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Role of an ATP-sensitive potassium channel opener, YM934, in mitochondrial energy production in ischemic/reperfused heart.

Abstract
We examined a possible mechanism of action of an ATP-sensitive potassium (K(ATP)) channel opener, YM934, for the improvement of energy metabolism in hearts subjected to 35-min ischemia and 60-min reperfusion. The treatment with 30 nM YM934 for the final 15 min of preischemia enhanced postischemic recovery of left ventricular developed pressure, attenuated the postischemic rise in left ventricular end-diastolic pressure, and suppressed the release of creatine kinase and ATP metabolites during reperfusion. The treatment also restored myocardial ATP and creatine phosphate contents and attenuated the decrease in mitochondrial oxygen consumption rate during reperfusion. The higher mitochondrial function was also seen in YM934-treated hearts at the end of ischemia. In another set of experiments, myocardial skinned bundles were incubated for 30 min under hypoxic conditions in the presence and absence of YM934, and then mitochondrial oxygen consumption rate was determined. Hypoxia decreased the mitochondrial oxygen consumption rate of skinned bundles to approximately 40% of the prehypoxic value. In contrast, the treatment of skinned bundles with 30 nM YM934 preserved the mitochondrial oxygen consumption rate during hypoxia. The effect of YM934 on the hypoxic skinned bundles was abolished by combined treatment with either the K(ATP) channel blocker glyburide or the mitochondrial K(ATP) channel blocker 5-hydroxydecanoate in a concentration-dependent manner. The results suggest that YM934 is capable of attenuating ischemia/reperfusion injury of isolated perfused hearts due to preservation of mitochondrial function during ischemia, probably through opening of mitochondrial K(ATP) channels.
AuthorsK Tanonaka, T Taguchi, M Koshimizu, T Ando, T Morinaka, T Yogo, F Konishi, S Takeo
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 291 Issue 2 Pg. 710-6 (Nov 1999) ISSN: 0022-3565 [Print] United States
PMID10525091 (Publication Type: Journal Article)
Chemical References
  • Anti-Arrhythmia Agents
  • Benzoxazines
  • Cyclic N-Oxides
  • Decanoic Acids
  • Hydroxy Acids
  • Oxazines
  • Phosphocreatine
  • 5-hydroxydecanoic acid
  • Adenosine Triphosphate
  • Creatine Kinase
  • Glyburide
  • 2H-1,4-benzoxazine, 3,4-dihydro-2,2-dimethyl-6-nitro-4-(2-pyridinyl)-, N-oxide
Topics
  • Adenosine Triphosphate (physiology)
  • Animals
  • Anti-Arrhythmia Agents (pharmacology)
  • Benzoxazines
  • Creatine Kinase (metabolism)
  • Cyclic N-Oxides (pharmacology)
  • Decanoic Acids (pharmacology)
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Glyburide (pharmacology)
  • Heart Ventricles (drug effects)
  • Hemodynamics (drug effects)
  • Hydroxy Acids (pharmacology)
  • Hypoxia (pathology)
  • In Vitro Techniques
  • Male
  • Mitochondria, Heart (drug effects, metabolism)
  • Oxazines (pharmacology)
  • Oxygen Consumption (drug effects)
  • Perfusion
  • Phosphocreatine (metabolism)
  • Rats
  • Rats, Wistar
  • Reperfusion Injury (metabolism)
  • Time Factors

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