title: Diazoxide protects against doxorubicin-induced cardiotoxicity in the rat.
abstract: OBJECTIVE
  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 biochemical 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.
authors.affiliation: Section of Clinical Pharmacology, Laboratory of Clinical Biochemistry, Haukeland University Hospital, 5021 Bergen, Norway. lisa.drange.hole@helse-bergen.no.
authors.forename: Lisa Drange
authors.initials: LD
authors.lastname: Hole
authors.forename: Terje Hjalmar
authors.initials: TH
authors.lastname: Larsen
authors.forename: Kjell Ove
authors.initials: KO
authors.lastname: Fossan
authors.forename: Fredrik
authors.initials: F
authors.lastname: Limé
authors.forename: Jan
authors.initials: J
authors.lastname: Schjøtt
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000493:pharmacokinetics; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D003981:Diazoxide / Q000627:therapeutic use*; D004317:Doxorubicin / Q000009:adverse effects* / Q000493:pharmacokinetics; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020107:Troponin T / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D020107:Troponin T; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D003981:Diazoxide