Abstract
Purpose: Nebivolol is a highly selective β1-adrenoceptor blocker with additional vasodilating properties. It has been shown that the nebivolol-induced vasorelaxation is nitric oxide (NO) dependent. The serine/ threonine protein kinase Akt phosphorylates endothelial cell NO synthase (eNOS) and enhances the ability of eNOS to generate NO. Previous studies have shown that the release of NO from the endothelium may be ascribed to the modulation of different types of K + channels. The current study was designed to determine whether K + channels or phosphatidylinositol-3-kinase (PI3K)/Akt may affect vasorelaxation induced by nebivolol in different rat arteries.
Methods: Rings of the rat aorta, carotid artery, femoral artery, and renal artery were suspended for isometric force recording. During contraction by KCl (60 mmol/L) or phenylephrine (PE; 10—6 mol/L; femoral artery and renal artery were precontracted by 10—5 mol/L), the effect of nebivolol (10—7-10— 5 mol/L) was obtained in the presence of different potassium channel, PI3K/Akt, or NOS inhibitors. Results: Nebivolol (10— 7-10—5 mol/L) relaxed precontractions induced by KCl and PE in different rat arteries, which was inhibited by the presence of the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 100 μmol/ L). The effect of nebivolol was concentration dependent. The exposure of the vessel rings to a selective inhibitor of PI3K wortmannin (5 × 10—7 mol/L) or a selective inhibitor of Akt (1L-6-hydroxymethyl-chiro-inositol 2-(R)-2-Omethyl-3-O-octadecylcarbonate, 10—5 mol/L) did not influence nebivolol-induced vasorelaxation. Similarly, K+ channels blockers, iberiotoxin (100 nmol/L), glibenclamide (0.1 mmol/L), 4-aminopyridine (1 mmol/L), or BaCl 2 (1 mmol/L) had no influence on the relaxation of nebivolol in arteries precontracted by PE. Conclusion: Nebivolol produced a concentration-dependent vasodilation in different rat arteries precontracted by PE or KCl. In the isolated rat aorta, carotid artery, femoral artery, and renal artery, neither K+ channels nor PI3K/Akt pathway was involved in the relaxation induced by nebivolol.