Diazoxide protects against doxorubicin-induced cardiotoxicity in the rat
| Autor: | Jan Schjøtt, Kjell Ove Fossan, Fredrik Limé, Terje H. Larsen, Lisa Drange Hole |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Cardiac function curve
Male Hydrogenperoxide Cardiotonic Agents Heart Diseases medicine.medical_treatment Pharmacology Ventricular Function Left Troponin T 5-hydroxydecanoate Diazoxide Ventricular Pressure Medicine Animals Pharmacology (medical) Doxorubicin Rats Wistar Saline Chemotherapy Cardiotoxicity Antibiotics Antineoplastic business.industry Doxorubicinol Myocardium Antagonist Heart Hydrogen Peroxide Ex vivo Rats Ventricular pressure Rat business medicine.drug Research Article |
| Zdroj: | BMC Pharmacology & Toxicology BMC Pharmacology and Toxicology |
| ISSN: | 2050-6511 |
| Popis: | Aim: Chemotherapy with doxorubicin is limited by cardiotoxicity. Free radical generation and mitochondrial dysfunction are thought to contribute to doxorubicin-induced cardiac failure. In this study we wanted to investigate if opening of mitochondrial KATP-channels by diazoxide is protective against doxorubicin cardiotoxicity, and if 5-hydroxydecanoate (5-HD), a selective mitochondrial KATP-channel antagonist, abolished any protection by this intervention. Methods: Wistar rats were divided into 7 groups (n = 6) and followed for 10 days with 5 intervention groups including the following treatments: (1) Diazoxide and doxorubicin, (2) diazoxide and 5-hydroxydecanoate (5-HD), (3) 5-HD and doxorubicin, (4) diazoxide and saline and (5) 5-HD and saline. On day 1, 3, 5 and 7 the animals received intraperitoneal (i.p.) injections with 10 mg/kg diazoxide and/or 40 mg/kg 5-HD, 30 minutes before i.p. injections with 3.0 mg/kg doxorubicin. One control group received only saline injections and the other control group received saline 30 minutes prior to 3.0 mg/kg doxorubicin. On day 10 the hearts were excised and Langendorff-perfused. Cardiac function was assessed by an intraventricular balloon and bioch emical effects by release of hydrogen peroxide (H2O2) and troponin-T (TnT) in effluate from the isolated hearts, and by myocardial content of doxorubicin. Results: Doxorubicin treatment produced a significant loss in left ventricular developed pressure (LVDP) (p < 0.05) and an increase in both H2O2 and TnT release in effluate (p < 0.05). Diazoxide significantly attenuated the decrease in LVDP (p < 0.05) and abolished the increased release of H2O2 and TnT (p < 0.05). 5-HD abolished the effects of pretreatment with diazoxide, and these effects were not associated with reduced myocardial accumulation of doxorubicin. Conclusions: Pretreatment with diazoxide attenuates doxorubicin-induced cardiac dysfunction in the rat, measured by physiological indices and TnT and H2O2 in effluate from isolated hearts. The effect could be mediated by opening of mitochondrial KATP-channels, reduced doxorubicin-associated free radical generation and decreased cardiomyocyte damage. Diazoxide represents a promising protective intervention against doxorubicin-induced acute cardiotoxicity. publishedVersion |
| Databáze: | OpenAIRE |
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