Bian J S, Zhang W M, Xia Q, Wong T M
Department of Physiology, Institute of Cardiovascular Science and Medicine, Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
J Mol Cell Cardiol. 1998 Oct;30(10):2103-10. doi: 10.1006/jmcc.1998.0774.
To determine whether the phospholipase C (PLC)/inositol 1,4,5 trisphosphate (IP3)/Ca2+ pathway mediates cardiac arrhythmias induced by kappa-opioid receptor stimulation, the effects of U50,488H, a selective kappa-opioid receptor agonist, on cardiac rhythm in a isolated perfused rat heart, intracellular calcium ([Ca2+]i) in a single ventricular myocyte and IP3 production in myocytes were studied in the presence and absence of PLC inhibitors. U50,488H, the effects of which had been shown to be abolished by a selective kappa-receptor antagonist, nor-binaltorphimine, induced arrhythmias dose-dependently and increased both [Ca2+]i and IP3-production in the heart. More importantly, the effects of U50,488H were blocked by PLC inhibitors, neomycin and streptomycin. To further confirm the selectivity of action of the PLC inhibitor, the effects of another PLC inhibitor U73122 and its inactive structural analog, U73343, on cardiac rhythm in the isolated perfused rat heart were compared. The former did, while the latter did not, block the arrhythmogenic effect of U50,488H. We also determined whether the effects of kappa-receptor stimulation involves a pertussis toxin (PTX)-sensitive G-protein. We found that pretreatment with PTX at 4 microg/l for 10 min, a treatment shown to affect PTX sensitive G-protein-mediated functions, attenuated significantly the U50,488H-induced arrhythmias. The present study provides evidence that kappa-receptor stimulation-induced cardiac arrhythmias involves, at least partly, the PLC/IP3/Ca2+ pathway as well as a PTX sensitive G-protein.
为了确定磷脂酶C（PLC）/肌醇1,4,5-三磷酸（IP3）/Ca2+信号通路是否介导κ-阿片受体刺激所诱发的心律失常，我们研究了选择性κ-阿片受体激动剂U50,488H在有无PLC抑制剂存在的情况下，对离体灌注大鼠心脏的心律、单个心室肌细胞内的钙浓度（[Ca2+]i）以及肌细胞中IP3生成的影响。U50,488H的作用已被选择性κ-受体拮抗剂nor-binaltorphimine消除，它能剂量依赖性地诱发心律失常，并增加心脏中的[Ca2+]i和IP3生成。更重要的是，U50,488H的作用被PLC抑制剂新霉素和链霉素阻断。为了进一步证实PLC抑制剂作用的选择性，我们比较了另一种PLC抑制剂U73122及其无活性结构类似物U73343对离体灌注大鼠心脏心律的影响。前者能阻断U50,488H的致心律失常作用，而后者则不能。我们还确定了κ-受体刺激的作用是否涉及百日咳毒素（PTX）敏感的G蛋白。我们发现，用4μg/ml的PTX预处理10分钟（这种处理已被证明会影响PTX敏感的G蛋白介导的功能）能显著减轻U50,488H诱发的心律失常。本研究提供了证据表明，κ-受体刺激诱发的心律失常至少部分涉及PLC/IP3/Ca2+信号通路以及PTX敏感的G蛋白。
