Anti-arrhythmic and electrophysiological effects of the endothelin receptor antagonists, BQ-123 and PD161721

The effects of the endothelin ETA, (BQ-123) and endothelin ETA/B (PD161721) receptor antagonists were investigated on ischaemia-induced arrhythmias and on the maximum following frequency. The study was carried out in Langendorff perfused rat hearts subjected to coronary artery occlusion in which the severity of arrhythmias, coronary perfusion pressure and heart rate were measured. The % incidence of ischaemia-induced irreversible ventricular fibrillation (ventricular fibrillation) was reduced significantly from 58%, in control rat hearts, to 0% (at 10(-7) and 10(-6) M PD161721 and 10(-6) M BQ-123 P < 0.05). Maximum following frequency was measured in guinea-pig isolated atria. In the presence of normal extracellular [K+], BQ-123 and PD161721, at 10(-6) M, significantly decreased the maximum following frequency from 9.0 +/- 0.7 to 7.2 +/- 0.4 and from 8.3 +/- 0.4 to 6.7 +/- 0.3 Hz, respectively (P < 0.05). These effects were not potentiated by raising the extracellular [K+] with the exception of 10(-9) M PD161721. In contrast, lignocaine's ability to reduce the maximum following frequency was greater in elevated (e.g. at 1.7 X 10(-4) M from 8.4 +/- 0.3 to 2.5 +/- 0.6 Hz) than in normal [K+] (from 9.0 +/- 0.3 to 4.9 +/- 0.5 Hz). In conclusion, both BQ-123 and PD161721 had an anti-fibrillatory effect in isolated rat hearts that may be due, at least in part, to an ability to reduce the maximum following frequency. This latter effect is unlikely to be due to Na+ channel blockade since it was not markedly potentiated by elevation of extracellular [K+]. (C) 2001 Published by Elsevier Science B.V.