Acta Physiologica Sinica, April 25, 2003, 55(2): 115-120

Received 2002-10-31 Accepted 2003-02-10

The study was supported by the Research Grants Council, Hong Kong and a Cardiovascular Physiology Research Fund donated by L.C.S.T. (Holdings) Ltd.

Corresponding author. Tel: 852-28199194; Fax: 852-28559730; E-mail: wongtakm@hkucc.hku.hk

Brief Review

Roles of kappa opioid receptors in cardioprotection against ischemia the signaling mechanisms

Tak Ming WONG*, Song WU

Department of Physiology, The University of Hong Kong, 4/F, Laboratory Block, Faculty of Medicine Building, 21 Sassoon Road, Hong Kong SAR, China

Abstract: There is evidence that the myocytes produce dynorphin and dynorphin-like peptides, which are kappa opioid receptor (κ-OR) agonists. Activation of κ-OR, a dominant opioid receptor in the heart, alters the cardiac function in vivo and in vitro. The observations suggest that the endogenous κ-opioid peptides may act as autocrines or paracrine in regulation of cardiac functions. Myocardial ischemia is a common cause of heart disorders, which is manifested in decreased myocardial performance, arrhythmia and infarct. When myocardial ischemia occurs, the sympathetic discharge increases, which in turn increases the work-load and oxygen consumption. This exacerbates the situation induced by ischemia. One of the mechanisms with which the body protects against ischemia-induced injury/arrhythmia is inhibition of stimulation of β-adrenoceptor (β-AR), the receptor mediating the actions of sympathetic stimulation. κ-Opioids inhibit the β-AR activation. The inhibition of the β-AR activation is due to inhibition of Gs-protein and to a lesser extent the adenylyl cyclase of the signaling pathway mediating β-AR stimulation by a pertussis sensitive G-protein that mediates κ-OR activation. Another mechanism against ischemia-induced injury is preconditioning, which is defined as prior exposures to ischemia or other insults make the heart more tolerant to subsequent and more severe insults. Protection occurs immediately or 1-3 days after preconditioning. κ-OR mediates protection of preconditioning with ischemia or metabolic inhibition, one of the consequences of ischemia, in the heart. Activation of κ-OR by U50488H, a selective κ-OR agonist (pharmacological preconditioning with U50488H, UP), activates protein kinase C (PKC), opens KATP channels and increases the production of heat shock proteins. Blockade of PKC, or closing of the KATP channels or inhibition of the synthesis of the heat shock protein abolishes the cardioprotection of UP. The findings indicate the important roles of PKC, the KATP channels and the heat shock protein in cardioprotection of UP. In addition, UP also attenuates the Ca2+ overload, a precipitating cause of cardiac injury, induced by ischemic insults, indicating that UP may confer cardioprotection via at least partly attenuating the Ca2+ overload. Most interestingly, blockade of the KATP channels with channel blockers, that abolishes the delayed cardioprotection of UP, also attenuates the inhibitory effect of UP on Ca2+ overload, suggesting that the cardioprotective effect of opening of the KATP channels may be due at least partly to the prevention/attenuation of Ca2+ overload.

Key words: kappa opioid receptor; myocardial ischemia; β-adrenoceptor; ischemic preconditioning

Kappa 阿片受体的抗缺血性心脏保护作用信息机制

黄德明*, 吴淞

香港大学医学院生理系, 香港沙宣道21号

摘要: 有证据表明, 心脏细胞产生强腓肽和强腓肽类多肽, 它们是 kappa 阿片受体 (κ-OR)的激动剂。κ-OR是心脏一种优势的阿片受体, 其激活可改变在体和离体心脏的功能。在正常和病理情况下, 内源性κ-阿片肽可能通过自分泌或旁分泌的方式调节心脏功能。心肌缺血是导致心脏功能紊乱的一个常见原因, 主要表现为心肌功能减弱, 心律失常及心肌梗塞等。心肌缺血时, 交感神经发放增强, 从而增加作功负荷及氧消耗量; 而这又使缺血引发的状况更为恶化。机体抵抗缺血引发心肌损害/心律失常的保护机制之一是抑制β-肾上腺素受体 (β-AR) 的兴奋。κ-OR 确实能抑制β-AR的激动。这种抑制主要是由于GS蛋白受到抑制, 也在较小程度上由于信息通路的腺苷酸环化酶的抑制。因为该种酶能通过对百日咳毒素敏感的G蛋白转导β-AR的激动。另一保护心肌对抗缺血性损害的机制是预处理。预处理是指预先受到缺血等损伤使心脏对随后更严重的损伤产生较强的耐受能力。这种保护作用可以在预处理后即时产生, 也可延至预处理后1-3天。在采用缺血或其产生的后果之一代谢抑制作为预处理而致的心脏保护中, κ-OR 参与媒介预处理的作用。用 κ-OR 的特异性激动剂U50488H激活κ-OR (U50488H 药理性预处理, UP) 可激活蛋白激酶C (PKC), 开放 ATP 敏感的钾通道(KATP channels)及增加热休克蛋白 (HSP) 的产生。阻断PKC的作用, 关闭KATP通道或抑制HSP的合成, 均可消除UP的心脏保护作用。这些发现表明, PKC、 KATP通道和HSP在UP的心脏保护中均具重要作用。此外, UP也能减低缺血造成心肌损害的因素之一, 即Ca2+的超负荷。这个事实表明UP发挥心脏保护作用至少部分地是通过减低Ca2+的超负荷。最有趣的是, 以阻断剂阻塞KATP通道, 在消除UP的延迟性心脏保护作用的同时也降低了UP对Ca2+超负荷的抑制作用。这个事实揭示了KATP通道开放所致的心脏保护作用至少部分地可能是由于防止或减低了Ca2+的超负荷。

关键词: kappa 阿片受体; 心肌缺血; β-肾上腺素受体; 缺血预处理

中图分类号: Q463