Effects of the myocardial‐selective α1‐adrenoceptor antagonist UK‐52046 and atenolol, alone and in combination, on experimental cardiac arrhythmias in dogs

1 Adrenaline‐induced arrhythmias in anaesthetized dogs respired with halothane were attenuated in 3 groups of 6 dogs by either UK‐52046, 3.8 ± 1.4μgkg−1 (mean ± s.e.mean), atenolol 14.6 ± 2.1 μgkg−1, or a combination containing equal amounts of the two drugs of 0.36 ± 0.1 μgkg−1. The pressor response to adrenaline was reduced (P < 0.01) by UK‐52046 but not by atenolol or the combination of both drugs. 2 In a group of 6 dogs with multiventricular ectopic beats 24 h after coronary artery ligation (CAL), UK‐52046, 32μgkg−1, increased the number of sinus beats in each 5min period from 137 ± 47 to 662 ± 99 (P < 0.01); this was associated with a significant (P < 0.01) fall in blood pressure. Atenolol in doses of up to 800μg kg−1 had no effect. 3 UK‐52046, 3.7 ± 1.4μgkg−1, prevented adrenaline‐induced arrhythmias 3–4 days after CAL in 6/6 conscious dogs; atenolol in doses of up to 100μgkg−1 produced an 84.4 ± 7.4% reduction in the number of ventricular ectopic beats. A combination containing 3.7 ± 1.1 μgkg−1 of each drug prevented the arrhythmia in 6/6 dogs. The pressor response to adrenaline was attenuated (P < 0.05) by UK‐52046, but resting blood pressure was unaffected by the different treatments. An increase (P < 0.01) in heart rate was associated with both UK‐52046 and the combination. 4 Neither UK‐52046 (doses up to 64μgkg−1) nor atenolol (up to 800μgkg−1) had any effect upon ouabain‐induced arrhythmias in 2 groups of 6 anaesthetized dogs. 5 In a study of the early (1a/1b) arrhythmias of acute myocardial ischaemia, the total number of ventricular ectopic beats occurring within 30min of CAL was not reduced by 4μgkg−1 UK‐52046 but fell (P < 0.01 compared with placebo) after 8μgkg−1 [median values with ranges for placebo, 4μgkg−1 and 8μgkg−1 respectively 190 (4–674), 246 (9–1204) and 12 (1–154)]. Both doses of UK‐52046 were associated with significant falls in blood pressure. 6 The arrhythmias produced by programmed electrical stimulation were studied in 2 groups of 6 conscious dogs, 7–30 days after CAL. With placebo, 4/6 dogs remained unchanged and 2 died: UK‐52046 prevented arrhythmias in 2/6, 2 remained unchanged and 2 died (P = 0.29). Compared with placebo, blood pressure fell with doses greater than 4μgkg−1. 7 These results indicate antiarrhythmic effects of UK‐52046 in a number of experimental models and suggest an enhanced role of α‐receptors in the genesis of ischaemia‐related arrhythmias. In several of the models used, UK‐52046 produced haemodynamic c