Disturbances of cardiac rhythm are among the most common causes of death in patients with heart disease. The drugs that are used to treat these arrhythmias are not fully understood, and in many cases, toxic. Recent promising research results from isolated tissue experiments have suggested a new approach to the use of combinations of agents, based on their frequency and voltage dependent actions. This project will evaluate frequency-dependent actions of one of the major groups of antiarrhythmic agents on cardiac conduction and arrhythmia behaviour in intact animals. The actions of antiarrhythmic drugs in-vivo will be correlated with results obtained in-vitro and predicted by the modulated receptor hypothesis. The experiments will: 1. Examine and contrast use-dependent effects of lidocaine, mexiletine and quinidine on conduction in-vivo. 2. Determine if in-vivo differences in use-dependent behavior by lidocaine, mexiletine and quinidine conform to the modulated receptor hypothesis. 3. Determine if drugs that selectively prolong the QT interval (inactivated state) will enhance rate-related conduction slowing more by mexiletine and lidocaine than by quinidine. 4. Determine if drugs that prolong the QT interval will selectively enhance the efficacy of lidocaine and mexiletine more than that of quinidine in suppressing a post-infarct arrhythmia. Ultimately, information will be used to determine optimal conditions for a favorable electrophysiologic and antiarrhythmic actions by antiarrhythmic drug combinations.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL036291-04
Application #
3351183
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1986-09-30
Project End
1990-08-31
Budget Start
1989-03-01
Budget End
1990-08-31
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Newman, D; Herre, J M; Chin, M et al. (1992) Effects of sympathetic stimulation on use dependence of lidocaine, mexiletine, and quinidine in an intact canine model. Can J Physiol Pharmacol 70:219-24
Landzberg, J S; Franklin, J O; Langberg, J J et al. (1988) The transponder system: a new method of precise catheter placement in the right atrium under echocardiographic guidance. J Am Coll Cardiol 12:753-6