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(Hypertension. 2007;50:652.)
© 2007 American Heart Association, Inc.

Original Articles

Nebivolol Induces Nitric Oxide Release in the Heart Through Inducible Nitric Oxide Synthase Activation

Angelo Maffei; Alba Di Pardo; Rosa Carangi; Pierluigi Carullo; Roberta Poulet; Maria T. Gentile; Carmine Vecchione; Giuseppe Lembo

From the Department of AngioCardioNeurology (A.M., A.D.P., R.C., P.C., R.P., M.T.G., C.V., G.L.), IRCCS Neuromed, Pozzilli, Italy; and the Department of Experimental Medicine (G.L.), La Sapienza University of Rome, Rome, Italy.

Correspondence to Giuseppe Lembo, Department of AngioCardioNeurology, IRCCS Neuromed, Localita’ Camerelle, 86077 Pozzilli, Italy. E-mail lembo{at}neuromed.it

Nebivolol is a ß1-adrenergic receptor antagonist that also reduces blood pressure by evoking endothelial NO production and vasodilation. We aimed at assessing whether nebivolol induces NO production also in the heart and delineating the molecular mechanisms involved. Using the fluorescent probe diaminofluorescein, we found that nebivolol induces a dose-dependent NO production in the heart, statistically significant already at 10^–7 mol/L. It is not an effect because of the blockade of ß1-adrenergic receptor, because this effect is not shared by another drug of the same class, atenolol. Because nebivolol has been reported to act as an agonist on other ß-adrenergic receptors, we tested NO production in the presence of receptor antagonists. Nebivolol was not able to induce NO production in presence of the ß3-antagonist SR59230A, indicating a fundamental role for ß3-adrenergic receptors in cardiac NO production by nebivolol. Moreover, inducible NO synthase inhibition abolishes NO release in the heart, indicating that nebivolol induces NO production by acting on the inducible isoform of the enzyme. The action of nebivolol on inducible NO synthase was confirmed by real-time PCR experiments, showing cardiac overexpression of inducible NO synthase but not neuronal NO synthase or endothelial NO synthase, after 5 hours of treatment with nebivolol. In conclusion, our study demonstrates that nebivolol also stimulates NO production in the heart. This action of nebivolol is exerted via a signaling pathway starting from the activation of ß3-adrenergic receptors and leading to overexpression of inducible NO synthase. Cardiac NO production by nebivolol could participate in the cardiovascular effects of nebivolol treatment in patients affected by hypertension and heart failure.

Key Words: adrenergic agents • adrenergic beta receptors • heart • NO • NO synthase

This article has been cited by other articles:

				A. Maffei and G. Lembo Nitric oxide mechanisms of nebivolol Therapeutic Advances in Cardiovascular Disease, August 1, 2009; 3(4): 317 - 327. [Abstract] [PDF]

				B. Rozec, M. Erfanian, K. Laurent, J.-N. Trochu, and C. Gauthier Nebivolol, a vasodilating selective beta(1)-blocker, is a beta(3)-adrenoceptor agonist in the nonfailing transplanted human heart. J. Am. Coll. Cardiol., April 28, 2009; 53(17): 1532 - 1538. [Abstract] [Full Text] [PDF]