Characterization of Cardiac Adenosine Receptor Systems

心脏功能由神经递质、神经调节剂和药物控制，这些药物与位于心肌膜上的特定受体结合。这些受体与各种效应器机制相互作用，调节细胞活动。腺苷在心脏中局部释放，作用于特定的细胞外、膜结合的受体，导致心脏收缩速度和力量的降低。此外，在运动、缺氧/缺血和衰竭心脏时，心肌中腺苷的释放速率会增加。然而，关于腺苷受体和腺苷受体的药理和生化特性：心肌细胞中的效应机制，人们知之甚少。该项目的长期目标是阐明腺苷受体激活导致心功能调节的机制，以便最终可以使用影响这一系统的药物干预来改变心功能。有两个具体的目标：(1)将进行广泛的药理和生化实验，以进一步确定心脏中的腺苷受体(S)的特征。这些实验将利用三种方法：(A)与激动剂和拮抗剂放射性配基的配体结合研究；(B)光亲和标记；(C)亲和层析和受体纯化。这些实验将确定心脏中是否存在一种以上的腺苷受体，以及心脏腺苷受体与中枢神经系统中的腺苷受体是否相同或不同。(2)进一步的实验将确定哪个效应系统(S)被心脏腺苷受体激活，从而导致腺苷受体激活所引起的生理变化。将探讨心脏受体调节心脏内cAMP水平的机制，以及腺苷受体与其他效应系统耦合的可能性。这一结果有望为腺苷受体控制心脏功能的过程提供基本的见解。

Cardiac function is controlled by neurotransmitters, neuromodulators, and drugs that bind to specific receptors located on the cardiac membrane. These receptors interact with various effector mechanisms to regulate cellular activity. Adenosine is locally released in the heart and acts on specific extracellular, membrane.bound receptors to cause decrease in the rate and force of contraction of the heart. Furthermore, the rate of adenosine release in the myocardium is increased during exercise, hypoxia/ischemia and in the failing heart. However, little is known concerning the pharmacological and biochemical characteristics of adenosine receptors and adenosine receptor: effector mechanisms in cardiac cells. The long term goal of this project is to elucidate the mechanisms by which activation of adenosine receptors lead to the regulation of cardiac function so that pharmacological interventions affecting this system can ultimately be used to modify cardiac function. There are two specific aims: (1) Extensive pharmacological and biochemical experiments will be performed to further characterize the adenosine receptor(s) in the heart. These experiments will utilize three approaches: (a) ligand binding studies with both agonist and antagonist radioligands; (b) photoaffinity labelling; and (c) affinity chromatography and receptor purification. These experiments will determine if more than one type of adenosine receptor exists in the heart and whether the cardiac adenosine receptors are the same or different from adenosine receptors in the CNS. (2) Additional experiments will determine which effector system(s) is/are activated by cardiac adenosine receptors to result in the physiological changes induced by activation of adenosine receptors. The mechanisms by which cardiac receptors modulate cAMP levels in the heart will be probed and the possibility that adenosine receptors couple to other effector systems will be examined. The results are anticipated to provide fundamental insights to the processes by which adenosine receptors control cardiac function.