ANTIARRYHTHMIC DRUG ACTION ON VMAX OF CARDIAC CELLS

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The objectives of the present investigation are: (1) To further test the modulated receptor hypothesis for the action of antiarrhythmic drugs on cardiac sodium channels. (2) To develop a faster and more complete search method for analysis of the experimental results, including upper and lower limits for the estimates. (3) To characterize the structure-activity relationship for lidocaine procainamide, aprindine and amiodarone derivatives. (4) To continue the development of a preparation that can be voltage clamped. (5) To study drug interactions in terms of modulated receptor hypothesis. It is hoped that this research will further improve our understanding of the action of antiarrhythmic drugs; that the elucidation of the QSAR will promote the development of better and safer antiarrhythmic drugs; that the drug interactions will provide better use of the currently available drugs. Guinea pig papillary muscles and single isolated cardiocytes will be voltage clamped. The sodium current or Vmax will be measured and these data will be used to estimate the drug blocked channels. By clamping the preparations to various potentials and different durations it is possible to determine the affinity and the kinetics of the interaction of antiarrhythmic drugs with sodium channels. The modulated receptor constants and the biophysical properties of the drugs will be correlated using cluster analysis techniques to unravel the structure activity relationship in a quantitative fashion (QSAR). The results of QSAR will be used to improve existing antiarrhythmic drugs and to design new ones.