Chen Mai, Zhou Jing-Jun, Kam Kenneth Wan-Lung, Qi Jian-Song, Yan Wing-Yi, Wu Song, Wong Tak-Ming
Department of Physiology, Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Br J Pharmacol. 2003 Oct;140(4):750-8. doi: 10.1038/sj.bjp.0705475.
The effect of preconditioning with U50488 H (UP), a selective kappa-opioid receptor (kappa-OR) agonist, on infarct size and intracellular Ca2+ ([Ca2+]i) in the heart subjected to ischaemic insults were studied and evaluated. U50488 H administered intravenously reduced the infarct size 18-48 h after administration in isolated hearts subjected to regional ischaemia/reperfusion (I/R). The effect was dose dependent. A peak effect was reached at 10 mg x kg-1 U50488 H and at 24 h after administration. The effect of 10 mg x kg-1 U50488 H at 24 h after administration was abolished by nor-binaltorphimine (nor-BNI), a selective kappa-OR antagonist, indicating the effect was kappa-OR mediated. The infarct reducing effect of U50488 H was attenuated when a selective blocker of mitochondrial (5-hydroxydecanoic acid, 5-HD) or sarcolemmal (HRM-1098) ATP-sensitive potassium channel (KATP) was coadministered with U50488 H 24 h before ischaemia or when 5-HD was administered just before ischaemia. U50488 H also attenuated the elevation in [Ca2+]i and reduction in electrically induced [Ca2+]i transient in cardiomyocytes subjected to ischaemic insults. The effects were reversed by blockade of KATP channel, which abolished the protective effect of preconditioning with U50488 H. The results indicated that mitochondrial KATP channel serves as both a trigger and a mediator, while sarcolemmal KATP channel as a trigger only, of delayed cardioprotection of kappa-OR stimulation. The effects of these channels may result from prevention/attenuation of [Ca2+]i overload induced by ischaemic insults.
研究并评估了选择性κ-阿片受体（κ-OR）激动剂U50488 H预处理对遭受缺血损伤心脏的梗死面积和细胞内钙离子浓度（[Ca2+]i）的影响。静脉注射U50488 H可使接受局部缺血/再灌注（I/R）的离体心脏在给药后18 - 48小时梗死面积减小。该效应呈剂量依赖性。在10 mg·kg-1 U50488 H时达到峰值效应，且在给药后24小时出现。选择性κ-OR拮抗剂nor-纳洛酮（nor-BNI）可消除给药后24小时10 mg·kg-1 U50488 H的效应，表明该效应是由κ-OR介导的。当在缺血前24小时将线粒体（5-羟基癸酸，5-HD）或肌膜（HRM-1098）ATP敏感性钾通道（KATP）的选择性阻滞剂与U50488 H共同给药时，或在缺血前即刻给予5-HD时，U50488 H的梗死面积减小效应减弱。U50488 H还可减轻遭受缺血损伤心肌细胞中[Ca2+]i的升高以及电诱导的[Ca2+]i瞬变的降低。KATP通道的阻断可逆转这些效应，这消除了U50488 H预处理的保护作用。结果表明，线粒体KATP通道既是κ-OR刺激延迟心脏保护的触发因素，也是介导因素，而肌膜KATP通道仅是触发因素。这些通道的作用可能是预防/减轻缺血损伤诱导的[Ca2+]i超载。
