This proposal is a continuation of studies designed to examine the electrophysiologic responses underlying the development of lethal arrhythmias in the post-infarct canine heart that is subjected to an acute ischemic event. Programmed electrical stimulation of the post-infarcted heart will be imployed in conjunction with intramyocardial composite electrode recordings to examine simultaneous electrical activity in the previously injured as well as the acutely ischemic myocardium. The similarity in response of the canine heart to that observed with the clinical use of programmed electrical stimulation makes this a valuable experimental method for the pre-clinical assessment of antiarrhythmic drug action in the setting of myocardial ischemic injury. Our laboratory has developed and successfully employed a canin model of """"""""sudden coronary death"""""""" in which ventricular fibrillation develops in response to a transient ischemic episode at a site remote from the infarct related vessel. We will continue to employ this model to study regional electrical events that precede the onset of ventricular fibrillation and the manner in which such alterations are modified by selected pharmacologic agents demonstrated to possess antiarrhythmic and/or antifibrillatory properties. Both experimental approaches, programmed electrical stimulation and the spontaneous development of ventricular fibrillation, provide unique opportunities to study selected pharmacologic interventions for their potential to prevent ventricular fibrillation as opposed to those agents that reduce the frequency of premature ventricular complexes and/or modify the cardiac response to provocative electrical stimuli. The animal models will also be employed to continue our investigations into the influence of pharmacologic and surgical modifications of cardiac autonomic nervous system imput with respect to the ability to alter the susceptibility of the injured heart to the induction of tachyarrhythmia and/or ventricular fibrillation. These studies will emphasize the importance of analyzing the actions of drugs on ischemically injured myocardium which serves as the substrate for life-threatening (reentrant/triggered) arrhythmias and the development of ventricular fibrillation as opposed to pharmacologic studies on normal cardiac tissue. The long term goal of the research proposal is to provide a rational basis for designing and evaluating potential pharmacologic interventions for the prevention of lethal cardiac arrhythmias. The animal species to be used in these studies is the mongrel dog.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
Zip Code
Friedrichs, G S; Chi, L; Black, S C et al. (1994) Antiarrhythmic agent, MS-551, protects against pinacidil + hypoxia-induced ventricular fibrillation in Langendorff-perfused rabbit isolated heart. J Cardiovasc Pharmacol 23:120-6
Chi, L; Friedrichs, G S; Oh, J Y et al. (1994) Effect of Ado A1- and A2-receptor activation on ventricular fibrillation during hypoxia-reoxygenation. Am J Physiol 267:H1447-54
Friedrichs, G S; Chi, L; Green, A L et al. (1994) Antifibrillatory effects of clofilium in the rabbit isolated heart. Br J Pharmacol 113:209-15
Black, S C; Butterfield, J L; Lucchesi, B R (1993) Protection against programmed electrical stimulation-induced ventricular tachycardia and sudden cardiac death by NE-10064, a class III antiarrhythmic drug. J Cardiovasc Pharmacol 22:810-8
Chi, L; Black, S C; Kuo, P I et al. (1993) Actions of pinacidil at a reduced potassium concentration: a direct cardiac effect possibly involving the ATP-dependent potassium channel. J Cardiovasc Pharmacol 21:179-90
Black, S C; Fagbemi, S O; Chi, L et al. (1993) Phorbol ester-induced ventricular fibrillation in the Langendorff-perfused rabbit heart: antagonism by staurosporine and glibenclamide. J Mol Cell Cardiol 25:1427-38
Lucchesi, B R; Chi, L; Friedrichs, G S et al. (1993) Antiarrhythmic versus antifibrillatory actions: inference from experimental studies. Am J Cardiol 72:25F-44F
Fagbemi, S O; Chi, L; Lucchesi, B R (1993) Antifibrillatory and profibrillatory actions of selected class I antiarrhythmic agents. J Cardiovasc Pharmacol 21:709-19
Friedrichs, G S; Chi, L; Black, S C et al. (1993) Antifibrillatory effects of ibutilide in the rabbit isolated heart: mediation via ATP-dependent potassium channels. J Pharmacol Exp Ther 266:1348-54
Chi, L G; Mu, D X; Lucchesi, B R (1991) Electrophysiology and antiarrhythmic actions of E-4031 in the experimental animal model of sudden coronary death. J Cardiovasc Pharmacol 17:285-95

Showing the most recent 10 out of 51 publications