Effects of the myocardial-selective alpha 1-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 +/- 1.4 micrograms kg-1 (mean +/- s.e.mean), atenolol 14.6 +/- 2.1 micrograms kg-1, or a combination containing equal amounts of the two drugs of 0.36 +/- 0.1 microgram kg-1. The pressor response to adrenaline was reduced (P less than 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, 32 micrograms kg-1, increased the number of sinus beats in each 5 min period from 137 +/- 47 to 662 +/- 99 (P less than 0.01); this was associated with a significant (P less than 0.01) fall in blood pressure. Atenolol in doses of up to 800 micrograms kg-1 had no effect. 3. UK-52046, 3.7 +/- 1.4 micrograms kg-1, prevented adrenaline-induced arrhythmias 3-4 days after CAL in 6/6 conscious dogs; atenolol in doses of up to 100 micrograms kg-1 produced an 84.4 +/- 7.4% reduction in the number of ventricular ectopic beats. A combination containing 3.7 +/- 1.1 micrograms kg-1 of each drug prevented the arrhythmia in 6/6 dogs. The pressor response to adrenaline was attenuated (P less than 0.05) by UK-52046, but resting blood pressure was unaffected by the different treatments. An increase (P less than 0.01) in heart rate was associated with both UK-52046 and the combination. 4. Neither UK-52046 (doses up to 64 micrograms kg-1) nor atenolol (up to 800 micrograms kg-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 30 min of CAL was not reduced by 4 micrograms kg-1 UK-52046 but fell (P less than 0.01 compared with placebo) after 8 micrograms kg-1 [median values with ranges for placebo, 4 micrograms kg-1 and 8 micrograms kg-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 4jg kg- '. 7. These results indicate antiarrhythmic effects of UK-52046 in a number of experimental models and suggest an enhanced role of alpha-receptors in the genesis of ischaemia-related arrhythmias. In several of the models used, UK-52046 produced haemodynamic changes in keeping with peripheral alpha-adrenoceptor antagonism.
Uprichard
A G
AG
Department of Therapeutics and Pharmacology, Queen's University of Belfast, Northern Ireland.
Harron
D W
DW
Wilson
R
R
Shanks
R G
RG
D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage*; D000634:Aminoquinolines / Q000008:administration & dosage*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D001262:Atenolol / Q000008:administration & dosage*; D003331:Coronary Vessels; D004285:Dogs; D004359:Drug Therapy, Combination; D004594:Electrophysiology; D004837:Epinephrine; D005260:Female; D006221:Halothane; D006439:Hemodynamics / Q000187:drug effects; D008026:Ligation; D008297:Male; D010042:Ouabain; D044005:Tetrahydroisoquinolines
D000317:Adrenergic alpha-Antagonists; D000634:Aminoquinolines; D044005:Tetrahydroisoquinolines; D001262:Atenolol; D010042:Ouabain; C058534:abanoquil; D006221:Halothane; D004837:Epinephrine