The ET_A receptor antagonist LU 135252 has no electrophysiological or anti-arrhythmic effects during myocardial ischaemia/reperfusion in dogs

The anti-arrhythmic effects of ET_A receptor antagonists during myocardial ischaemia and reperfusion remain controversial. Moreover, the electrophysiological mechanism has not yet been identified. The aim of this study was to investigate the potential anti-arrhythmic and electrophysiological effects of the ET_A receptor antagonist LU 135252 (LU) during myocardial ischaemia and reperfusion in a canine model. A bolus of LU (1mg/kg; n = 10) or saline (control; n = 10) was injected into the left anterior descending coronary artery before ligation of this vessel for 30min, which was followed by a 90-min reperfusion period. LU bolus administration (0.5mg/kg) was repeated every 30min. There were no differences in mean arterial blood pressure or coronary blood flow between the two groups. The determined left ventricular ischaemic mass was 25.5±1.8% and 27.8±2.2% of the total left ventricular mass in the control and LU groups respectively. The total incidence of ventricular fibrillation during ischaemia and reperfusion was 40% in the control and 50% in the LU group (not significantly different). The incidence of non-sustained and sustained ventricular tachycardias during ischaemia, reperfusion and over the whole period (ischaemia plus reperfusion) in the control group was 50%, 50% and 70% respectively, and that in the LU group was 80%, 70% and 100% respectively (no significant differences between groups). The number of ventricular premature beats was not decreased by LU during either ischaemia or reperfusion [median (25th–75th percentile): ischaemia, 20 (13–37) and 56 (32–130) for LU and control groups respectively; reperfusion, 15 (2–21) and 39 (7–74) respectively; ischaemia+reperfusion, 16 (4–35) and 43 (10–82) respectively; no significant differences between groups]. During ischaemia, the monophasic action potential duration at 90% repolarization (MAPD₉₀) decreased significantly, while during reperfusion a significant prolongation of MAPD₉₀ was observed in the left anterior descending region that was similar in the two groups. In conclusion, LU did not affect repolarization changes and did not have anti-arrhythmic effects during either ischaemia or reperfusion in this model.