ADENOSINE--BIOLOGICAL CARDIOPROTECTIVE AGENT

腺苷--生物心脏保护剂

• 批准号: 3361421
• 负责人: AMIR PELLEG
• 金额: $ 19.09万
• 依托单位: HAHNEMANN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3361421
• 关键词: G protein; adenosine; beta antiadrenergic agent; biological signal transduction; cardiotonic agents; catecholamines; disease /disorder model; dogs; electrophysiology; heart pharmacology; myocardial ischemia /hypoxia

Adenosine, released from myocardial cells myocardial ischemia and catecholamine stimulation is a physiological modulator of the cardiovascular system. It effects, mediated by specific receptors, are due to a direct action on the membrane and an indirect, anti-adrenergic, action. Recently, adenosine had been viewed as a biological cardioprotective agent which plays an important role in pathophysiologic conditions. However, the mechanisms of adenosine's actions in vivo are not fully known. In particular, little is known regarding mechanisms of adenosine's effects on cardiac electrophysiology, arrhythmogenesis and inotropism. Furthermore, the ability of adenosine to antagonize the effects of catecholamines in vivo is highly controversial. Thus, the proposed studies are aimed to characterize the cardiac electrophysiologic and inotropic effects of adenosine in vivo and to determine the mechanistic role of the indirect anti-adrenergic action in these effects. For this purpose several canine models already established in our laboratory will be used. These include, (a) chronic AV conduction block and ventricular escape rhythm, enabling the comparative simultaneous evaluation of adenosine actions on the sinus node and ventricular pacemakers, (b) femoral artery to left anterior descending coronary artery shunt, enabling localized perturbations and intramyocardial pressure determination, and (c) femoral to anterior septal artery tachycardias. Using these models the following quantitative data will be obtained: 1. The negative chronotropic and dromotropic effects of adenosine in normal myocardium; 2. The differential sensitivity of cardiac pacemakers to adenosine; 3. The effects of adenosine on the electrophysiologic and inotropic actions catecholamines; and 4. The effects of adenosine on non-reentrant ventricular arrhythmias. Specially, the administration of catecholamine, adrenergic receptor blocker, adenosine antagonists, adenosine deaminase inhibitors and adenosine transport inhibitors in norma, ischemic and autonomically perturbed animals will be used to determine the mechanism of the actions of adenosine in vivo. Furthermore studies with competitive receptor-selective adenosine inhibitors and agents which modulate specific adenosine receptors and G- proteins in adenosine's actions. The proposed studies will systematically elucidate the basic mechanisms of the electrophysiologic, inotropic and anti-adrenergic actions of adenosine in a series of well defined experimental conditions in vivo and will characterize its role as a biological cardioprotective agent. This information is critical to the ultimate clinical application cardioprotective agents which depend on the action of adenosine for their modulating effects.

心肌缺血时心肌细胞释放腺苷 儿茶酚胺刺激是一种生理调节剂 心血管系统。 它的作用由特定受体介导，是由于 对膜的直接作用和间接的抗肾上腺素能作用， 行动。 最近，腺苷被视为一种生物活性物质。 心脏保护剂，在病理生理学中发挥重要作用 状况。 然而，腺苷在体内的作用机制尚不明确。 完全知道。特别是，人们对于其机制知之甚少。 腺苷对心脏电生理、心律失常的影响 正性肌力。 此外，腺苷具有拮抗 儿茶酚胺在体内的作用存在很大争议。 因此， 拟议的研究旨在表征心脏电生理学 腺苷在体内的和正性肌力作用并确定其机制 间接抗肾上腺素作用在这些作用中的作用。 为了这 目的我们实验室已经建立了几个犬类模型 用过的。这些包括，(a) 慢性房室传导阻滞和心室逸搏 节律，能够对腺苷进行比较同步评估 对窦房结和心室起搏器的作用，(b) 股动脉 冠状动脉左前降支分流术，可实现局部 扰动和心肌内压力测定，以及（c）股骨 前间隔动脉心动过速。 使用这些模型如下 将获得定量数据： 1. 负变时性和 腺苷在正常心肌中的促促作用； 2. 差速器 心脏起搏器对腺苷的敏感性； 3. 腺苷的作用 儿茶酚胺的电生理和正性肌力作用；和 4. 腺苷对非折返性室性心律失常的影响。 特别， 给予儿茶酚胺、肾上腺素受体阻滞剂、腺苷 拮抗剂、腺苷脱氨酶抑制剂和腺苷转运 正常、缺血和自主神经紊乱的动物中的抑制剂将 用于确定腺苷在体内的作用机制。 竞争性受体选择性腺苷的进一步研究 调节特定腺苷受体和 G- 的抑制剂和药剂 腺苷作用中的蛋白质。拟议的研究将系统地 阐明电生理、正性肌力和肌力的基本机制 腺苷的一系列明确的抗肾上腺素作用 体内实验条件并将表征其作为 生物心脏保护剂。 该信息对于 最终的临床应用心脏保护剂取决于 腺苷的调节作用。