Kim Jae-Gak, Sung Hui-Jin, Ok Seong-Ho, Kwon Seong-Chun, Cheon Kwang Seong, Kim Hye Jung, Chang Ki Churl, Shin Il-Woo, Lee Heon-Keun, Chung Young-Kyun, Sohn Ju-Tae
a Department of Anesthesiology and Pain Medicine, Gyeongsang National University Hospital, Jinju 660-702, Korea.
b Department of Physiology, Kwandong University College of Medicine, Kangneung 201-701, Korea.
Can J Physiol Pharmacol. 2011 Sep;89(9):681-9. doi: 10.1139/y11-065. Epub 2011 Aug 23.
Dexmedetomidine, a full agonist of the α2B-adrenoceptor that is mainly involved in vascular smooth muscle contraction, is primarily used for analgesia and sedation in intensive care units. High-dose dexmedetomidine produces hypertension in children and adults. The goal of this in vitro study was to investigate the role of the calcium (Ca(2+)) sensitization mechanism involving Rho-kinase, protein kinase C (PKC), and phosphoinositide 3-kinase (PI3-K) in mediating contraction of isolated rat aortic smooth muscle in response to dexmedetomidine. The effect of dexmedetomidine on the intracellular Ca(2+) level ([Ca(2+)]i) and tension was measured simultaneously. Dexmedetomidine concentration-response curves were generated in the presence or absence of the following antagonists: rauwolscine, Y 27632, LY 294002, GF 109203X, and verapamil. Dexmedetomidine-induced phosphorylation of PKC and membrane translocation of Rho-kinase were detected with Western blotting. Rauwolscine, Y 27632, GF 109203X, LY 294002, and verapamil attenuated dexmedetomidine-induced contraction. The slope of the [Ca(2+)]i-tension curve for dexmedetomidine was higher than that for KCl. Dexmedetomidine induced phosphorylation of PKC and membrane translocation of Rho-kinase. These results suggest that dexmedetomidine-induced contraction involves a Ca(2+) sensitization mechanism mediated by Rho-kinase, PKC, and PI3-K that is secondary to α2-adrenoceptor stimulation in rat aortic smooth muscle.
右美托咪定是主要参与血管平滑肌收缩的α2B肾上腺素能受体的完全激动剂，主要用于重症监护病房的镇痛和镇静。高剂量右美托咪定可使儿童和成人出现高血压。本体外研究的目的是探讨涉及Rho激酶、蛋白激酶C（PKC）和磷脂酰肌醇3激酶（PI3-K）的钙（Ca(2+)）敏化机制在介导右美托咪定引起的离体大鼠主动脉平滑肌收缩中的作用。同时测定右美托咪定对细胞内Ca(2+)水平（[Ca(2+)]i）和张力的影响。在存在或不存在以下拮抗剂的情况下生成右美托咪定浓度-反应曲线：萝芙木碱、Y 27632、LY 294002、GF 109203X和维拉帕米。用蛋白质印迹法检测右美托咪定诱导的PKC磷酸化和Rho激酶的膜转位。萝芙木碱、Y 27632、GF 109203X、LY 294002和维拉帕米减弱了右美托咪定诱导的收缩。右美托咪定的[Ca(2+)]i-张力曲线斜率高于氯化钾的。右美托咪定诱导PKC磷酸化和Rho激酶膜转位。这些结果表明，右美托咪定诱导的收缩涉及由Rho激酶、PKC和PI3-K介导的Ca(2+)敏化机制，但该机制继发于大鼠主动脉平滑肌中的α2肾上腺素能受体刺激。
