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(Circulation. 2005;112:1198-1205.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Endothelial β₃-Adrenoreceptors Mediate Nitric Oxide–Dependent Vasorelaxation of Coronary Microvessels in Response to the Third-Generation β-Blocker Nebivolol

Chantal Dessy, PhD^*; Julie Saliez, BSc^*; Philippe Ghisdal, PhD; Géraldine Daneau, BSc; Irina I. Lobysheva, PhD; Françoise Frérart, BSc; Catharina Belge, MD; Karima Jnaoui, PhD; Philippe Noirhomme, MD; Olivier Feron, PhD; Jean-Luc Balligand, MD, PhD

From the Unit of Pharmacology and Therapeutics (C.D., J.S., P.G., G.D., I.I.L., F.F., C.B., K.J., O.F., J.-L.B.) and the Department of Cardiac Surgery (P.N.), Université Catholique de Louvain Medical School, Brussels, Belgium.

Correspondence to Jean-Luc Balligand, MD, PhD, Department of Medicine, Unit of Pharmacology and Therapeutics, FATH 5349, Université Catholique de Louvain, 53 Ave Mounier, B-1200 Brussels, Belgium. E-mail Balligand{at}mint.ucl.ac.be

Received December 30, 2004; revision received April 16, 2005; accepted May 9, 2005.

Background— The therapeutic effects of nonspecific β-blockers are limited by vasoconstriction, thus justifying the interest in molecules with ancillary vasodilating properties. Nebivolol is a selective β₁-adrenoreceptor antagonist that releases nitric oxide (NO) through incompletely characterized mechanisms. We identified endothelial β₃-adrenoreceptors in human coronary microarteries that mediate endothelium- and NO-dependent relaxation and hypothesized that nebivolol activates these β₃-adrenoreceptors.

Methods and Results— Nebivolol dose-dependently relaxed rodent coronary resistance microarteries studied by videomicroscopy (10 µmol/L, –86±6% of prostaglandin F2 contraction); this was sensitive to NO synthase (NOS) inhibition, unaffected by the β_1-2-blocker nadolol, and prevented by the β_1-2-3-blocker bupranolol (P<0.05; n=3 to 8). Importantly, nebivolol failed to relax microarteries from β₃-adrenoreceptor–deficient mice. Nebivolol (10 µmol/L) also relaxed human coronary microvessels (–71±5% of KCl contraction); this was dependent on a functional endothelium and NO synthase but insensitive to β_1-2-blockade (all P<0.05). In a mouse aortic ring assay of neoangiogenesis, nebivolol induced neocapillary tube formation in rings from wild-type but not β₃-adrenoreceptor– or endothelial NOS–deficient mice. In cultured endothelial cells, 10 µmol/L nebivolol increased NO release by 200% as measured by electron paramagnetic spin trapping, which was also reversed by NOS inhibition. In parallel, endothelial NOS was dephosphorylated on threonine⁴⁹⁵, and fura-2 calcium fluorescence increased by 91.8±23.7%; this effect was unaffected by β_1-2-blockade but abrogated by β_1-2-3-blockade (all P<0.05).

Conclusions— Nebivolol dilates human and rodent coronary resistance microarteries through an agonist effect on endothelial β₃-adrenoreceptors to release NO and promote neoangiogenesis. These properties may prove particularly beneficial for the treatment of ischemic and cardiac failure diseases through preservation of coronary reserve.

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