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 junctional channels. Since closure of these channels has been considered arrhythmogenic, we wanted to elucidate, how activation and repolarization wavefronts 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 slowed conduction without affecting action potential morphology. We submitted isolated rabbit hearts (Langendorff-technique) to increasing concentrations of palmitoleic acid (0.2, 1, 2, 5, 10, 20 microM), while 256 channel epicardial potential mapping was carried out. 3. In presence of PA activation recovery intervals (ARI) at the 256 electrodes became highly inhomogeneous with a dramatic increase in the dispersion of activation recovery intervals (from 6 to 35 ms, P>0.01; EC50=7 microM), 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 microM), to prolongation of atrioventricular conduction time (from 58 to 107 ms, P<0.01; EC50=8 microM) of total activation time (from 7 to 14 ms, P<0.05, EC50=11 microM) 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 transversal velocities were assessed showing that PA reduced transversal conduction velocity more distinctly than longitudinal. 5. With regard to maximum effects and EC50 values we conclude that gap junction uncoupling by PA mainly affects atrioventricular conduction, ARI-dispersion and ventricular activation pattern. As important arrhythmogenic effects of uncoupling enhancement of dispersion with concomitant disturbation of the normal activation pattern and slowing of conduction might be considered.
Dhein
S
S
Institute of Pharmacology, University of Halle, Germany. stefan.dheim@medizin.uni-halle.de
Krüsemann
K
K
Schaefer
T
T
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D017629:Gap Junctions / Q000187:drug effects* / Q000502:physiology; D006329:Heart Conduction System / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000166:cytology; D009431:Neural Conduction / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010496:Pericardium / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D014475:Uncoupling Agents / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology; D017725:Ventricular Pressure / Q000187:drug effects / Q000502:physiology
D005229:Fatty Acids, Monounsaturated; D014475:Uncoupling Agents; C008757:palmitoleic acid