Antiarrhythmic effects of BN-063, a newly synthesized adenosine A1 agonist, on myocardial ischaemia in rats.
1. It has been shown that adenosine is able to reduce the severity of arrhythmias induced by myocardial ischaemia. In isolated preparations, the antiarrhythmic effect of adenosine on ventricular myocardium is known to antagonize the catecholamine-induced stimulation of intracellular cyclic AMP production, an effect mediated via adenosine A1 receptors. 2. The aim of this study was to evaluate the antiarrhythmic effect of BN-063 (1-cyclopropylisoguanosine), a newly synthesized selective adenosine A1 agonist, on ventricular arrhythmias in rats. 3. Arrhythmias were induced by left coronary artery ligation or by administration of isoprenaline (7 mg kg-1) subcutaneously. Pretreatment with BN-063 (0.25, 0.5 and 1.0 mg kg-1) 10 min prior to occlusion significantly delayed the onset of ventricular arrhythmias, reduced the total number of ventricular premature contraction (VPC) and ventricular tachycardia (VT), decreased the incidence of VT and ventricular fibrillation (VF) and mortality during the first 30 min following left coronary artery ligation. In contrast, pretreatment with 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an adenosine A1 antagonist, was arrhythmogenic during the ischaemic period. The rate-pressure product, an index for indirect measurement of myocardial oxygen consumption, was also significantly reduced by BN-063 during ligation time. 4. The incidence of VT, VF and mortality was also significantly reduced when BN-063 was administered after left coronary artery ligation. 5. BN-063 converted the VF induced by isoprenaline to normal sinus rhythm and improved the survival rate. 6. It is concluded that, through activation of adenosine A1 receptors, BN-063 can suppress ventricular arrhythmias induced by myocardial ischaemia and catecholamines. The antiarrhythmic actions of BN-063 may be mediated by reducing heart rate and antagonizing the stimulatory effects of catecholamine in myocardial ischaemia.
Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan.
Y M
YM
Lee
J W
JW
Chern
M H
MH
Yen
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000517:prevention & control; D005260:Female; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D017207:Rats, Sprague-Dawley
D000889:Anti-Arrhythmia Agents; D015221:Potassium Channels; D058906:Purinergic P1 Receptor Agonists; D006151:Guanosine; C090504:1-cyclopropylisoguanosine; D007545:Isoproterenol