Sánchez Ana, Villalba Nuria, Martínez Ana Cristina, García-Sacristán Albino, Hernández Medardo, Prieto Dolores
Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid, Spain.
Eur J Pharmacol. 2008 May 31;586(1-3):283-7. doi: 10.1016/j.ejphar.2008.03.002. Epub 2008 Mar 13.
The aim of the present study was to investigate the mechanisms underlying the vasorelaxation induced by the selective phosphodiesterase 5 (PDE5) inhibitor vardenafil in rat penile small arteries. Segments of the rat dorsal penile artery were mounted in microvascular myographs for isometric tension recording. Concentration-response curves for vardenafil (1 nM-3 microM) and other PDE inhibitors (sildenafil, rolipram and milrinone) were constructed by adding cummulative concentrations of the drugs to arteries precontracted with phenylephrine. The effect of mechanical endothelial cell removal and of selective blockers of the nitric oxide (NO)/cGMP pathway and K+ channels were evaluated on the vardenafil relaxant responses. Vardenafil was the most potent of the four PDE inhibitors tested that maximally relaxed penile arteries, pD2 and maximum relaxation being 6.96+/-0.08 and 97+/-1% (n=48), respectively. Blockade of guanylate cyclase with ODQ (5 microM), mechanical removal of the endothelium or inhibition of NO synthase with l-NOARG (100 microM) markedly reduced vardenafil-induced relaxations, without altering maximum response. Inhibitors of both the cGMP-dependent (PKG) and the cAMP-dependent (PKA) protein kinases, Rp-8-Br-PET-cGMPS (5 microM) and Rp-8-CPT-cAMPS (50 microM), respectively, both reduced vardenafil relaxant responses and the later abolished that of rolipram. Vardenafil-elicited relaxation was reduced by the selective inhibitor of the large-conductance Ca2+-activated K+ channels (BK(Ca)), iberiotoxin (30 nM) and also by the ATP-sensitive K+ channel (K(ATP)) inhibitor, glibenclamide (1 microM). Vardenafil induces a potent vasodilatation in rat penile arteries that is partially dependent on the endothelium and the NO/cGMP pathway and involves activation of both BK(Ca) and K(ATP) channels.
本研究的目的是探究选择性磷酸二酯酶5（PDE5）抑制剂伐地那非诱导大鼠阴茎小动脉血管舒张的潜在机制。将大鼠阴茎背动脉段安装在微血管肌动描记器上以记录等长张力。通过向用去氧肾上腺素预收缩的动脉中累积添加药物浓度，构建伐地那非（1 nM - 3 μM）和其他PDE抑制剂（西地那非、咯利普兰和米力农）的浓度 - 反应曲线。评估机械去除内皮细胞以及一氧化氮（NO）/环磷酸鸟苷（cGMP）途径和钾通道的选择性阻滞剂对伐地那非舒张反应的影响。伐地那非是所测试的四种PDE抑制剂中最有效的，能最大程度地舒张阴茎动脉，pD2和最大舒张率分别为6.96±0.08和97±1%（n = 48）。用ODQ（5 μM）阻断鸟苷酸环化酶、机械去除内皮细胞或用L - 硝基精氨酸甲酯（L - NOARG，100 μM）抑制一氧化氮合酶均显著降低伐地那非诱导的舒张，且不改变最大反应。分别为依赖cGMP的蛋白激酶（PKG）和依赖cAMP的蛋白激酶（PKA）的抑制剂Rp - 8 - 溴 - PET - cGMPS（5 μM）和Rp - 8 - CPT - cAMPS（50 μM），均降低伐地那非的舒张反应，且后者消除了咯利普兰的舒张反应。大电导钙激活钾通道（BK(Ca)）的选择性抑制剂iberiotoxin（30 nM）和ATP敏感性钾通道（K(ATP)）抑制剂格列本脲（1 μM）均降低伐地那非引起的舒张。伐地那非在大鼠阴茎动脉中诱导强效血管舒张，这部分依赖于内皮细胞和NO/cGMP途径，并涉及BK(Ca)和K(ATP)通道的激活。
