Antiarrhythmic effect of amiodarone on doxorubicin acute toxicity in working rat hearts.
OBJECTIVE
The clinical application of doxorubicin, a potent cytotoxic agent, is limited by a dose dependent cardiotoxicity and by the acquired resistance of the neoplastic cells. Recently, the sensitivity of resistant cancer cells to doxorubicin has been enhanced by the acute administration of amiodarone. The aim of this study was to investigate whether or not this potentiates the cardiotoxicity of doxorubicin.


METHODS
Hearts from rats pretreated or not with amiodarone 50 mg.kg-1.d-1 for 5 d were perfused via the left atrium with a Krebs-Henseleit solution containing, or not, doxorubicin 6 mg.litre-1. After 40 min of perfusion, the left main coronary artery was ligated and the ligature was maintained for 10 min. It was then cut and reperfusion continued for 10 min. The cardiac output, heart rate, and mean fibrillation duration induced by the reperfusion were measured by timed collections and ECG recordings.


METHODS
32 adult male Sprague-Dawley rats (250-300 g) were used throughout the study.


RESULTS
After 40 min of perfusion, the cardiac output in the control and amiodarone groups was constant, but significant decreases of 25.5 and 30.4% were noted in both doxorubicin groups. The mean fibrillation durations observed during reperfusion were 331(73), 66(22), 444(86), and 22(9) s for the control, amiodarone, doxorubicin and amiodarone-doxorubicin groups respectively.


CONCLUSIONS
Amiodarone, while maintaining its antiarrhythmic effect, did not potentiate the negative inotropic effect of doxorubicin. These results suggest that the cardiotoxicity produced by the clinically acute administration of amiodarone with doxorubicin is not greater than that caused by doxorubicin given alone.
Lambert
C
C
Research Center, Hôpital du Sacré-Coeur de Montréal, Quebec, Canada.
Mossiat
C
C
Tannière-Zeller
M
M
Maupoil
V
V
Rochette
L
L
D000638:Amiodarone / Q000627:therapeutic use / Q000633:toxicity*; D000818:Animals; D002302:Cardiac Output / Q000187:drug effects*; D003326:Coronary Circulation / Q000187:drug effects*; D004317:Doxorubicin / Q000633:toxicity*; D004347:Drug Interactions; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009924:Organ Culture Techniques; D051381:Rats; D011919:Rats, Inbred Strains; D014693:Ventricular Fibrillation / Q000188:drug therapy*
D004317:Doxorubicin; D000638:Amiodarone