Activation of mitochondrial ATP-sensitive potassium channels delays ischemia-induced cellular uncoupling in rat heart

Acta Pharmacol Sin. 2004 Jan;25(1):22-8.

Abstract

Aim: To test the hypothesis that cellular uncoupling induced by myocardial ischemia is mediated by activation of mitochondrial ATP-sensitive potassium channels (mitoKATP).

Methods: Rat hearts were perfused on a Langendorff apparatus and subjected to 40-min ischemia followed by 30-min reperfusion (I/R). Changes in cellular coupling were monitored by measuring whole-tissue resistance.

Results: (1) In hearts subjected to I/R, the onset of uncoupling started at (13.3+/-1.0) min of ischemia; (2) Ischemic preconditioning (IPC) delayed the onset of uncoupling until (22.7+/-1.3) min. Blocking mitoKATP channels with 5-hydroxydecanoate (5-HD) before the IPC abolished the uncoupling delay [(12.6+/-1.6) min]; (3) Calcium preconditioning (CPC) had the same effect as IPC. And this effect was reversed by blocking the mitoKATP channel again. In the CPC group the onset of uncoupling occurred after (20.6+/-1.3) min, and this was canceled by 5-HD [(13.6+/-0.8) min]; (4) In hearts pretreated with the specific mitoKATP channel opener diazoxide before sustained ischemia, the onset was delayed to (18.4+/-1.4) min; (5) 5-HD canceled the protective effects of diazoxide (12.6+/-1.0) min; and both the L-type Ca2+ channel inhibitor verapamil and the free radical scavenger N-(2-mercaptopropionyl)glycine, reduced the extended onset time induced by diazoxide [to (13.3+/-1.8) min and (13.4+/-2.1) min, respectively].

Conclusion: IPC and CPC delay the onset of cellular uncoupling induced by acute ischemia in rat heart, and the underlying mechanism involves activation of the mitoKATP channels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Adenosine Triphosphate / physiology
  • Animals
  • Decanoic Acids / pharmacology
  • Diazoxide / pharmacology
  • Hydroxy Acids / pharmacology
  • Ion Channel Gating / drug effects
  • Ion Channel Gating / physiology
  • Ischemic Preconditioning, Myocardial*
  • Male
  • Mitochondria, Heart / metabolism*
  • Myocardial Reperfusion Injury / etiology
  • Myocardial Reperfusion Injury / metabolism*
  • Potassium Channels / drug effects*
  • Rats
  • Rats, Sprague-Dawley
  • Verapamil / pharmacology

Substances

  • Decanoic Acids
  • Hydroxy Acids
  • Potassium Channels
  • 5-hydroxydecanoic acid
  • Adenosine Triphosphate
  • Verapamil
  • Diazoxide