was also increased in hypertensive subjects. Nitric oxide synthase activity increased after therapy with celiprolol (4.2 ± 0.5 to 8.9 ± 0.4%; p < 0.01), and superoxide anion generation decreased (17.5 ± 8.1 to 3.0 ± 1.0 nmoles/106 cells/10 minutes; p < 0.01). Platelet aggregation also decreased during celiprolol therapy. The increase in superoxide radical generation, decrease in nitric oxide synthase activity, and increased platelet aggregation may relate to the pathophysiology of hypertension. The novel effects of celiprolol described in this study may be the basis of cardioprotective effects of β blockers.