Mustafa S Jamal, Morrison R Ray, Teng Bunyen, Pelleg Amir
Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, WV 26505-9229, USA.
Handb Exp Pharmacol. 2009(193):161-88. doi: 10.1007/978-3-540-89615-9_6.
Adenosine is an autacoid that plays a critical role in regulating cardiac function, including heart rate, contractility, and coronary flow. In this chapter, current knowledge of the functions and mechanisms of action of coronary flow regulation and electrophysiology will be discussed. Currently, there are four known adenosine receptor (AR) subtypes, namely A(1), A(2A), A(2B), and A(3). All four subtypes are known to regulate coronary flow. In general, A(2A)AR is the predominant receptor subtype responsible for coronary blood flow regulation, which dilates coronary arteries in both an endothelial-dependent and -independent manner. The roles of other ARs and their mechanisms of action will also be discussed. The increasing popularity of gene-modified models with targeted deletion or overexpression of a single AR subtype has helped to elucidate the roles of each receptor subtype. Combining pharmacologic tools with targeted gene deletion of individual AR subtypes has proven invaluable for discriminating the vascular effects unique to the activation of each AR subtype. Adenosine exerts its cardiac electrophysiologic effects mainly through the activation of A(1)AR. This receptor mediates direct as well as indirect effects of adenosine (i.e., anti-beta-adrenergic effects). In supraventricular tissues (atrial myocytes, sinuatrial node and atriovetricular node), adenosine exerts both direct and indirect effects, while it exerts only indirect effects in the ventricle. Adenosine exerts a negative chronotropic effect by suppressing the automaticity of cardiac pacemakers, and a negative dromotropic effect through inhibition of AV-nodal conduction. These effects of adenosine constitute the rationale for its use as a diagnostic and therapeutic agent. In recent years, efforts have been made to develop A(1)R-selective agonists as drug candidates that do not induce vasodilation, which is considered an undesirable effect in the clinical setting.
腺苷是一种自体活性物质，在调节心脏功能（包括心率、心肌收缩力和冠状动脉血流）中发挥关键作用。在本章中，将讨论目前关于冠状动脉血流调节和电生理学的功能及作用机制的知识。目前，已知有四种腺苷受体（AR）亚型，即A(1)、A(2A)、A(2B)和A(3)。已知所有这四种亚型均参与调节冠状动脉血流。一般来说，A(2A)AR是负责冠状动脉血流调节的主要受体亚型，它以内皮依赖性和非依赖性方式扩张冠状动脉。其他AR的作用及其作用机制也将进行讨论。单一AR亚型靶向缺失或过表达的基因修饰模型越来越受欢迎，这有助于阐明每种受体亚型的作用。将药理学工具与单个AR亚型的靶向基因缺失相结合，已被证明对于区分每种AR亚型激活所特有的血管效应非常有价值。腺苷主要通过激活A(1)AR发挥其心脏电生理作用。该受体介导腺苷的直接和间接作用（即抗β肾上腺素能作用）。在室上性组织（心房肌细胞、窦房结和房室结）中，腺苷发挥直接和间接作用，而在心室中仅发挥间接作用。腺苷通过抑制心脏起搏器的自律性发挥负性变时作用，并通过抑制房室结传导发挥负性变传导作用。腺苷的这些作用构成了其用作诊断和治疗药物的理论基础。近年来，人们努力开发A(1)R选择性激动剂作为候选药物，这些激动剂不会诱导血管舒张，而血管舒张在临床环境中被认为是一种不良效应。
