Cilostazol induces vasodilation through the activation of Ca(2+)-activated K(+) channels in aortic smooth muscle.
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.
Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 200-701, South Korea.
Hongliang
H
Li
Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 200-701, South Korea.
Da Hye
DH
Hong
Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 200-701, South Korea.
Youn Kyoung
YK
Son
Institute of Medical Sciences, Department of Obstetrics and Gynecology, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon, 200-701, South Korea.
Sung Hun
SH
Na
Department of Biomedical Engineering, and Center for Marine-Integrated Biomedical Technology (BK21 Plus), Pukyong National University, Busan, 608-737, South Korea.
Won-Kyo
WK
Jung
Department of Physiology, Konkuk University School of Medicine, Chungju, 380-701, South Korea.
Young Min
YM
Bae
Department of Physiology, Department of Biomedical Sciences, and Ischemic/hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
Eun Young
EY
Seo
Department of Physiology, Department of Biomedical Sciences, and Ischemic/hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
Sung Joon
SJ
Kim
Department of Microbiology, Inje University College of Medicine, Busan, 614-735, South Korea. Electronic address: cihima@inje.ac.kr.
Il-Whan
IW
Choi
Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 200-701, South Korea. Electronic address: parkws@kangwon.ac.kr.
Won Sun
WS
Park
D000067956:Adenylyl Cyclase Inhibitors / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D000077407:Cilostazol; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000819:agonists* / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D000067956:Adenylyl Cyclase Inhibitors; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D026902:Potassium Channel Blockers; D047428:Protein Kinase Inhibitors; D013777:Tetrazoles; D014665:Vasodilator Agents; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D000077407:Cilostazol
Big-conductance Ca(2+)-activated K(+) channel; Cilostazol; Protein kinase A; Vasorelaxation