There is intense interest in the concept that prolongation of cardiac repolarization may be an important mechanism whereby drugs suppress arrhythmias. However, marked repolarization increases have also been associated with induction of arrhythmias. Our initial clinical and in vitro studies of this arrhythmia- provoking action demonstrated that long cycle lengths and low extracellular potassium markedly potentiated the repolarization- prolonging effect of quinidine; under these conditions, a distinctive polymorphic ventricular tachycardia (Torsades de Pointes) developed in patients and early after depolarizations (EADS) were elicited in canine Purkinje fibers. In the previous period of support, studies were conducted to further evaluate our working hypothesis that EADs are linked to the genesis of Torsades de Pointes. One of the most important findings to date is that ventricular muscle blunts the action potential prolongation and EAD induction by quinidine in Purkinje tissue. We will now further examine the impact of modulation of Purkinje-ventricular coupling by interventions such as altered Cai (e.g. digitalis) and Cao, drugs (quinidine, amiodarone) and medium chain alcohols. We have implemented a computer model of porpagating Purkinje and ventricular muscle action potentials liked with variable axial resistivities in a one-dimensional cable which will be refined in parallel with experimental results. In this way, the hypothesis that EADs cause arrhythmias in vivo will be further tested and conditions which are important for the genesis or suppression of EAD-mediated arrhythmias identified. Despite increasing interest in the use of repolarization-prolonging drugs in the management of cardiac arrhythmias, little information is available on the ionic mechanism(s) whereby they exert this effect. In the past year we have accumulated evidence that the interaction of quinidine and amiodarone with the delayed rectifier IK (a repolarizing current) in voltage-clamped guinea pig ventricular myocytes is time- and voltage-dependent. These date suggest that drug effects on IK are modulated by the state of this potassium channel. A second major goal of the studies we now propose is to further test this hypothesis. We will initially characterize the effects of quinidine and amiodarone on IK as a function of initial channel state. Subsequently, we will examine the effects of these and other structurally related agents in other tissues (Purkinje, atrial). The results will not only characterize the impact of channel state on drug effect, but will also be used to quantify drug action in a multistate model of drug-channel interactions. Through this series of studies, therefore, we will increase our understanding of the fundamental mechanisms whereby drugs prolong repolarization and induce arrhythmias; in this way, the development and clinical use of repolarization- prolonging antiarrhythmic drugs will be improved.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL032694-04A1
Application #
3344117
Study Section
Cardiovascular Study Section (CVA)
Project Start
1984-08-01
Project End
1993-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37203
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Balser, J R; Bennett, P B; Hondeghem, L M et al. (1991) Suppression of time-dependent outward current in guinea pig ventricular myocytes. Actions of quinidine and amiodarone. Circ Res 69:519-29
Balser, J R; Roden, D M; Bennett, P B (1991) Single inward rectifier potassium channels in guinea pig ventricular myocytes. Effects of quinidine. Biophys J 59:150-61
Tamkun, M M; Knoth, K M; Walbridge, J A et al. (1991) Molecular cloning and characterization of two voltage-gated K+ channel cDNAs from human ventricle. FASEB J 5:331-7
Balser, J R; Bennett, P B; Roden, D M (1990) Time-dependent outward current in guinea pig ventricular myocytes. Gating kinetics of the delayed rectifier. J Gen Physiol 96:835-63
Campbell, R M; Woosley, R L; Iansmith, D H et al. (1990) Lack of triggered automaticity despite repolarization abnormalities due to bepridil and lidoflazine. Pacing Clin Electrophysiol 13:30-6
Balser, J R; Roden, D M; Bennett, P B (1990) Global parameter optimization for cardiac potassium channel gating models. Biophys J 57:433-44
Fish, F A; Prakash, C; Roden, D M (1990) Suppression of repolarization-related arrhythmias in vitro and in vivo by low-dose potassium channel activators. Circulation 82:1362-9
Fish, F A; Roden, D M (1989) A prolonged QTc interval. Is it an important effect of antiarrhythmic drugs? Med Toxicol Adverse Drug Exp 4:400-11
Thompson, K A; Murray, J J; Blair, I A et al. (1988) Plasma concentrations of quinidine, its major metabolites, and dihydroquinidine in patients with torsades de pointes. Clin Pharmacol Ther 43:636-42

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