The cellular electrophysiologic basis for antiarrhythmic drug action may depend on what antiarrhythmic effect is considered. The present proposal focuses on the factors responsible for cycle length stability in two distinct forms of reentry and drug effects on these factors. With respect to reentry in homogenerous tissue around a fixed barrier in which the impules moves through relatively refractory tissue, studies will define drug effects on the shape and position of the refractory curve during steady pacing after premature beats. The refractory curve relates the conduction velocity of an impulse to its coupling interval from the previous beat when it conducts through tissue that has not recovered full excitability. Lidocaine, quinidine, bretylium, and N-acetyl procainamide will be studied in isolated strips of canine atrial and ventricular muscle and in a specific model of reentry around atrial tissue above the tricuspid ring using intracellular electrodes. This analysis will provide a framework for integrating drug effects on action potential duration, time course of repolarization and depression and slow recovery of excitatory sodium currents during pertubations of cycle length. It is expected that changes in the shape of the refractory curve due to drug effects both will explain how drugs may cause instability and termination of reentry or facilitate termination by premature stimulation. It is also expected that differential effects on the refractory curve by drugs with slow vs. fast kinetics of recovery from use-dependent block of sodium channels will help explain how use-dependent properties of Type I drugs contribute to their antiarrhythmic action. Long-term objective includes constructing a mathematical model using this information that predicts drug effects on the tendency for damped or undamped cycle length oscillation and termination in reentry. Future studies will also expand to heterogeneous reentrant circuits. Other studies in this proposal concern factor determining stability of the central refractory barrier in the leading circle form of reentry. It is proposed that use-dependent properties of Type I drugs depress excitability of tissue just outside the central zone that has an active membrane response while they favor recovery of excitability in the central refractory zone by decreasing penetration of the impulses that electotonically depolarized this area. This would favor instability of the central barrier that might terminate the tachycardia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Unknown (R23)
Project #
5R23HL032106-03
Application #
3448620
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1984-04-01
Project End
1987-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104