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.

该提议的总体目的是确定机制 腺苷会影响心室超速抑制。 建立直接 腺苷对超速抑制的影响，需要证明 腺苷在停止刺激后加剧了停顿 独立于减慢自发速率。 初步研究 孤立的豚鼠的心脏表明，腺苷显着增加 与其他干预措施相比，暂停持续时间的大小 产生类似的驱动前速率放缓（例如体温过低）。 为了进一步阐明腺苷及其作用机理的作用， 计划实验。 在孤立的灌注豚鼠心中， 腺苷作用的逆转将通过脉冲压力尝试 注射特定的腺苷拮抗剂。 因为腺苷会导致 起搏器轮班，暂停持续时间的增加可能性 必须排除这种效果。 因此，在孤立的兔子Purkinje中 纤维，腺苷引起的起搏器主导地位转移的影响将 通过多个细胞内记录进行研究。 最后，单身 孤立的猪Purkinje细胞（这种制剂不包括起搏器 移位），腺苷对驱动后超极化的影响，斜率 第4阶段去极化，阈值电位和K+电导将是 通过用斑块进行整个细胞记录和电压夹调查 电极。 各种技术的专业知识（心脏细胞隔离，脉冲 压力喷射，电压夹）将在协助时获得 发起人确定影响的离子电导 单个AV节点细胞中的腺苷。 成功实现这一目标 项目将进一步深入了解总体机制 心室超速抑制。 此外，建立 腺苷的作用可能会改变心室的临床方法 心室纤颤后，完全心脏障碍，鼻窦停滞不前 逮捕或要求在心肌缺血期间起搏器故障 腺苷大量生产。