Cardioprotective effects of nicorandil, a mitochondrial potassium channel opener against doxorubicin-induced cardiotoxicity in rats

Basic Clin Pharmacol Toxicol. 2013 Sep;113(3):158-66. doi: 10.1111/bcpt.12078. Epub 2013 Jun 1.

Abstract

Doxorubicin is a chemotherapeutic drug used to treat solid and haematopoietic tumours. Its use is limited by a major side effect of cardiotoxicity. It was reported that doxorubicin-induced cardiotoxicity is mediated through oxidative stress coupled with impaired NO bioavailability and NF-κB activation. Nicorandil, a mitochondrial ATP-dependent potassium (KATP ) channel opener, was reported to be cardioprotective on ischaemic myocardium. However, the effect of nicorandil against doxorubicin-induced cardiotoxicity has not yet been clarified. Accordingly, six groups of rats were used. The first three groups were injected with vehicle, nicorandil (3 mg/kg) orally and doxorubicin (a single intraperitoneal injection of 20 mg/kg), respectively. Group four was treated with nicorandil, whereas group five was treated with glibenclamide and then nicorandil starting 2 days before doxorubicin and continued for five consecutive days. Group six was treated with glibenclamide alone. At the end of the experiment, the rats were killed. Cardiac enzyme indexes were measured in serum. Heart tissues were processed for determination of nitrite/nitrate, NF-κB protein expression, glutathione (GSH), lipid peroxide (TBARS) levels and superoxide production. In addition to body-weight reduction, doxorubicin produced cardiotoxicity as indicated from the increase in lactate dehydrogenase (LDH), creatine kinase (CK) activities, TBARS, superoxide production, NF-κB expression and caspase-3 activity. Moreover, doxorubicin decreased GSH and nitrite/nitrate levels. Histopathological examination of doxorubicin-treated hearts revealed degenerative changes. On the other hand, nicorandil protected cardiac tissues against doxorubicin cardiotoxicity as demonstrated from normalization of cardiac biochemical and oxidative stress parameters and amelioration of histopathological changes. Glibenclamide, a blocker of the KATP channel, reversed most of the cardiac effects of nicorandil.

MeSH terms

  • Animals
  • Antihypertensive Agents / pharmacology*
  • Antineoplastic Agents / adverse effects*
  • Cardiovascular Diseases / chemically induced*
  • Dose-Response Relationship, Drug
  • Doxorubicin / adverse effects*
  • Glutathione / biosynthesis
  • Glyburide / pharmacology
  • Lipid Peroxidation
  • Male
  • NF-kappa B / biosynthesis
  • Nicorandil / pharmacology*
  • Rats
  • Rats, Wistar
  • Superoxides / metabolism
  • Weight Loss

Substances

  • Antihypertensive Agents
  • Antineoplastic Agents
  • NF-kappa B
  • Superoxides
  • Nicorandil
  • Doxorubicin
  • Glutathione
  • Glyburide