Wong Tak Ming, Wu Song
Department of Physiology, The University of Hong Kong, 4/F, Laboratory Block, Faculty of Medicine Building, Hong Kong SAR, PR China.
Sheng Li Xue Bao. 2003 Apr 25;55(2):115-20.
There is evidence that the myocytes produce dynorphin and dynorphin-like peptides, which are kappa opioid receptor (kappa-OR) agonists. Activation of kappa-OR, a dominant opioid receptor in the heart, alters the cardiac function in vivo and in vitro. The observations suggest that the endogenous kappa-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 beta-adrenoceptor (beta-AR), the receptor mediating the actions of sympathetic stimulation. kappa-Opioids inhibit the beta-AR activation. The inhibition of the beta-AR activation is due to inhibition of Gs-protein and to a lesser extent the adenylyl cyclase of the signaling pathway mediating beta-AR stimulation by a pertussis sensitive G-protein that mediates kappa-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. kappa-OR mediates protection of preconditioning with ischemia or metabolic inhibition, one of the consequences of ischemia, in the heart. Activation of kappa-OR by U50488H, a selective kappa-OR agonist (pharmacological preconditioning with U50488H, UP), activates protein kinase C (PKC), opens K(ATP) channels and increases the production of heat shock proteins. Blockade of PKC, or closing of the K(ATP) 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 K(ATP) channels and the heat shock protein in cardioprotection of UP. In addition, UP also attenuates the Ca(2+) overload, a precipitating cause of cardiac injury, induced by ischemic insults, indicating that UP may confer cardioprotection via at least partly attenuating the Ca(2+) overload. Most interestingly, blockade of the K(ATP) channels with channel blockers, that abolishes the delayed cardioprotection of UP, also attenuates the inhibitory effect of UP on Ca(2+) overload, suggesting that the cardioprotective effect of opening of the K(ATP) channels may be due at least partly to the prevention/attenuation of Ca(2+) overload.
有证据表明心肌细胞可产生强啡肽和类强啡肽肽，它们是κ阿片受体（κ-OR）激动剂。κ-OR是心脏中主要的阿片受体，其激活可在体内和体外改变心脏功能。这些观察结果表明内源性κ阿片肽可能作为自分泌或旁分泌物质参与心脏功能的调节。心肌缺血是心脏疾病的常见原因，表现为心肌功能下降、心律失常和梗死。当心肌缺血发生时，交感神经放电增加，进而增加工作负荷和氧消耗。这会加剧缺血所引发的状况。机体抵御缺血诱导的损伤/心律失常的机制之一是抑制β-肾上腺素能受体（β-AR）的刺激，β-AR是介导交感神经刺激作用的受体。κ阿片类物质可抑制β-AR的激活。β-AR激活的抑制是由于对Gs蛋白的抑制以及在较小程度上对信号通路中腺苷酸环化酶的抑制，该信号通路通过介导κ-OR激活的百日咳敏感G蛋白介导β-AR刺激。另一种抵御缺血诱导损伤的机制是预处理，其定义为先前暴露于缺血或其他损伤可使心脏对随后更严重的损伤更具耐受性。保护作用在预处理后立即或1 - 3天出现。κ-OR介导心脏对缺血或代谢抑制（缺血的后果之一）预处理的保护作用。选择性κ-OR激动剂U50488H（用U50488H进行药理学预处理，UP）激活κ-OR，可激活蛋白激酶C（PKC）、开放K(ATP)通道并增加热休克蛋白的产生。阻断PKC、关闭K(ATP)通道或抑制热休克蛋白的合成可消除UP的心脏保护作用。这些发现表明PKC、K(ATP)通道和热休克蛋白在UP的心脏保护作用中起重要作用。此外，UP还可减轻缺血性损伤诱导的Ca(2+)超载，Ca(2+)超载是心脏损伤的一个促发因素，这表明UP可能至少部分通过减轻Ca(2+)超载来提供心脏保护。最有趣的是，用通道阻滞剂阻断K(ATP)通道可消除UP的延迟心脏保护作用，同时也减弱了UP对Ca(2+)超载的抑制作用，这表明开放K(ATP)通道的心脏保护作用可能至少部分归因于预防/减轻Ca(2+)超载。
