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Nicorandil, a potent cardioprotective agent, acts by opening mitochondrial ATP-dependent potassium channels
1Institute of Molecular Cardiobiology, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Objectives:
To determine the mechanism of cardioprotection afforded by nicorandil, an orally efficacious antianginal drug, we examined its effects on ATP-dependent potassium (K(ATP)) channels.
Background:
Nicorandil can mimic ischemic preconditioning, while mitochondrial K(ATP) (mitoK(ATP)) channels rather than sarcolemmal K(ATP) (surfaceK(ATP)) channels have emerged as the likely effectors.
Methods:
Flavoprotein fluorescence and membrane current in intact rabbit ventricular myocytes were measured simultaneously to assay mitoK(ATP) channel and surface K(ATP) channel activities, respectively. In a cell-pelleting model of ischemia, cells permeable to trypan blue were counted as killed by 60 and 120 min of ischemia.
Results:
Nicorandil (100 micromol/liter) increased flavoprotein oxidation but not membrane current; a 10-fold higher concentration recruits both mitoK(ATP) and surfaceK(ATP) channels. Pooled dose-response data confirm that nicorandil concentrations as low as 10 micromol/liter turn on mitoK(ATP) channels, while surfaceK(ATP) current requires exposure to millimolar concentrations. Nicorandil blunted the rate of cell death in a pelleting model of ischemia; this cardioprotective effect was prevented by the mitoK(ATP) channel blocker 5-hydroxydecanoate but was unaffected by the surfaceK(ATP) channel blocker HMR1098.
Conclusions:
Nicorandil exerts a direct cardioprotective effect on heart muscle cells, an effect mediated by selective activation of mitoK(ATP) channels.
Insights
Nicorandil protects heart cells by activating mitochondrial ATP-dependent potassium (mitoK(ATP)) channels. This selective activation, rather than sarcolemmal K(ATP) channels, mediates its cardioprotective effects during ischemia.
Area of Science:
- Cardiology
- Pharmacology
- Cell Biology
Background:
- Nicorandil mimics ischemic preconditioning, a phenomenon that protects the heart from damage.
- Mitochondrial ATP-dependent potassium (mitoK(ATP)) channels are implicated as key mediators of this protective effect, more so than sarcolemmal K(ATP) channels.
Purpose of the Study:
- To elucidate the precise mechanism by which nicorandil provides cardioprotection.
- To investigate the role of ATP-dependent potassium (K(ATP)) channels, specifically mitochondrial (mitoK(ATP)) and sarcolemmal (surfaceK(ATP)) channels, in nicorandil's action.
Main Methods:
- Simultaneous measurement of flavoprotein fluorescence (indicating mitoK(ATP) activity) and membrane current (indicating surfaceK(ATP) activity) in rabbit ventricular myocytes.
- Assessment of cell viability using trypan blue exclusion in a cellular model of ischemia.
Main Results:
- Nicorandil selectively activated mitoK(ATP) channels at low concentrations (10 micromol/liter), evidenced by increased flavoprotein oxidation.
- Higher concentrations of nicorandil were required to activate surfaceK(ATP) channels.
- Nicorandil reduced cell death during ischemia, an effect blocked by a mitoK(ATP) channel inhibitor (5-hydroxydecanoate) but not by a surfaceK(ATP) channel inhibitor (HMR1098).
Conclusions:
- Nicorandil directly protects heart muscle cells.
- This cardioprotection is achieved through the selective activation of mitochondrial K(ATP) channels.