Differential effects of nebivolol versus metoprolol on functional sympatholysis in hypertensive humans

Abstract

In young healthy humans, sympathetic vasoconstriction is markedly blunted during exercise to optimize blood flow to the metabolically active muscle. This phenomenon known as functional sympatholysis is impaired in hypertensive humans and rats by angiotensin II-dependent mechanisms, involving oxidative stress and inactivation of nitric oxide (NO). Nebivolol is a β1-adrenergic receptor blocker that has NO-dependent vasodilatory and antioxidant properties. We therefore asked whether nebivolol would restore functional sympatholysis in hypertensive humans. In 21 subjects with stage 1 hypertension, we measured muscle oxygenation and forearm blood flow responses to reflex increases in sympathetic nerve activity evoked by lower body negative pressure at rest, and during rhythmic handgrip exercise at baseline, after 12 weeks of nebivolol (5-20 mg/d) or metoprolol (100-300 mg/d), using a double-blind crossover design. We found that nebivolol had no effect on lower body negative pressure-induced decreases in oxygenation and forearm blood flow in resting forearm (from -29±5% to -30±5% and from -29±3% to -29±3%, respectively; P=NS). However, nebivolol attenuated the lower body negative pressure-induced reduction in oxygenation and forearm blood flow in exercising forearm (from -14±4% to -1±5% and from -15±2% to -6±2%, respectively; both P<0.05). This effect of nebivolol on oxygenation and forearm blood flow in exercising forearm was not observed with metoprolol in the same subjects, despite a similar reduction in blood pressure. Nebivolol had no effect on sympathetic nerve activity at rest or during handgrip, suggesting a direct effect on vascular function. Thus, our data demonstrate that nebivolol restored functional sympatholysis in hypertensive humans by a mechanism that does not involve β1-adrenergic receptors. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01502787.

Keywords: exercise; hypertension; muscle blood flow; sympathetic nervous system.

Conflict of interest statement

Conflict of Interest

WV received research funding from Forest Research Institute. Others have no conflict of interest to disclose.

Figures

Figure 1

Original recordings of forearm muscle oxygenation (HbO2+MbO2) responses to lower body negative pressure (LBNP) applied at rest and during rhythmic handgrip in one hypertensive subject at baseline, after 12 weeks of nebivolol, and after 12 weeks of metoprolol. LBNP induced similar decrease in muscle oxygenation at rest when compared to during nebivolol and metoprolol treatment. During handgrip, LBNP evoked reduction in muscle oxygenation, which was attenuated by nebivolol but not by metoprolol in the same subject, despite similar reduction in BP. Complete forearm vascular occlusion after the exercise produced the maximal decrease in muscle oxygenation that was used to determine the total labile signal (TLS).

Figure 2

Summary data showing changes in A. muscle oxygenation, B. FBF, C. FVC, and D. SNA in response to LBNP at rest and during handgrip in 21 hypertensive subjects. * P

Figure 3

Summary data showing the changes in MAP, FVR, and plasma F2-IsoP in response to intravenous infusion of Ang II (3 ng/kg/min) in hypertensive subjects at baseline (no drug), after treatment with nebivolol for 12 weeks, and after metoprolol for 12 weeks. * P