Diazoxide-induced cardioprotection requires signaling through a redox-sensitive mechanism

Robert A. Forbes, Charles Jr Steenbergen, Elizabeth Murphy

Research output: Contribution to journalArticle

Abstract

Diazoxide, a selective opener of the mitochondrial ATP-sensitive potassium channel, has been shown to elicit tolerance to ischemia in cardiac myocytes and in perfused heart. However, the mechanism of this cardioprotection is poorly understood. Because reactive oxygen species (ROS) are recognized as important intracellular signaling molecules and have been implicated in ischemic preconditioning, we examined diazoxide-induced ROS production in adult cardiomyocytes. Cells treated with 50 μmol/L diazoxide showed a 173% increase in ROS production relative to baseline. 5-Hydroxydecanoate was found to attenuate the diazoxide-induced increase in ROS generation. The diazoxide-induced increase in ROS also was abrogated by the addition of either the antioxidant N-acetylcysteine (NAC) or N-mercaptopropionylglycine. We also examined the ability of NAC to block the protective effects of diazoxide in the perfused rat heart. After 20 minutes of global ischemia and 20 minutes of reflow, hearts perfused with 100 μmol/L, diazoxide before ischemia showed significantly improved postischemic contractile function relative to untreated hearts (84% versus 29% of initial left ventricular developed pressure, respectively). Hearts treated with diazoxide in the presence of 4 mmol/L NAC recovered 53% of initial left ventricular developed pressure, whereas hearts treated with NAC alone recovered 46% of preischemic function. Using 31P NMR spectroscopy, we found that, similar to preconditioning, diazoxide significantly attenuated ischemia-induced intracellular acidification and enhanced postischemic recovery of phosphocreatine levels, both of which were blocked by cotreatment with NAC. These data suggest that the cardioprotective actions of diazoxide are mediated by generation of a pro-oxidant environment.

Original languageEnglish (US)
Pages (from-to)802-809
Number of pages8
JournalCirculation Research
Volume88
Issue number8
StatePublished - Apr 27 2001
Externally publishedYes

Fingerprint

Diazoxide
Oxidation-Reduction
Acetylcysteine
Reactive Oxygen Species
Ischemia
Ventricular Pressure
Cardiac Myocytes
Tiopronin
KATP Channels
Ischemic Preconditioning
Phosphocreatine
Magnetic Resonance Spectroscopy
Antioxidants

Keywords

  • Cardioprotection
  • Dichlorofluorescin diacetate
  • Intracellular pH
  • Reactive oxygen species

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Diazoxide-induced cardioprotection requires signaling through a redox-sensitive mechanism. / Forbes, Robert A.; Steenbergen, Charles Jr; Murphy, Elizabeth.

In: Circulation Research, Vol. 88, No. 8, 27.04.2001, p. 802-809.

Research output: Contribution to journalArticle

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