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

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.