DRUGS EFFECT ON DEVELOPMENT OF CARDIAC FAILURE

左心室肥大（LVH）独立地使人类易于发生 可能致命的心律失常，特别是在存在急性心律失常的情况下 缺血我们的假设是肥大的心室细胞 对急性缺血发作特别敏感。最终 这项工作的目标是确定这种敏感性的机制， 描述新旧药物如何抑制或预防危及生命的 与肥大和缺血相关的心律失常。为了实现这一 目标，我们已经挑选出研究I-KATP，一个复极化电流在 心脏由ATP j的代谢和消耗控制。我们的理由 这样做是基于我们和其他人最近的发现：1）I-KATP 急性心肌缺血时激活降低动作电位 时间（APD）直接和间接-在后者的情况下， 降低I-CaL，电压依赖性电流; 2）I-KATP的调节 随细胞位置而变化; 3）在缺乏ATP的情况下，内源性KATP LVH时通道开放概率增加; 4）ATP和H+ KATP通道的内在活性的调节被LVH改变; 5） KATP通道开放剂（PCO）激活I-KATP，这是一种与 ATP的抑制作用; 6）PCO可能是抗或促进 心脏通过其I-KATP激活和导致APD缩短; 和7）较老的更传统的抗疟疾药物，奎尼丁和 维拉帕米，抑制I-KATP。 具体的假设是：慢性压力超负荷将差异 影响KATP通道的调节和细胞之间的差异 心内膜和心外膜区域，从而夸大了 区域反应性和增加电不稳定性， 心肌肥厚; LVH改变了细胞 缺血期间对一类新药物的反应性，PCO，和旧的 抗抑郁药三个具体的目标测试这些假设：1） 正常猫和肥大猫I-KATP调节的特征 心室肌细胞，并在有限的条件下，作为一个 心室内位置的功能; 2）检查PCO和闭合器， 奎尼丁和维拉帕米，影响正常和肥大的I-KATP 细胞，以及它们如何影响细胞电生理学和自发 心肌肥厚心肌缺血时的心律紊乱 探讨KATP通道开放状态增加的基础 可能性和改变的调节。膜片钳的特征是I- KATP在操纵底物、核苷酸、[H+]和药物期间。 微电极表征药物在正常和肥厚LV中的作用 关于猫这种多层面的方法将以下特点联系起来： 抗心律失常药物的亚微观通道和微小电流 行动

Left ventricular hypertrophy (LVH) independently predisposes humans to potentially fatal arrhythmias, especially in the presence of acute ischemia. Our overall hypothesis is that hypertrophied ventricular cells are particularly sensitive to episodes of acute ischemia. The ultimate goal of this work is to define mechanisms underlying this sensitivity and to describe how new and old drugs suppress or prevent life threatening arrhythmias associated with hypertrophy and ischemia. To accomplish this goal, we have singled out for study I-KATP, a repolarizing current in the heart controlled by metabolism and depletion of ATPj. Our reasons for doing so are based on recent findings by ourselves and others: 1) I-KATP activation during acute myocardial ischemia decreases action potential duration (APD) both directly and indirectly--in the latter case by decreasing I-CaL, a voltage-dependent current; 2) Regulation of I-KATP varies with cell location; 3) In the absence of ATP, intrinsic KATP channel open-state probability is increased in LVH; 4) Both ATP and H+ regulation of the KATP channel's intrinsic activity are altered by LVH; 5) KATP channel openers (PCO) activate I-KATP, an effect opposite to the inhibiting effect of ATP; 6) PCO may be anti- or proarrhythmic in the heart through their activation of I-KATP and resulting shortening of APD; and 7) Older more traditional antiarrhythmic drugs, quinidine and verapamil, inhibit I-KATP. Specific hypotheses are: Chronic pressure overload will differentially affect regulation of both KATP channel and cellular differences between endocardial and epicardial regions, and thus exaggerate differences in regional responsiveness and increase electrical instability in hypertrophied myocardium during ischemia; and LVH alters cellular responsiveness during ischemia to a new class of drugs, the PCO, and older antiarrhythmic drugs. Three specific aims test these hypotheses: 1) Characterize regulation of I-KATP in feline normal and hypertrophied ventricular muscle cells, and for a limited number of conditions, as a function of location within the ventricle; 2) Examine how PCO and closers, and quinidine and verapamil, affect I-KATP in normal and hypertrophied cells, and how they influence cellular electrophysiology and spontaneous rhythm disturbances during ischemia of the coronary-perfused hypertrophied LV; and 3) Explore the basis for increased KATP channel open-state probability and altered regulation in LVH. Patch clamping characterizes I- KATP during manipulation of substrates, nucleotides, [H+] and drugs. Microelectrodes characterize drug actions in normal and hypertrophied LV of cats. This multifaceted approach relates characteristics of submicroscopic channels and minute currents to cardiac antiarrhythmic drug actions.