EFFECT OF DRUGS ON DEVELOPMENT OF CARDIAC FAILURE

慢性压力超负荷所致的心室肥厚 在实验动物中，伴随着电生理 功能障碍，临床上常与进行性有关 由于心律失常导致的心力衰竭和/或猝死。其基础是 从过载到电功能障碍的进展 心律失常仍不清楚。我们的实验室一直在研究 实验性慢性压力超负荷与高血压的关系 肥厚室壁的电生理功能障碍 组织，包括正常和正常的心律失常机制 肥大的心脏。这些结果导致了这样的建议： 心室游离壁上的心内膜细胞是第一个 心肌细胞会受到压力过载的影响， 由此导致的局部电生理学差异。 左心室，尤其是动作电位时程和 难治性，是严重脑缺血的基础 肥厚心脏的电生理障碍。 细胞K+电流的改变可能是这两种现象的原因 慢性压力超负荷与动作电位延长 急性缺血期大鼠的促关节功能增强 脑室肥大。为了检验这些假说，有三个 提出了完整的具体目标和实验方案：1. 对正常人和正常人的电生理特性进行表征 肥大的心内膜下和心外膜下细胞 分离细胞的制备和完整脑室的保留 重要的蜂窝架构；2.比较 离体电生理反应与在位正常电生理反应 急性缺血时心内膜和心外膜细胞肥大； 3.确定行动变化背后的机制 心肌缺血时肥厚心肌的潜在持续时间 接触一种抗心律失常的原型药物奎尼丁。 方法学包括肾血管性高血压的产生和 常规微电极技术；膜片钳技术 肥大的心肌细胞被用来确定单一的 ATP敏感性钾通道在其缺血反应中的作用。对.的使用 单细胞和全组织相结合的研究方法 电生理变化将引出无法获得的信息 单单通过这两种技术。总的来说，这些实验将 辨别电功能障碍的区域性机制 压力超负荷-肥厚的心脏和提供一个机械 了解这类心脏的明显倾向的基础 增强心律失常的活动性和药物治疗 缺血性心律失常。

Ventricular hypertrophy due to chronic pressure overload is accompanied in experimental animals, by electrophysiolgic dysfunction, and is often associated clinically with progressive heart failure and/or sudden death due to arrhythmias. The basis for the progression form overload to electrical dysfunction and arrhythmias remains unclear. Our laboratory has been studying the relationships between experimental chronic pressure overload and electrophysiological dysfunction in hypertrophied ventricular tissue, including the mechanism of arrhythmias in normal and hypertrophied hearts. The results lead to the suggestion that endocardial cells on the ventricular free wall are the first cardiac cells to be affected by pressure overload, and that consequent chronic differences in regional electrophysiology of the left ventricle, especially action potential duration and refractoriness, underlie serious ischemia-induced electrophysiologic disturbances in the hypertrophied heart. Alteration of cellular K+ currents may be responsible for both action potential prolongation in chronic pressure overload and the enhanced arthythmogenicity during acute ischemia in the hypertrophied ventricle. To examine these hypotheses, three integrated specific aims and sets of experiments are outlined: 1. To characterize electrophysiologic properties of normal and hypertrophied subendocardial and subepicardial cells using preparations of isolated cells, and intact ventricles retaining important cellular architecture; 2. To compare the electrophysiologic responses of isolated and in situ normal and hypertrophied endo- and epicardial cells during acute ischemia; and 3. to determine the mechanisms underlying the changes in action potential duration of hypertrophied myocardium during ischemia and exposure to a prototype antiarrhythmic drug, quinidine. Methodology includes production of renovascular hypertension and conventional microelectrode technology; patch clamping of isolated hypertrophied myocytes is used to determine the role of unitary ATP-sensitive K+ channels in their ischemic response. The use of combined single cell and whole tissue approaches to study electrophysiologic changes will elicit information not obtainable by either technique alone. Collectively, the experiments will distinguish regional mechanisms of electrical dysfunction of the pressure overloaded-hypertrophied heart and provide a mechanistic basis for both understanding the apparent propensity of such hearts for enhanced arrhythmic activity and the pharmacologic management of ischemic arrhythmias.