Increase in gap junction conductance by an antiarrhythmic peptide

Impaired cellular coupling is thought to be a very important factor for the genesis of cardiac arrhythmia. Cellular coupling is mediated by gap junctions. However, there are no therapeutic agents or experimental substances yet that increase cellular coupling. In addition, it has been shown that most antiarrhythmic drugs available now possess serious adverse effects. Thus, there is an urgent need for new antiarrhythmic agents. Previous studies using epicardial mapping in isolated rabbit hearts provided indirect evidence supporting the hypothesis that a newly synthesised antiarrhythmic peptide (Gly-Ala-Gly-4Hyp-Pro-Tyr-CONH2 = AAP10) might act via an increase in cellular, i.e., gap junctional coupling. The aim of the present study was to test this hypothesis. Measurement of the stimulus-response interval in papillary muscle showed a decrease of about 10% after application of 1 microM AAP10. These results are compatible with the hypothesis of AAP10 acting on gap junctions. In order to prove this hypothesis, gap junction conductance was measured directly by performing double-cell voltage-clamp experiments in isolated pairs of guinea-pig myocytes. During a 10 min control period gap junction conductance slowly decreased with a rate of -2.5 +/- 2.0 nS/min. After application of 10 nM AAP10 this behaviour reversed and gap junction conductance now increased with +1.0 +/- 0.7 nS/min. Upon washout of AAP10 gap junction conductance again decreased with a rate similar to that under control conditions. Another important finding was that we could not detect any other actions of AAP10 on cardiac myocytes. All parameters of the transmembrane action potential remained unchanged and, similarly, no changes in the IV relationship of single cardiac myocytes treated with 10 nM AAP10 could be observed. We conclude that AAP10 increases gap junction conductance, i.e., cellular coupling in the heart. This finding might be the first step towards the development of a new class of antiarrhythmic agents.