Effects of the gap junction uncoupler palmitoleic acid on the activation and repolarization wavefronts in isolated rabbit hearts

1 The heart normally acts as an electrical syncytium coupled via gap juncti onal channels. Since closure of these channels has been considered arrhythm ogenic, we wanted to elucidate, how activation and repolarization wavefront s are altered during progressive pharmacological gap junctional uncoupling. 2 We used the well known gap junction uncoupler palmitoleic acid (PA). The specificity of PA was tested in rabbit papillary muscles, which exhibited s lowed conduction without affecting action potential morphology. We submitte d isolated rabbit hearts (Langendorff-technique) to increasing concentratio ns of palmitoleic acid (0.2, 1, 2, 5, 10, 20 mu M), while 256 channel epica rdial potential mapping was carried out. 3 In presence of PA activation recovery intervals (ARI) at the 256 electrod es became highly inhomogeneous with a dramatic increase in the dispersion o f activation recovery intervals (from 6 to 35 ms, P> 0.01; EC50 = 7 mu M), while the mean ARI-duration at 256 sites remained stable. PA led to marked alterations of the activation pattern, expressed as percentage of unchanged activation vectors (reduction from 32 to 10%, P<0.01, EC50=3.3 mu M), to p rolongation of atrioventricular conduction time (from 58 to 107 ms, P<0.01; EC50 = 8 mu M) of total activation time (from 7 to 14 ms, P<0.05, EC50 = 1 1 mu M) and of QRS-complex-duration. 4 In additional experiments the ventricle was paced via a bipolar electrode during the mapping procedure. From the isochrones longitudinal and transve rsal velocities were assessed showing that PA reduced transversal conductio n velocity more distinctly than longitudinal. 5 With regard to maximum effects and EC, values we conclude that gap juncti on uncoupling by PA mainly affects atrioventricular conduction, ARI-dispers ion and ventricular activation pattern. As important arrhythmopenic effects of uncoupling enhancement of dispersion with concomitant disturbation of t he normal activation pattern and slowing of conduction might be considered.