Ischemia and Reperfusion, Induced Arrhythmias in the Rat: Effects of Xanthine Oxidase Inhibition with Allopurinol

• Published in: Circulation research 1984-10, Vol.55 (4), p.545-548
• Main Authors: Manning, Allan S, Coltart, D John, Hearse, David J
• Format: Article
• Language: English
• Subjects: Allopurinol - pharmacology; Animals; Antianginal agents. Coronary vasodilator agents; Arrhythmias, Cardiac - etiology; Arrhythmias, Cardiac - physiopathology; Arteries; Biological and medical sciences; Cardiovascular system; Coronary Disease - complications; Coronary Disease - physiopathology; Coronary Vessels - physiology; Free Radicals; Hemodynamics; Ligation; Male; Medical sciences; Perfusion; Pharmacology. Drug treatments; Rats; Rats, Inbred Strains; Xanthine Oxidase - antagonists & inhibitors
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.55.4.545

We have investigated the possibility that xanthine oxidase-linked free radical production has a role in the genesis of arrhythmias during ischemia and reperfusion. In this study, rats were treated with allopurinol (20 mg/kg, orally, 24 hours before study, plus 20 mg/kg, iv, 15 minutes prior to study). Using an anesthetized open-chest preparation with either coronary artery occlusion for 30 minutes, or 5 minutes followed by 10 minutes reperfusion, we monitored and compared the rhythm disturbances in experimental vs. placebo-treated rats (n = 18 in each group). Allopurinol treatment reduced the incidence of ventricular tachycardia during ischemia from 88% to 50% (P < 0.05) and the number of premature ventricular complexes from 471 ± 120 to 116 ± 46 (P < 0.02), but the treatment had no effect upon the incidence or duration of ventricular fibrillation or upon mortality. In contrast, far more dramatic protection was observed during reperfusion after 5 minutes of ischemia. Allopurinol treatment reduced the incidence of ventricular fibrillation from 67% to 11% (P < 0.01), reduced the mean duration of fibrillation from 230 ± 70 to 14 ± 1 seconds (P < 0.05), and reduced mortality by half (10/18 to 4/18), although this did not reach a level of statistical significance. In addition, the mean duration of tachycardia was reduced from 83 ± 26 to 38 ± 8 seconds (P < 0.05). Allopurinol pretreatment thus affords some protection against ischemia-induced arrhythmias, but a higher degree of protection against reperfusion-induced arrhythmias. Allopurinol inhibits xanthine oxidase activity, and, in turn, this inhibits superoxide radical production. Since free radical generation has been implicated in the genesis of tissue injury during ischemia and reperfusion, and since the severity of this injury can influence vulnerability to both ischemia and reperfusion-induced arrhythmias, we would propose that free radical formation by xanthine oxidase, or its consequences, is a new factor to consider in relation to the vulnerability of tissue to ischemia and reperfusion-induced arrhythmias.