Endothelial beta3-adrenoreceptors mediate nitric oxide-dependent vasorelaxation of coronary microvessels in response to the third-generation beta-blocker nebivolol
| Autor: | Philippe Ghisdal, Philippe Noirhomme, Jean-Luc Balligand, Karima Jnaoui, Irina Lobysheva, Olivier Feron, Catharina Belge, Françoise Frérart, Julie Saliez, Géraldine Daneau, Chantal Dessy |
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| Přispěvatelé: | UCL - MD/MINT - Département de médecine interne, UCL - MD/CHIR - Département de chirurgie, UCL - (SLuc) Service de chirurgie cardiovasculaire et thoracique, UCL - (SLuc) Service de médecine interne générale |
| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
Male
medicine.medical_specialty Endothelium Nitric Oxide Synthase Type III Adrenergic beta-Antagonists Endothelium-derived factors Vasodilation Endothelial NOS Nitric Oxide Nitric oxide Nebivolol chemistry.chemical_compound Mice Physiology (medical) Internal medicine Coronary Circulation medicine Animals Humans Benzopyrans Phosphorylation Rats Wistar Nitrites Tube formation Nitrates biology business.industry Microcirculation Nitric oxide synthase Rats medicine.anatomical_structure Endocrinology chemistry Receptors Adrenergic beta Ethanolamines Receptors Adrenergic beta-3 Bupranolol biology.protein Calcium Endothelium Vascular Angiogenesis Cardiology and Cardiovascular Medicine business medicine.drug |
| Zdroj: | Circulation, Vol. 112, no.8, p. 1198-1205 (2005) |
| Popis: | 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 β 1 -adrenoreceptor antagonist that releases nitric oxide (NO) through incompletely characterized mechanisms. We identified endothelial β 3 -adrenoreceptors in human coronary microarteries that mediate endothelium- and NO-dependent relaxation and hypothesized that nebivolol activates these β 3 -adrenoreceptors. Methods and Results— Nebivolol dose-dependently relaxed rodent coronary resistance microarteries studied by videomicroscopy (10 μmol/L, −86±6% of prostaglandin F2α 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 3 -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 3 -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 threonine 495 , 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 Conclusions— Nebivolol dilates human and rodent coronary resistance microarteries through an agonist effect on endothelial β 3 -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. |
| Databáze: | OpenAIRE |
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