Fryer Ryan M, Auchampach John A, Gross Garrett J
Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee 53226, USA.
Cardiovasc Res. 2002 Aug 15;55(3):520-5. doi: 10.1016/s0008-6363(02)00316-4.
This review focuses on target receptors that have been shown to have the potential to mimic the cardioprotective effect of ischemic preconditioning (IPC). There is an abundance of information concerning the intracellular mechanisms and membrane-bound receptors responsible for IPC. Important intracellular mediators of this cardioprotection likely reside in the activation of multiple kinase cascades. The major players in IPC are thought to include protein kinase C, tyrosine kinases, and members of the mitogen-activated protein kinase signaling family and these topics will be covered in more detail in other papers of this focused issue. However, many of these kinase-mediated mechanisms are triggered by the activation of transmembrane spanning receptors, some of which may be manipulated therapeutically to induce cardioprotection in humans with unstable angina or who are at risk for myocardial infarction. In this review, we will discuss the evidence supporting the possibility of manipulating several of these G protein-coupled receptors as potential therapeutic targets. Stimulation of numerous receptors has been targeted as possible triggers for IPC. Some of those that have been identified include A(1) adenosine, alpha(1) adrenergic, M(2) muscarinic, B(2) bradykinin, delta(1) opioid, AT(1) angiotensin, and endothelin-1 receptors. In general, these receptors are thought to couple to inhibitory G proteins. In this review, we will focus on the most likely therapeutic candidates for cardioprotection, namely adenosine, opioid, and bradykinin receptors since selective agonists and antagonists, either alone or in combination, have most often been shown to mimic or block IPC in numerous animal models and man, respectively. This is not meant to completely rule out other receptors since it is clear that IPC is a phenomenon with multiple pathways that appear to be responsible for the cardioprotection observed.
本综述聚焦于已显示出具有模拟缺血预处理（IPC）心脏保护作用潜力的靶受体。关于负责IPC的细胞内机制和膜结合受体有大量信息。这种心脏保护作用的重要细胞内介质可能存在于多个激酶级联反应的激活中。IPC的主要参与者被认为包括蛋白激酶C、酪氨酸激酶以及丝裂原活化蛋白激酶信号家族的成员，这些主题将在本专题的其他论文中更详细地阐述。然而，许多这些激酶介导的机制是由跨膜受体的激活触发的，其中一些受体可通过治疗手段进行调控，以在不稳定型心绞痛患者或有心肌梗死风险的人群中诱导心脏保护作用。在本综述中，我们将讨论支持将其中几种G蛋白偶联受体作为潜在治疗靶点进行调控的可能性的证据。刺激众多受体已被视为IPC的可能触发因素。其中一些已被确定的受体包括A(1)腺苷、α(1)肾上腺素能、M(2)毒蕈碱、B(2)缓激肽、δ(1)阿片样物质、AT(1)血管紧张素和内皮素-1受体。一般来说，这些受体被认为与抑制性G蛋白偶联。在本综述中，我们将重点关注最有可能用于心脏保护的治疗候选物，即腺苷、阿片样物质和缓激肽受体，因为选择性激动剂和拮抗剂单独或联合使用时，在众多动物模型和人体中最常被证明可模拟或阻断IPC。这并非意味着完全排除其他受体，因为很明显IPC是一种具有多种途径的现象，这些途径似乎对观察到的心脏保护作用负责。
