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 if nebivolol would restore functional sympatholysis in hypertensive humans. In 21 subjects with stage I hypertension, we measured muscle oxygenation and forearm blood flow (FBF) responses to reflex increases in sympathetic nerve activity (SNA) evoked by lower body negative pressure (LBNP) at rest and during rhythmic handgrip exercise at baseline, after 12 weeks of nebivolol (5–20 mg/day), or metoprolol (100–300 mg/day), using a double-blind crossover design. We found that nebivolol had no effect on LBNP-induced decreases in oxygenation and FBF in resting forearm (from −29±5 to −30±5% and from −29±3 to −29±3%, respectively; p=NS). However, nebivolol attenuated the LBNP-induced reduction in oxygenation and FBF 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 FBF in exercising forearm was not observed with metoprolol in the same subjects despite a similar reduction in BP. Nebivolol had no effect on SNA 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.

Differential effects of nebivolol vs. metoprolol on microvascular function in hypertensive humans

“…Other subunits such as NOX1, NOX2, or p22 phox may be altered during treatment. Nevertheless, our previous studies demonstrated no significant difference in the plasma levels of oxidative stress marker F2-isoprostanes in response to intravenous angiotensin II infusion in hypertensive patients after nebivolol treatment compared with metoprolol (24).…”

“…Treatment with metoprolol in our study also induced a small but significant increase in body weight, which may further increase in sympathetic vasoconstrictor activity. However, this is unlikely because the absolute increase in body weight is modest (1.4 kg) and our previous study showed no change in sympathetic nerve activity with the same dose of metoprolol in hypertensive patients (24). Previous studies have demonstrated an association between obesity with impaired microvascular recruitment in response to euglycemic hyperinsulinemia (4) and ingestion of mixed meal in normal volunteers (16).…”

“…However, L-NAME failed to prevent the increase in MBV during mild exercise (13). Our previous study in hypertensive patients demonstrated an augmented sympathetic mediated vasoconstriction during exercise (34), which was unaltered by metoprolol treatment (24). Nevertheless, assessment of blood flow in our previous studies was limited to the level of conduit (brachial) artery.…”

Exercise training improves functional sympatholysis in spontaneously hypertensive rats through a nitric oxide-dependent mechanism

“…Evidence suggests that functional sympatholysis is impaired in hypertensive animals (61) and patients (49,58). Additionally, the sympathetically mediated blood pressure response to exercise is also abnormally elevated in hypertensive animals (32,(41)(42)(43)(44)52) and patients (11,12,36,58).…”

Pleiotropic Effect of Nebivolol: Recent Data

“…При АГ происходят серьезные нарушения этого механизма, в основном, в результате действия ангиотензина II, вызывающему инактивацию NO. Price et al (2013) показали, что небиволол восстанавливает работу функционального симпатолиза по несвязанному с β 1 -адренорецепторами механизму, прямым путём, благодаря действию непосредственно на сосуды [8].…”