Heat stress protects against electrophysiological damages induced by acute doxorubicin exposure in isolated rat hearts.
The use of anthracycline antibiotics as anticancer agents is limited by their cardiac toxicity. Heat stress (HS) is known to confer protection against various myocardial injuries such as ischemia-reperfusion induced damage. This cardioprotective mechanism is associated with an increase in endogenous antioxidative defenses and heat stress proteins (HSPs) synthesis. The aim of this study was thus to investigate whether HS could protect against acute doxorubicin cardiotoxicity using the isolated rat heart model. Rats were either heat stressed (42 degrees C for 15 min) or sham anesthetized. 24 h later, their hearts were isolated and retrogradely perfused at constant flow. Following 30-min of stabilization, hearts were perfused during 70 min with modified-Krebs solution containing 6 mg/l doxorubicin. Control hearts were perfused under identical conditions but without doxorubicin. Different hemodynamic and electrophysiological parameters were assessed in hearts from the four experimental groups. Doxorubicin exposure decreased left ventricular developed pressure (approximately -60% of baseline) and increased coronary perfusion pressure (approximately +230% of baseline). Prior HS did not modify these effects. Incidence of ventricular fibrillation (VF) was significantly enhanced by doxorubicin exposure (66% vs 0% in control group). Moreover, the ventricular action potential duration (APD) was significantly shortened in the presence of doxorubicin. Prior HS prevented both increase in VF incidence and shortening of APD. We conclude that prior heat stress protects myocardium against electrophysiological injury, but not against hemodynamic damage, induced by acute doxorubicine exposure. Further investigations are required to elucidate the precise mechanisms involved in this effect.
Joyeux
M
M
Laboratoire Stress Cardiovasculaires et Pathologies Associées, Université Joseph Fourier, UFR de Pharmacie, Grenoble, France.
Godin-Ribuot
D
D
Faure
P
P
Demenge
P
P
Ribuot
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000633:toxicity; D002316:Cardiotonic Agents / Q000627:therapeutic use; D004317:Doxorubicin / Q000009:adverse effects* / Q000633:toxicity; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D018882:Heat Stress Disorders / Q000188:drug therapy* / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D000970:Antineoplastic Agents; D002316:Cardiotonic Agents; D004317:Doxorubicin