Adenosine primes the opening of mitochondrial ATP-sensitive potassium channels: a key step in ischemic preconditioning?
BACKGROUND
Adenosine can initiate ischemic preconditioning, and mitochondrial ATP-sensitive potassium (K(ATP)) channels have emerged as the likely effectors. We sought to determine the mechanistic interactions between these 2 observations.


RESULTS
The mitochondrial flavoprotein oxidation induced by diazoxide (100 micromol/L) was used to quantify mitochondrial K(ATP) channel activity in intact rabbit ventricular myocytes. Adenosine (100 micromol/L) increased mitochondrial K(ATP) channel activity and abbreviated the latency to mitochondrial K(ATP) channel opening. These potentiating effects were entirely prevented by the adenosine receptor antagonist 8-(p-sulfophenyl)-theophylline (100 micromol/L) or by the protein kinase C inhibitor polymyxin B (50 micromol/L). The effects of adenosine and diazoxide reflected mitochondrial K(ATP) channel activation, because they could be blocked by the mitochondrial K(ATP) channel blocker 5-hydroxydecanoate (500 micromol/L). In a cellular model of simulated ischemia, adenosine mitigated cell injury; this cardioprotective effect was blocked by 5-hydroxydecanoate but not by the surface-selective K(ATP) channel blocker HMR1098. Moreover, adenosine augmented the cardioprotective effect of diazoxide. A quantitative model of mitochondrial K(ATP) channel gating reproduced the major experimental findings.


CONCLUSIONS
Our results support the hypothesis that adenosine receptor activation primes the opening of mitochondrial K(ATP) channels in a protein kinase C-dependent manner. The findings provide tangible links among various key elements in the preconditioning cascade.
Sato
T
T
Institute of Molecular Cardiobiology, Johns Hopkins University, Baltimore, MD 21205, USA.
Sasaki
N
N
O'Rourke
B
B
Marbán
E
E
D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005420:Flavoproteins / Q000378:metabolism; D006880:Hydroxy Acids / Q000494:pharmacology; D019194:Ischemic Preconditioning; D008565:Membrane Proteins / Q000187:drug effects* / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D011112:Polymyxin B / Q000494:pharmacology; D015221:Potassium Channels; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D058915:Purinergic P1 Receptor Antagonists; D011817:Rabbits; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
D003652:Decanoic Acids; D004791:Enzyme Inhibitors; D005420:Flavoproteins; D006880:Hydroxy Acids; D008565:Membrane Proteins; D015221:Potassium Channels; D058915:Purinergic P1 Receptor Antagonists; C117780:mitochondrial K(ATP) channel; C052853:5-hydroxydecanoic acid; C031433:8-(4-sulfophenyl)theophylline; D013806:Theophylline; D011493:Protein Kinase C; D011112:Polymyxin B; D000241:Adenosine; D003981:Diazoxide