Nebivolol, but not metoprolol, lowers blood pressure in nitric oxide-sensitive human hypertension

Abstract

Nebivolol, unlike other selective β1-receptor blockers, induces vasodilation attributable to increased NO bioavailability. The relative contribution of this mechanism to the blood pressure (BP)-lowering effects of nebivolol is unclear because it is normally masked by baroreflex buffering. Autonomic failure provides a unique model of hypertension devoid of autonomic modulation but sensitive to the hypotensive effects of NO potentiation. We tested the hypothesis that nebivolol would decrease BP in these patients through a mechanism independent of β-blockade. We randomized 20 autonomic failure patients with supine hypertension (14 men; 69±2 years) to receive a single oral dose of placebo, nebivolol 5 mg, metoprolol 50 mg (negative control), and sildenafil 25 mg (positive control) on separate nights in a double-blind, crossover study. Supine BP was monitored every 2 hours from 8:00 pm to 8:00 am. Compared with placebo, sildenafil and nebivolol decreased systolic BP during the night (P<0.001 and P=0.036, by mixed-effects model, maximal systolic BP reduction 8-hour postdrug of -20±6 and -24±9 mm Hg, respectively), whereas metoprolol had no effect. In a subanalysis, we divided patients into sildenafil responders (BP fall>20 mm Hg at 4:00 am) and nonresponders. Nebivolol significantly lowered systolic BP in sildenafil responders (-44±13 mm Hg) but not in nonresponders (1±11 mm Hg). Despite lowering nighttime BP, nebivolol did not worsen morning orthostatic tolerance compared with placebo. In conclusion, nebivolol effectively lowered supine hypertension in autonomic failure, independent of β1-blockade. These results are consistent with the hypothesis that NO potentiation contributes significantly to the antihypertensive effect of nebivolol.

Keywords: autonomic nervous system; hypertension; nebivolol; nitric oxide.

© 2014 American Heart Association, Inc.

Figures

Figure 1

Effect of a single oral dose of placebo, metoprolol (50mg), nebivolol (5mg) and sildenafil (25mg) on nighttime blood pressure (A) and heart rate (B) in autonomic failure patients with supine hypertension. Medications were administered at 8 PM. Changes from baseline (8 PM) in supine systolic blood pressure (ΔSBP) and heart rate (ΔHR) are expressed as mean±SEM. Sildenafil and nebivolol decreased blood pressure significantly compared with placebo (P

Figure 2

Comparison of the changes in supine systolic blood pressure (ΔSBP; Panel A) and heart rate (ΔHR; Panel B) from baseline (8 PM) to the time of the maximal blood pressure effect (4 AM, 8 hours postdrug). Nebivolol produced a significantly greater decrease SBP compared to metoprolol. Heart rate was similarly decreased in both groups. Values are expressed as mean±SEM. The P values were generated by Wilcoxon signed-rank test.

Figure 3

Effect of medications on nocturnal urinary sodium excretion (UNa+/Cr) (A) and morning upright blood pressure (calculated as the area under the curve of upright systolic blood pressure [AUCsbp] during a 10-minute standing test) (B). There were no significant differences either outcome between groups. Values are expressed as mean±SEM. Comparisons between groups were performed using one-way ANOVA.

Figure 4

Comparison of the effect of nebivolol on systolic blood pressure (ΔSBP) between responders (n=11) and non-responders (n=9) to sildenafil. Response to sildenafil was defined as a drop from baseline in SBP >20 mmHg measured at 4 AM (maximal response). Responders to sildenafil had a significant decrease in SBP with nebivolol compared with non-responders, in whom nebivolol had no effect. Values are expressed as mean±SEM. The P values were generated by Wilcoxon signed-rank test.