Antimony-induced cardiomyopathy in guinea-pig and protection by L-carnitine.
Antimony (Sb) is the mainstay for the treatment of Leishmaniasis. It has serious, often lethal, cardiovascular side effects. The objective of this study was to examine the effects of Sb treatment upon the electrocardiogram (ECG), myocyte contractility (assessed by monitoring sarcomere length during field stimulation), whole-cell action potential (AP) and calcium current (I(Ca)) of the guinea-pig and to evaluate L-carnitine as a cardioprotective agent. Guinea-pigs received daily injections of either saline, Sb(V), Sb(III), L-carnitine or L-carnitine with Sb(III). Eight lead ECGs were recorded under halothane anaesthesia every 4 days. At the end of each treatment regime, animals were killed and ventricular myocytes were enzymatically isolated. Treatment with Sb(V) for 26 days prolonged the QT interval of the ECG. Treatment with Sb(III) was lethal within 2 days for approximately 50% of the animals. The survivors showed ECG alterations similar to those described in man: T wave flattening and/or inversion, depression of the ST segment, and elongation of RR and QT intervals. Their ventricular myocytes showed impaired contraction responses to changes in stimulus frequency, elongated AP and reduced I(Ca). Combined treatment with L-carnitine and Sb(III) delayed mortality. Prior treatment with L-carnitine followed by combined treatment with L-carnitine and Sb(III) reduced mortality to <10% over 12 days and these animals showed normal ECG. Their myocytes showed normal contractility and AP. It is concluded that L-carnitine has a preventive cardioprotective role against antimony-induced cardiomyopathy. The mechanism of action of L-carnitine may be to counter oxidative stress caused by Sb(III).
Alvarez
Marco
M
CNRS UMR 6542, Physiologie des Cellules Cardiaques et Vasculaires, Faculté des Sciences, Parc de Grandmont, 37200 Tours, France.
Malécot
Claire O
CO
Gannier
François
F
Lignon
Jacques M
JM
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000965:Antimony / Q000008:administration & dosage / Q000494:pharmacology*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002331:Carnitine / Q000008:administration & dosage / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004562:Electrocardiography / Q000187:drug effects; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology; D007273:Injections, Intramuscular; D008133:Long QT Syndrome / Q000188:drug therapy; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects; D013997:Time Factors
D002316:Cardiotonic Agents; D000965:Antimony; D002331:Carnitine