Activation of mitochondrial ATP-dependent potassium channels by nitric oxide.
BACKGROUND
Nitric oxide (NO) has been implicated as a mediator of "second-window" ischemic preconditioning, and mitochondrial ATP-dependent K(+) (mitoK(ATP)) channels are the likely effectors. The links between NO and mitoK(ATP) channels are unknown.


RESULTS
We measured mitochondrial redox potential as an index of mitoK(ATP) channel opening in rabbit ventricular myocytes. The NO donor S-nitroso-N-acetyl-DL-penicillamine (SNAP, 0.1 to 1 mmol/L) oxidized the mitochondrial matrix dose-dependently without activating sarcolemmal K(ATP) channels. SNAP-induced oxidation was blocked by the selective mitoK(ATP) channel blocker 5-hydroxydecanoate and by the NO scavenger 2-(4-carboxyphenyl)-4,4', 5,5'-tetramethylimidazole-1-oxyl-3-oxide. SNAP-induced mitochondrial oxidation was detectable either by photomultiplier tube recordings of flavoprotein fluorescence or by confocal imaging. SNAP also enhanced the oxidative effects of diazoxide when both agents were applied together. Exposure to 1 mmol/L 8Br-cGMP failed to mimic the effects of SNAP.


CONCLUSIONS
NO directly activates mitoK(ATP) channels and potentiates the ability of diazoxide to open these channels. These results provide novel mechanistic links between NO-induced cardioprotection and mitoK(ATP) channels.
Sasaki
N
N
Institute of Molecular Cardiobiology, Johns Hopkins University, Baltimore, MD 21205, USA.
Sato
T
T
Ohler
A
A
O'Rourke
B
B
Marbán
E
E
D000818:Animals; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D005420:Flavoproteins / Q000378:metabolism; D006352:Heart Ventricles; D008564:Membrane Potentials; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020110:Pinacidil / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits; D026423:S-Nitroso-N-Acetylpenicillamine; D012508:Sarcolemma / Q000187:drug effects / Q000502:physiology
D005420:Flavoproteins; D020030:Nitric Oxide Donors; D015221:Potassium Channels; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D020110:Pinacidil; D010396:Penicillamine; D006152:Cyclic GMP; D003981:Diazoxide