ROLE OF ADENOSINE IN VENTRICULAR OVERDRIVE SUPPRESSION

腺苷在心室过度驱动抑制中的作用

• 批准号: 3087154
• 负责人: ROBERT C JR WESLEY
• 金额: $ 7.44万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1989-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3087154
• 关键词: action potentials; adenosine; arrhythmia; atrial fibrillation; atrioventricular node; cardiac output; cardiotonic agents; electrophysiology; heart Purkinje's fiber; heart block; heart conduction system; heart output disorder; heart pacemaker tissue; heart rate; membrane potentials; myocardial ischemia /hypoxia; oxygen microelectrode

The overall aim of this proposal is to determine the mechanism whereby adenosine affects ventricular overdrive suppression. To establish a direct effect of adenosine on overdrive suppression, it is required to demonstrate that adenosine potentiates the pause following cessation of stimulation independent of slowing the spontaneous rate. Preliminary studies in isolated guinea pig hearts have shown that adenosine markedly increases the magnitude of the pause duration when compared to other interventions producing similar degrees of pre-drive rate slowing (e.g., hypothermia). To further elucidate the role of adenosine and its mechanism of action, the following experiments are planned. In isolated perfused guinea pig hearts, reversal of the adenosine effects will be attempted by pulse-pressure injection of specific adenosine antagonists. Since adenosine can cause pacemaker shift, the possibility that the increase in pause duration is due to such effect must be ruled out. Thus, in isolated rabbit Purkinje fibers, the effect of adenosine-induced shift in pacemaker dominance will be investigated with multiple intracellular recordings. Finally, in single isolated porcine Purkinje cells (a preparation that excludes pacemaker shift), the effect of adenosine on post-drive hyperpolarization, slope of phase 4 depolarization, threshold potential, and K+ conductance will be investigated by whole cell recording and voltage clamp with patch electrodes. Expertise in various techniques (cardiac cell isolation, pulse pressure injection, voltage clamp) will be gained while assisting the sponsor to determine the ionic conductances underlying the effect of adenosine in single AV nodal cells. Successful accomplishment of this project will provide further insight into the overall mechanism of ventricular overdrive suppression. Furthermore, the establishment of a role for adenosine may alter the clinical approach to ventricular standstill following ventricular fibrillation, complete heart block, sinus arrest, or demand pacemaker failure during myocardial ischemia where adenosine is produced in large amounts.

该提案的总体目标是确定机制 腺苷影响心室超速抑制。 建立直接 腺苷对过度驱动抑制的影响，需要证明 腺苷会增强刺激停止后的暂停 与减慢自发速率无关。 初步研究于 离体豚鼠心脏表明，腺苷显着增加 与其他干预措施相比，暂停持续时间的长短 产生相似程度的预驱动速率减慢（例如体温过低）。 为了进一步阐明腺苷的作用及其作用机制， 计划进行以下实验。 在离体灌注豚鼠心脏中， 将通过脉压尝试逆转腺苷效应 注射特异性腺苷拮抗剂。 由于腺苷可导致 起搏器移位，暂停持续时间增加的可能性 必须排除这种影响。 因此，在离体兔浦肯野 纤维，腺苷引起的起搏器优势转变的影响将 通过多个细胞内记录进行研究。 最后，在单 分离的猪浦肯野细胞（一种不含起搏器的制剂） 移），腺苷对驱动后超极化的影响，斜率 第 4 相去极化、阈电位和 K+ 电导将是 通过全细胞记录和带贴片的电压钳进行研究 电极。 各种技术的专业知识（心肌细胞分离、脉冲 压力注入，电压钳位）将在协助的同时获得 赞助商确定影响的离子电导 单个房室结细胞中的腺苷。 成功实现这一目标 项目将进一步深入了解整体机制 心室超速抑制。 此外，设立一个 腺苷的作用可能会改变心室的临床治疗方法 心室颤动、完全性心脏传导阻滞、窦性心脏传导阻滞后停止 心肌缺血期间心脏骤停或要求起搏器失效 腺苷大量产生。