SR 33589, a new amiodarone-like antiarrhythmic agent: anti-adrenoceptor activity in anaesthetized and conscious dogs

• Published in: European journal of pharmacology Vol. 279; no. 1; pp. 25 - 32
• Main Authors: Hodeige, Dominique, Heyndrickx, Jean-Pierre, Chatelain, Pierre, Manning, Allan
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 06.06.1995; Elsevier
• Subjects: Administration, Oral; Adrenergic Antagonists - pharmacology; Amiodarone; Amiodarone - pharmacology; Anesthesia; Animals; Anti-adrenoceptor activity; Anti-Arrhythmia Agents - pharmacology; Antiarrhythmic (class III); Antiarythmic agents; Benzofurans - pharmacology; Biological and medical sciences; Blood Pressure - drug effects; Cardiovascular system; Dogs; Dronedarone; Electrocardiography - drug effects; Female; Heart Rate - drug effects; Injections, Intravenous; Isoproterenol - pharmacology; Male; Medical sciences; Pharmacology. Drug treatments; SR 33589; Antiarrhythmic (class III); Amiodarone; Anti-adrenoceptor activity; SR 33589; Fissipedia; Carnivora; Vertebrata; Mammalia; Analog; Animal; Antagonist; Mechanism of action; Adrenergic receptor; Dog; Biological activity; Antiarrhythmia agent
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/0014-2999(95)00130-D

We have assessed the ability of amiodarone and the new amiodarone-like antiarrhythmic agent, SR 33589 ( N,N-dibutyl-3-[4-((2-butyl-5-methylsulphonamido)benzofuran-3-yl-carbonyl)phenoxy]propylamine), to inhibit the effects of adrenoceptor stimulation in anaesthetized and conscious dogs. In anaesthetized, atropinized dogs, adrenoceptor stimulation was achieved (i) by i.v. administration of adrenaline and measurement of increased blood pressure (ii) by i.v. administration of isoprenaline and measurement of increased heart rate and decreased blood pressure. In conscious dogs, adrenoceptor stimulation was achieved by i.v. administration of isoprenaline and measurement of increased heart rate. In anaesthetized, atropinized dogs, both amiodarone and SR 33589 inhibited to similar extents, α-adrenoceptor stimulation (as indicated by attenuation of adrenaline-induced increases in blood pressure). The β 1-adrenoceptor inhibitory activity of SR 33589 (as demonstrated by blockade of isoprenaline-induced increases in heart rate) was significant, but less marked than amiodarone (heart rate elevation reduced by 39%, P < 0.001 with 10 mg/kg SR 33589 and by 52%, P < 0.01 with 10 mg/kg amiodarone). In contrast, its β 2-adrenoceptor antagonistic activity (as demonstrated by blockade of isoprenaline-induced reduction in blood pressure) was more marked (mean blood pressure decrease reduced by 69%, P < 0.01 with 10 mg/kg SR 33589 and by 31%, P < 0.05 with 10 mg/kg amiodarone). In conscious dogs, both SR 33589 and amiodarone (12.5, 25 and 50 mg/kg p.o.) inhibited isoprenaline-induced increases in heart rate by approximately the same amount for varying durations depending on the dose. Thus, like amiodarone, SR 33589 can partially inhibit the effects of stimulation of the adrenoceptor system that may play a pivotal role in the onset of severe ventricular rhythm disturbances.