ACTIONS OF THE ANTIARRHYTHMIC PEPTIDE AAP10 ON INTERCELLULAR COUPLING

Disturbances in gap junction distribution and a decrease in the connex in43 content of the heart were shown to occur after myocardial infarct ion and in ischemic heart disease, respectively. These changes are now thought to play an important role in the genesis of arrhythmias assoc iated with these diseases. It is thought that agents that call increas e cellular coupling might be beneficial in these situations. Recently, we presented data showing that the synthetic peptide AAP10 acts antia rrhythmically in a model of regional ischemia. The data suggested that AAP10 might act via an increase in cellular coupling. The goal of thi s study was to establish whether AAP10 can interact with cardiac gap j unctions. Measurements of the stimulus-response-interval (SRI) in guin ea pig papillary muscle showed that high concentrations of AAP10/1 (mu M) can decrease the SRI by about 10% under normoxic conditions. At lo wer concentrations (10 nM) AAP10 had no effect on SRI under normoxic c onditions but prevented the increase in the SRI induced by perfusion w ith hypoxic, glucose-free Tyrode's solution. Double-cell voltage-clamp experiments confirmed that AAP10 can interact with cardiac gap juncti ons. 10 nM APP10 could either diminish or reverse the run-down of gap junction conductance normally observed in pairs of guinea pig ventricu lar myocytes. During control gap junction conductance decreased with a rate of -2.5 +/- 2.0 nS/min. After application of 10 nM AAP10 gap jun ction conductance increased with a rate of +1.0 +/- 0.7 nS/min (p < 0. 01). After washout of AAP10 gap junction conductance decreased again w ith a rate not significantly different from control. Our results show that AAP10 does interact with gap junctions. Because no other effects of AAP10 on other electrophysiological parameters could be found, this action on gap junctions might be the basis of AAP10's antiarrhythmic effect seen in previous studies.