Li Hongliang, Hong Da Hye, Son Youn Kyoung, Na Sung Hun, Jung Won-Kyo, Bae Young Min, Seo Eun Young, Kim Sung Joon, Choi Il-Whan, Park Won Sun
Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 200-701, South Korea.
Institute of Medical Sciences, Department of Obstetrics and Gynecology, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon, 200-701, South Korea.
Vascul Pharmacol. 2015 Jul;70:15-22. doi: 10.1016/j.vph.2015.01.002. Epub 2015 Mar 5.
We investigated the vasorelaxant effect of cilostazol and related signaling pathways in phenylephrine (Phe)-induced pre-contracted aortic rings. Cilostazol induced vasorelaxation in a concentration-dependent manner when aortic rings were pre-contracted with Phe. Application of the voltage-dependent K(+) (Kv) channel inhibitor 4-AP, the ATP-sensitive K(+) (K(ATP)) channel inhibitor glibenclamide, and the inwardly rectifying K(+) (Kir) channel inhibitor Ba(2+) did not alter the vasorelaxant effect of cilostazol; however, pre- and post-treatment with the big-conductance Ca(2+)-activated K(+) (BK(Ca)) channel inhibitor paxilline inhibited the vasorelaxant effect of cilostazol. This vasorelaxant effect of cilostazol was reduced in the presence of an adenylyl cyclase or a protein kinase A (PKA) inhibitor, but not a protein kinase G inhibitor. Inside-out single channel recordings revealed that cilostazol induced the activation of BK(Ca) channel activity. The vasorelaxant effect of cilostazol was not affected by removal of the endothelium. In addition, application of a nitric oxide synthase inhibitor and a small-conductance Ca(2+)-activated K(+) (SK(Ca)) channel inhibitor did not affect cilostazol-induced vasorelaxation. We conclude that cilostazol induced vasorelaxation of the aorta through activation of BK(Ca) channel via a PKA-dependent signaling mechanism independent of endothelium.
我们研究了西洛他唑在去氧肾上腺素（Phe）诱导的预收缩主动脉环中的血管舒张作用及相关信号通路。当主动脉环用Phe预收缩时，西洛他唑以浓度依赖的方式诱导血管舒张。应用电压依赖性钾（K(+)）通道抑制剂4-氨基吡啶（4-AP）、ATP敏感性钾（K(ATP)）通道抑制剂格列本脲和内向整流钾（Kir）通道抑制剂钡（Ba(2+)）均未改变西洛他唑的血管舒张作用；然而，用大电导钙（Ca(2+)）激活钾（BK(Ca)）通道抑制剂帕吉林进行预处理和后处理均抑制了西洛他唑的血管舒张作用。在存在腺苷酸环化酶或蛋白激酶A（PKA）抑制剂但不存在蛋白激酶G抑制剂的情况下，西洛他唑的这种血管舒张作用减弱。外向内单通道记录显示，西洛他唑诱导BK(Ca)通道活性的激活。西洛他唑的血管舒张作用不受内皮去除的影响。此外，应用一氧化氮合酶抑制剂和小电导钙（Ca(2+)）激活钾（SK(Ca)）通道抑制剂均不影响西洛他唑诱导的血管舒张。我们得出结论，西洛他唑通过依赖PKA的信号传导机制激活BK(Ca)通道，从而诱导主动脉的血管舒张，且该过程不依赖于内皮。
