Background-Activation of the sympathetic nervous system has important prognostic implications in chronic heart failure.Nonselective versus selective ␤-adrenergic receptor antagonists may have differential effects on norepinephrine release from nerve terminals mediated by prejunctional ␤ 2 -adrenergic receptors. Methods and Results-Thirty-six patients with chronic heart failure were randomized to the nonselective ␤-blocker carvedilol or the selective ␤-blocker metoprolol (double-blind). Measurements of hemodynamics and cardiac and systemic norepinephrine spillover as well as microneurographic recordings of muscle sympathetic nerve traffic were made before and after 4 months of therapy. In the carvedilol group (nϭ17), there were significant reductions in both total body (Ϫ1.7Ϯ0.5 nmol/min, PϽ0.01) and cardiac norepinephrine spillover (Ϫ87Ϯ29 pmol/min, PϽ0.01). By contrast, in the metoprolol group (nϭ14), there were no significant changes in total body or cardiac norepinephrine spillover. Responses in the carvedilol group were significantly different from those observed in the metoprolol group (PϽ0.05). Both agents caused a reduction in heart rate and increases in pulse pressure, although mean arterial pressure did not change. Importantly, microneurographic measures of sympathetic nerve traffic to skeletal muscle did not change in either group. Conclusions-Therapy with carvedilol caused significant decreases in systemic and cardiac norepinephrine spillover, an indirect measure of norepinephrine release. Such changes were not observed in patients treated with metoprolol. There was no effect of either agent on sympathetic efferent neuronal discharge to skeletal muscle. These findings suggest that carvedilol, a nonselective ␤-blocker, caused its sympathoinhibitory effect by blocking peripheral, prejunctional ␤-adrenergic receptors. (Circulation. 2001;104:2194-2199.)

The response to Ach confirms the hypothesis that continuous GTN causes endothelial dysfunction. The responses to L-NMMA suggest that GTN therapy causes abnormalities in nitric oxide synthase (NOS) function; the vasodilation observed at the lowest infused concentration of L-NMMA in the GTN group also suggests that continuous GTN therapy is associated with a NOS-mediated production of a vasoconstrictor.