The Endothelin-A Antagonist LU 135 252 Supresses Ischemic Ventricular Extrasystoles and Fibrillation in Pigs and Prevents Hypoxic Cellular Decoupling

The endothelin-A (ETA) antagonist LU 135 252 (1 mg/kg, n = 10) or saline (control, n = 10) was injected i.v. into anesthetized pigs 15 min before occlusion of the last third of the left anterior descending coronary artery (LAD) for up to 90 min. Then, or when ventricular fibrillation occurred, the ischemic mass was determined and amounted to about 13% of ventricular mass in all groups. Heart rate, QT interval, blood pressure, and the left ventricular contractility parameter LV dp/dtmax were not altered by LU in the 15 min pretreatment period. The lower dose of the ETA antagonist had only marginal antiarrhythmic effects. At the 3 mg/kg dose, LU prolonged the time of regular sinus rhythm within the first 20 min of ischemia by 50% (mean +/- SEM: 12 +/- 2 min in control vs. 18 +/- 1 after LU; p < 0.05) and reduced the number of ventricular extrasystoles by 87% (54 +/- 18 vs. 7 +/- 3; p < 0.05). The total incidence of ventricular fibrillation (VF) (80% vs. 50%; p = 0.17) and also the incidence of late VF (ischemia > 20 min) was reduced by 3 mg/kg LU (78% vs. 38%; p = 0.12). In vitro, LU (10(-6) mol/L) prevented the hypoxia-induced (N2 gassing) impairment of intercellular coupling, measured as the delay between a direct stimulus and a distal action potential in guinea pig papillary muscles.