A NEW SYNTHETIC ANTIARRHYTHMIC PEPTIDE REDUCES DISPERSION OF EPICARDIAL ACTIVATION RECOVERY INTERVAL AND DIMINISHES ALTERATIONS OF EPICARDIAL ACTIVATION PATTERNS INDUCED BY REGIONAL ISCHEMIA - A MAPPING STUDY

Common antiarrhythmic agents affect ionic membrane channels and thereb y alter cellular electrical activity. Since this accounts for the proa rrhythmic effects as well we tried to find new substances with differe nt profiles of actions. A new antiarrhythmic peptide, H2N-Gly-Ala-Gly- 4Hyp-Pro-Tyr-CONH2, (AAP10), was synthetized using the Fmoc-strategy. This peptide was analyzed for its electrophysiological profile of acti on in normal isolated rabbit hearts perfused according to the Langendo rff technique either under control conditions or after induction of a regional ischemia. For this purpose 256 channel epicardial mapping was employed allowing the determination of the timepoints of activation a t each electrode thus identifying the origins of epicardial activation (socalled breakthrough-points, BTP). Epicardial spread of activation was then described mathematically by activation vectors which gave dir ection and velocity of the epicardial activation wave at each electrod e. Single heart beats were analyzed under control conditions and under treatment with AAP10 or under regional ischemia with or without AAP10 -pretreatment (10(-8) mol/l). We calculated the percentage of similar vectors (VEC) with unaltered direction (deviation less than or equal t o 5 degrees) and the percentage of identical breakthroughpoints (devia tion less than or equal to 1 mm)compared to control conditions. In add ition, apparent epicardial velocities, total activation time of a give n region and activation-recovery interval (ARI) as well as dispersion of ARI (i.e. standard deviation of ARI) and distribution of ARI were a nalyzed. Under control conditions treatment with AAP10 (10(-10) to 31 0(-7) mol/l) led to a significant decrease in ARI-dispersion without a lteration of any of the other parameters under investigation. Left ven tricular regional ischemia resulted in a marked alteration of the acti vation patterns (a significant decrease in vectorfield- and breakthrou ghpoint-similarity) which could be significantly inhibited by pretreat ment with AAP10. In addition, we found that AAP10 depressed the increa se in ARI-dispersion during the first minutes of ischemia and accelera ted normalization of ARI-dispersion during reperfusion. In additional experiments, it could be shown that AAP10 did not alter action potenti al duration, maximum dU/dt, amplitude or resting membrane potential of isolated guinea pig muscles using a common intracellular action poten tial recording technique. From these results it is concluded that (a) AAP10 inhibits ischemia induced alterations of the activation pattern (b) that it decreases ARI-dispersion (c) that this effect seems not to be due to an action on ionic channels (d) that the effect of AAP10 ma y be due to an improvement of cellular coupling and finally (e) that A AP10 may be an interesting new approach to the problem of prophylaxis of ischemia-associated ventricular arrhythmias.