DRUGS EFFECT ON DEVELOPMENT OF CARDIAC FAILURE

左心室肥厚(LVH)独立地使人类易患 潜在致命的心律失常，尤其是在急性心律失常的情况下 缺血症。我们的总体假设是肥大的心室细胞 对急性缺血发作特别敏感。终极的 这项工作的目标是定义这种敏感性和 描述新旧药物如何抑制或防止危及生命 与肥厚和缺血相关的心律失常。要做到这一点 Goal，我们已经挑选了I-KATP进行研究，这是一种在 心脏受ATPj代谢和耗竭的控制。我们的理由是 这样做是基于我们和其他人最近的发现：1)I-KATP 急性心肌缺血时的激活降低动作电位 持续时间(Apd)直接和间接--在后一种情况下 电压依赖性电流I-Cal的降低；2)I-KATP的调节 随着细胞位置的不同而变化；3)在没有ATP的情况下，固有的KATP 通道开放状态概率在LVH中增加；4)ATP和H+ 左心室肥厚改变对KATP通道固有活性的调节；5) KATP通道开放剂(PCO)激活I-KATP，这一作用与 ATP的抑制作用；6)PCO可能具有抗或促心律失常的作用。 通过激活I-KATP，使动作电位时程缩短； 7)更古老的传统抗心律失常药物，奎尼丁和 维拉帕米，抑制I-KATP。 具体的假设是：慢性压力超负荷将不同地 影响KATP通道的调节和细胞间差异 心内膜和心外膜区域，从而夸大了 区域响应性和增加的电力不稳定性 缺血时心肌肥厚；左心室肥厚改变细胞 缺血时对新型药物PCO及更老药物的反应性 抗心律失常药物。三个具体目标验证了这些假设：1) I-KATP在猫正常和肥大中的调节特征 心室肌细胞，在有限的条件下， 脑室内定位的功能；2)检查PCO和封堵器， 奎尼丁和维拉帕米对正常和肥厚心肌I-KATP的影响 细胞，以及它们如何影响细胞电生理学和自发性 冠脉灌注肥厚患者缺血时的节律紊乱 LV；3)探讨KATP通道开放状态增加的基础 左心室肥厚发生的可能性和调节改变。膜片钳的特征是I- KATP在底物、核苷酸、[H+]和药物的操纵过程中。 微电极表征正常和肥厚左室壁的药物作用 猫科动物。这种多方面的方法涉及到 心脏抗心律失常药物的亚显微通道和微电流 行为。

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.