Protection by ITF 1300, a heparin ion-pair complex, against arrhythmias induced by regional ischemia and reperfusion in the isolated rat heart: possible mechanism of action.
We examined the effects of the heparin ion-pair complex ITF 1300 on ventricular fibrillation (VF) and other arrhythmias elicited by regional ischemia and by reperfusion in isolated rat hearts (n = 12 per group). During 30-min ischemia, 1, 3, and 10 mg/L ITF 1300 reduced the incidence of VF concentration dependently, with complete abolition of VF at the highest concentration (p < 0.05). Similar but weaker effects were observed for other arrhythmias [ventricular tachycardia (VT) and salvos]. Reperfusion-induced arrhythmias (elicited after 10- or 30-min regional ischemia) were affected similarly, with complete abolition of VF at the highest drug concentration (p < 0.05). Coronary blood flow (CBF), recovery of CBF during reperfusion, and occluded zone sizes were little affected (p = NS). ITF 1300 caused concentration-dependent bradycardia, PR interval widening, and QT widening. In further studies, we examined the roles of these changes in mediating the antiarrhythmic effects. Left atrial pacing at a rate close to control rate (300 beats/min) abolished the antiarrhythmic effects of ITF 1300 and the QT widening, indicating that bradycardia and QT widening were important in mediating the antiarrhythmic effects. Doubling the calcium concentration in the perfusion solution prevented ITF 1300-induced PR widening, indicating that calcium antagonist activity probably mediated the drug's effects on this variable. However, the antiarrhythmic effect of ITF 1300 was not affected by high calcium perfusion. ITF 1300 is an effective antiarrhythmic agent in a model of ischemic heart disease. Its effects are mediated primarily by heart rate-dependent QT widening and were not related to possible calcium antagonist activity.
Curtis
M J
MJ
Department of Pharmacology, King's College, University of London, England.
Barsby
R W
RW
Forster
R
R
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000517:prevention & control*; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002304:Cardiac Pacing, Artificial; D003326:Coronary Circulation / Q000187:drug effects; D004562:Electrocardiography / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006493:Heparin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D066298:In Vitro Techniques; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000150:complications* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar
D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D005343:Fibrinolytic Agents; C078918:ITF 300; D006493:Heparin; D002118:Calcium