Selective pharmacological agents implicate mitochondrial but not sarcolemmal K(ATP) channels in ischemic cardioprotection.
BACKGROUND
Pharmacological evidence has implicated ATP-sensitive K(+) (K(ATP)) channels as the effectors of cardioprotection, but the relative roles of mitochondrial (mitoK(ATP)) and sarcolemmal (surfaceK(ATP)) channels remain controversial.


RESULTS
We examined the effects of the K(ATP) channel blocker HMR1098 and the K(ATP) channel opener P-1075 on surfaceK(ATP) and mitoK(ATP) channels in rabbit ventricular myocytes. HMR1098 (30 micromol/L) inhibited the surfaceK(ATP) current activated by metabolic inhibition, whereas the drug did not blunt diazoxide (100 micromol/L)-induced flavoprotein oxidation, an index of mitoK(ATP) channel activity. P-1075 (30 micromol/L) did not increase flavoprotein oxidation but did elicit a robust surfaceK(ATP) current that was completely inhibited by HMR1098. These results indicate that HMR1098 selectively inhibits surfaceK(ATP) channels, whereas P-1075 selectively activates surface K(ATP) channels. In a cellular model of simulated ischemia, the mitoK(ATP) channel opener diazoxide (100 micromol/L), but not P-1075, blunted cellular injury. The cardioprotection afforded by diazoxide or by preconditioning was prevented by the mitoK(ATP) channel blocker 5-hydroxydecanoate (500 micromol/L) but not by the surfaceK(ATP) channel blocker HMR1098 (30 micromol/L).


CONCLUSIONS
The cellular effects of mitochondria- or surface-selective agents provide further support for the emerging consensus that mitoK(ATP) channels rather than surfaceK(ATP) channels are the likely effectors of cardioprotection.
Sato
T
T
Institute of Molecular Cardiobiology, Johns Hopkins University, Baltimore, Md, USA.
Sasaki
N
N
Seharaseyon
J
J
O'Rourke
B
B
Marbán
E
E
D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D004553:Electric Conductivity; D006146:Guanidines / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D008929:Mitochondria, Heart / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000473:pathology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D012508:Sarcolemma / Q000378:metabolism*; D014665:Vasodilator Agents / Q000494:pharmacology
D006146:Guanidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011725:Pyridines; D014665:Vasodilator Agents; C073896:N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine; D000255:Adenosine Triphosphate