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Coordinate interaction between ATP-sensitive K+ channel and Na+, K+-ATPase modulates ischemic preconditioning
1Department of Cardiovascular Medicine, Kyoto University, Graduate School of Medicine, Kyoto, Japan.
Circulation
|December 22, 1998
Summary
Digoxin blocks the protective effects of ischemic preconditioning (IPC) by inhibiting ATP-sensitive K+ (KATP) channels, revealing a key interaction with Na+,K+-ATPase for modulating cardiac protection.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Physiology
Background:
- Ischemic preconditioning (IPC) limits infarct size, a protective mechanism previously shown to be abolished by digoxin.
- ATP-sensitive K+ (KATP) channels are implicated in the cardioprotective effects of IPC.
Purpose of the Study:
- To investigate the functional interaction between Na+,K+-ATPase and KATP channels in modulating IPC.
- To determine the mechanism by which digoxin interferes with IPC.
Main Methods:
- Rabbit models of myocardial infarction were used to assess infarct size (IS).
- Ischemic preconditioning (IPC) was induced via brief coronary artery occlusion.
- Patch-clamp electrophysiology was employed on single ventricular myocytes to study KATP channel activity under metabolic stress.
Main Results:
- IPC and cromakalim (a KATP channel opener) significantly reduced IS.
- Digoxin abolished the IS-limiting effect of IPC but not that of cromakalim.
- Digoxin inhibited KATP channel opening in metabolically stressed myocytes, dependent on subsarcolemmal ATP levels.
Conclusions:
- The infarct size-limiting effect of IPC is modulated by a functional interaction between KATP channels and Na+,K+-ATPase.
- Subsarcolemmal ATP concentration plays a critical role in this interaction and the effects of digoxin.