The objective of this research proposal is to define and discover the properties of antiarrhythmic drugs that are necessary for preventing or terminating ventricular arrhythmias caused by anisotropic reentry, a form of reentry dependent on nonuniform anisotropic conduction properties. Studies will be done on the epicardial border zone (EBZ) of canine hearts with healing infarcts where reentrant circuits will be mapped with a 320 electrode array. Pharmacological agents that block different membrane ion channels will be administered either systemically or directly into the EBZ through its coronary blood supply to evaluate their effects on anisotropic conduction, refractoriness (evaluated by local stimulation) and time course of action potential repolarization (determined from optical recordings). We will determine the mechanism(s) by which class III antiarrhythmic drugs that block different components (IKr and IKs) of the delayed rectifier current influence the initiation and maintenance of reentrant excitation by comparing the effects of sotalol and dofetilide (IKr blocker) with an experimental drug, NE 10644 (IKs blocker). We will investigate whether prolongation of refractoriness by increasing inward current with either Bay K 8644 or ibutilide exerts different electrophysiological effects than reducing an outward current. Since epicardial border zone cells have abnormal repolarization that may be a result of an enhanced Ca dependent outward current, the possible antiarrhythmic effects of blocking this current with ryanodine and DIDs will be explored. The role of the ATP-sensitive K channel in causing reentry in healing infarcts will be investigated by blocking it with glyburide. Since the slow conduction causing anisotropic reentry is caused by 'poor' electrical coupling among myocardial fiber bundles, we will investigate the effects of further uncoupling with heptanol on reentrant excitation. Finally, we will define the mechanism of action of class I antiarrhythmic agents (procainamide, lidocaine, flecainide) on anisotropic reentry and determine the reason why these drugs are often ineffective in this clinical setting. The information that we obtain from these studies will enable us to propose optimal designs for antiarrhythmic drugs that will have maximum efficacy for the prevention of ventricular tachycardia caused by anisotropic reentry.
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