Selective mitochondrial adenosine triphosphate-sensitive potassium channel activation is sufficient to precondition human myocardium.
OBJECTIVE
Recently, the mitochondrial adenosine triphosphate-sensitive potassium channel has been suggested to be the final common effector of myocardial preconditioning. The purpose of this study is to determine whether selective mitochondrial adenosine triphosphate-sensitive potassium channel activation alone can precondition human myocardium from an ischemia/reperfusion insult.


METHODS
Isolated human right atrial trabeculae were placed in tissue baths, paced, and subjected to 30 minutes of normothermic hypoxia (ischemia) followed by 45 minutes of reoxygenation (reperfusion). Trabeculae were preconditioned with a selective mitochondrial adenosine triphosphate-sensitive potassium channel opener (diazoxide 30 micromol/L) or a nonselective purinergic agonist, adenosine (125 micromol/L), for 5 minutes (adenosine) followed by a 10-minute washout period. Developed force at end reperfusion (mean +/- standard error) was compared with baseline, and tissue creatine kinase and adenosine triphosphate levels were measured after ischemia/reperfusion.


RESULTS
Trabeculae subjected to ischemia/reperfusion exhibited 30% +/- 2% of baseline developed force, whereas trabeculae subjected to selective adenosine triphosphate-sensitive potassium channel opening (diazoxide) and nonselective purinergic agonist (adenosine) recovered to 55% +/- 7% and 46% +/- 3% of baseline developed force, respectively. Tissue creatine kinase activity was preserved in both the diazoxide- and adenosine-treated trabeculae (5.4 +/- 12 and 5.4 +/- 14 micromol/L per gram wet tissue) compared with ischemia/reperfusion (1.8 +/- 0.2 U/mg wet tissue). Adenosine triphosphate levels at end reperfusion were also increased in the trabeculae treated with selective (diazoxide) and nonselective (adenosine) adenosine triphosphate-sensitive potassium channel opener (4.1 +/- 0.01 and 4. 4 +/- 0.2 micromol/L per gram wet tissue) compared with trabeculae subjected to ischemia/reperfusion (1.5 +/- 0.1 micromol/L per gram wet tissue).


CONCLUSIONS
These results suggest that selective mitochondrial adenosine triphosphate-sensitive potassium channel activation preconditions human myocardium and the protection conferred is equal to that of adenosine preconditioning. Targeted openers of mitochondrial adenosine triphosphate- sensitive potassium channels promote constructive protection of myocellular energy levels, contractile function, and cellular viability in human myocardium after ischemia/reperfusion.
Department of Surgery, University of Colorado Health Sciences Center, Denver, CO 80262, USA. ben.pomerantz@uchsc.edu
B J
BJ
Pomerantz
T N
TN
Robinson
T D
TD
Morrell
J K
JK
Heimbach
A
A
Banerjee
A H
AH
Harken
D000241:Adenosine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology*; D000704:Analysis of Variance; D003402:Creatine Kinase / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D006801:Humans; D008929:Mitochondria, Heart / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology* / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D015221:Potassium Channels; D014665:Vasodilator Agents; D000255:Adenosine Triphosphate; D003402:Creatine Kinase; D000241:Adenosine; D003981:Diazoxide