Department of Pharmacology, Shanxi Medical University, Taiyuan, Shanxi Province, People's Republic of China.
J Cardiovasc Pharmacol Ther. 2009 Dec;14(4):332-8. doi: 10.1177/1074248409350138.
Nebivolol is a highly selective beta(1)-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.
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.
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 N(G)-nitro-L-arginine methyl ester (L-NAME; 100 micromol/ L). The effect of nebivolol was concentration dependent. The exposure of the vessel rings to a selective inhibitor of PI3K wortmannin (5 x 10(-7) mol/L) or a selective inhibitor of Akt (1L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-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.
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.
比索洛尔是一种高选择性的β1-肾上腺素受体阻滞剂，具有额外的血管扩张作用。已经表明，比索洛尔诱导的血管舒张依赖于一氧化氮（NO）。丝氨酸/苏氨酸蛋白激酶 Akt 磷酸化内皮细胞一氧化氮合酶（eNOS），并增强 eNOS 生成 NO 的能力。先前的研究表明，NO 从内皮细胞的释放可能归因于不同类型的 K(+)通道的调节。本研究旨在确定 K(+)通道或磷脂酰肌醇-3-激酶（PI3K）/Akt 是否可能影响不同大鼠动脉中比索洛尔诱导的血管舒张。
大鼠主动脉、颈总动脉、股动脉和肾动脉的环被悬挂用于等长力记录。在用 KCl（60 mmol/L）或苯肾上腺素（PE；10(-6)mol/L）收缩时，在不同的钾通道、PI3K/Akt 或 NOS 抑制剂存在下获得比索洛尔（10(-7)-10(-5)mol/L）的作用。
比索洛尔（10(-7)-10(-5)mol/L）松弛不同大鼠动脉中由 KCl 和 PE 引起的预收缩，NOS 抑制剂 N(G)-硝基-L-精氨酸甲酯（L-NAME；100μmol/L）的存在抑制了这种作用。比索洛尔的作用呈浓度依赖性。血管环暴露于 PI3K 的选择性抑制剂wortmannin（5 x 10(-7)mol/L）或 Akt 的选择性抑制剂（1L-6-羟甲基-手性肌醇 2-（R）-2-O-甲基-3-O-十八烷基碳酸酯，10(-5)mol/L）并不影响比索洛尔诱导的血管舒张。同样，K(+)通道阻滞剂， Iberiotoxin（100nmol/L）、Glibenclamide（0.1mmol/L）、4-氨基吡啶（1mmol/L）或 BaCl(2)（1mmol/L）对 PE 预收缩的动脉中比索洛尔的舒张没有影响。
比索洛尔在 PE 或 KCl 预收缩的不同大鼠动脉中产生浓度依赖性血管舒张。在分离的大鼠主动脉、颈总动脉、股动脉和肾动脉中，K(+)通道或 PI3K/Akt 途径均不参与比索洛尔诱导的舒张。
