title: 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.
abstract: Common antiarrhythmic agents affect ionic membrane channels and thereby alter cellular electrical activity. Since this accounts for the proarrhythmic effects as well we tried to find new substances with different profiles of actions. A new antiarrhythmic peptide, H2N-Gly-Ala-Gly-4 Hyp-Pro-Tyr-CONH2 (AAP 10), was synthetized using the Fmoc-strategy. This peptide was analyzed for its electrophysiological profile of action in normal isolated rabbit hearts perfused according to the Langendorff 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 at 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 direction and velocity of the epicardial activation wave at each electrode. Single heart beats were analyzed under control conditions and under treatment with AAP 10 or under regional ischemia with or without AAP 10-pretreatment (10(-8) mol/l). We calculated the percentage of similar vectors (VEC) with unaltered direction (deviation < or = 5 degrees) and the percentage of identical breakthroughpoints (deviation < or = 1 mm) compared to control conditions. In addition, apparent epicardial velocities, total activation time of a given region and activation-recovery interval (ARI) as well as dispersion of ARI (i.e. standard deviation of ARI) and distribution of ARI were analyzed. Under control conditions treatment with AAP 10 (10(-10) to 3 x 10(-7) mol/l) led to a significant decrease in ARI-dispersion without alteration of any of the other parameters under investigation. Left ventricular regional ischemia resulted in a marked alteration of the activation patterns (a significant decrease in vectorfield- and breakthroughpoint-similarity) which could be significantly inhibited by pretreatment with AAP 10. In addition, we found that AAP 10 depressed the increase in ARI-dispersion during the first minutes of ischemia and accelerated normalization of ARI-dispersion during reperfusion. In additional experiments, it could be shown that AAP 10 did not alter action potential duration, maximum dU/dt, amplitude or resting membrane potential of isolated guinea pig muscles using a common intracellular action potential recording technique.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Institut für Pharmacologie, Universität zu Köln, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Dhein
authors.forename: N
authors.initials: N
authors.lastname: Manicone
authors.forename: A
authors.initials: A
authors.lastname: Müller
authors.forename: R
authors.initials: R
authors.lastname: Gerwin
authors.forename: U
authors.initials: U
authors.lastname: Ziskoven
authors.forename: A
authors.initials: A
authors.lastname: Irankhahi
authors.forename: C
authors.initials: C
authors.lastname: Minke
authors.forename: W
authors.initials: W
authors.lastname: Klaus
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000595:Amino Acid Sequence; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008969:Molecular Sequence Data; D017202:Myocardial Ischemia / Q000503:physiopathology*; D009842:Oligopeptides / Q000494:pharmacology*; D011817:Rabbits
chemical_list: C090806:AAP 10; D000889:Anti-Arrhythmia Agents; D009842:Oligopeptides