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  • Title: Endothelial beta3-adrenoreceptors mediate nitric oxide-dependent vasorelaxation of coronary microvessels in response to the third-generation beta-blocker nebivolol.
    Author: Dessy C, Saliez J, Ghisdal P, Daneau G, Lobysheva II, Frérart F, Belge C, Jnaoui K, Noirhomme P, Feron O, Balligand JL.
    Journal: Circulation; 2005 Aug 23; 112(8):1198-205. PubMed ID: 16116070.
    Abstract:
    BACKGROUND: The therapeutic effects of nonspecific beta-blockers are limited by vasoconstriction, thus justifying the interest in molecules with ancillary vasodilating properties. Nebivolol is a selective beta1-adrenoreceptor antagonist that releases nitric oxide (NO) through incompletely characterized mechanisms. We identified endothelial beta3-adrenoreceptors in human coronary microarteries that mediate endothelium- and NO-dependent relaxation and hypothesized that nebivolol activates these beta3-adrenoreceptors. METHODS AND RESULTS: Nebivolol dose-dependently relaxed rodent coronary resistance microarteries studied by videomicroscopy (10 micromol/L, -86+/-6% of prostaglandin F2alpha contraction); this was sensitive to NO synthase (NOS) inhibition, unaffected by the beta(1-2)-blocker nadolol, and prevented by the beta(1-2-3)-blocker bupranolol (P<0.05; n=3 to 8). Importantly, nebivolol failed to relax microarteries from beta3-adrenoreceptor-deficient mice. Nebivolol (10 micromol/L) also relaxed human coronary microvessels (-71+/-5% of KCl contraction); this was dependent on a functional endothelium and NO synthase but insensitive to beta(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 beta3-adrenoreceptor- or endothelial NOS-deficient mice. In cultured endothelial cells, 10 micromol/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 threonine(495), and fura-2 calcium fluorescence increased by 91.8+/-23.7%; this effect was unaffected by beta(1-2)-blockade but abrogated by beta(1-2-3)-blockade (all P<0.05). CONCLUSIONS: Nebivolol dilates human and rodent coronary resistance microarteries through an agonist effect on endothelial beta3-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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