DRUGS EFFECT ON DEVELOPMENT OF CARDIAC FAILURE

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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.