The cellular mechanisms involved in the vasodilator effect of nebivolol on the renal artery.
Nebivolol is known as a highly selective beta1-adrenoceptor antagonist. Based on the reported vasodilator effect of nebivolol, we examined the cellular mechanisms by which the drug induces renal artery vasodilation, an issue of potential relevance for condition associated with high blood pressure. To this purpose, myograph and patch-clamp techniques were used. Small mouse renal arteries were placed in the myograph chamber, and after the optimal concentration for the vasodilator effect of nebivolol was established (50 microM), the arteries were further investigated to assess the potential contribution of nitric oxide (NO) and of Ca2+ ions to the nebivolol-induced effect, by exposing the arteries to the specific inhibitors such as N(G)-nitro-L-arginine methylester (L-NAME, 100 microM), ethylenglycol-bis-(beta-amino-ethylen ester) N,N'-tetraacetic acid (EGTA, 4 microM) and thapsigargin (1 microM). The expression of NO synthase was evaluated by the Western-blot technique. Using myograph and patch-clamp techniques applied on intact renal artery, we investigated the role of beta2-adrenoceptors, of myoendothelial junctions and of Ca(2+)-activated K+ channels in the vasodilatory effects of nebivolol, using 100 microM butoxamine, 40 microM 18 beta-glycyrrhetinic acid, 1 mM tetraethylammonium, and 100 nM iberiotoxin, respectively. The results showed that the cellular mechanisms of the vasodilator effect of nebivolol on the renal artery entail (i) activation of the endothelial beta2-adrenoceptor, (ii) participation of [Ca2+]i, (iii) increase in NO and eNOS, and (iv) activation of Ca(2+)-activated K+ channels. The cellular mechanisms underlying vasodilator effect of nebivolol on the artery explain the favorable effect of this drug in hypertension.
Georgescu
Adriana
A
Institute of Cellular Biology and Pathology Nicolae Simionescu, 8, BP Hasdeu Street, PO Box 35-14, 050568-Bucharest, Romania. georgescu@mail.instcellbiopath.ro
Pluteanu
Florentina
F
Flonta
Maria-Luisa
ML
Badila
Elisabeta
E
Dorobantu
Maria
M
Popov
Doina
D
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology*; D066298:In Vitro Techniques; D042541:Intracellular Space / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D000068577:Nebivolol; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology; D012077:Renal Artery / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D024681:Potassium Channels, Calcium-Activated; D018343:Receptors, Adrenergic, beta-2; D014665:Vasodilator Agents; D000068577:Nebivolol; D009569:Nitric Oxide; D004533:Egtazic Acid; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester