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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

Naunyn-Schmiedeberg's Archives of Pharmacology volume 350, pages 174–184 (1994)Cite this article

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-4Hyp-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 <-5°) and the percentage of identical breakthroughpoints (deviation ≤ 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*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.

From these results it is concluded that (a) AAP 10 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 AAP 10 may be due to an improvement of cellular coupling and finally (e) that AAP 10 may be an interesting new approach to the problem of prophylaxis of ischemia-associated ventricular arrhythmias.

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Affiliations

  1. Institut für Pharmakologie, Universität zu Köln, Geuelerstrasse 24, D-50931, Köln, Germany

    S. Dhein, N. Manicone, A. Müller, R. Gerwin, U. Ziskoven, A. Irankhahi, C. Minke & W. Klaus

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  1. S. Dhein
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  2. N. Manicone
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  3. A. Müller
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  4. R. Gerwin
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  5. U. Ziskoven
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  6. A. Irankhahi
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  7. C. Minke
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  8. W. Klaus
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Correspondence to: S. Dhein at the above address

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Dhein, S., Manicone, N., Müller, A. et al. A new synthetic antiarrhythmic peptide reduces dispersion of epicardial activation recovery interval and diminishes alterations of epicardial activation patterns induced by regional ischemia. Naunyn-Schmiedeberg's Arch Pharmacol 350, 174–184 (1994). https://doi.org/10.1007/BF00241093

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  • DOI: https://doi.org/10.1007/BF00241093

Key words

  • Antiarrhythmic peptide
  • Cellular communication
  • Action potential dispersion
  • Epicardial mapping
  • Arrhythmia
  • Cardiac ischemia