Selective mitochondrial KATP channel opening controls human myocardial preconditioning: too much of a good thing?
BACKGROUND
Paradoxically, patients with noninsulin-dependent diabetes mellitus experience a higher cardiovascular mortality rate than patients with insulin-dependent diabetes mellitus. We have shown that K(ATP) channel inhibition, with oral sulfonylureas, prevents myocardial preconditioning and may explain the paradox of cardiovascular death in patients with noninsulin-dependent diabetes mellitus. Cardiac preconditioning is an attractive protective strategy against any elective ischemia/reperfusion (I/R) injury. The relationship between the K(ATP) channels and human myocardial preconditioning has not previously been elucidated.


METHODS
Human atrial trabeculae were harvested, placed in organ baths, and paced (1 Hz). Developed force was recorded during simulated 37 degrees C I/R (30/45 or 45/60 minutes). Before I/R, trabeculae were treated transiently with a selective mitochondrial K(ATP) channel opener for 5 minutes, followed by a 10-minute washout, or were exposed to the channel opener throughout ischemia. Recovery of function is expressed as percentage of baseline developed force. Conserved creatine kinase activity (units per gram of wet tissue) was measured at the end of reperfusion as an indicator of cellular protection.


RESULTS
Transient mitochondrial K(ATP) channel opening provided protection from both I/R insults. Surprisingly, there was no protection afforded by continuous mitochondrial K(ATP) channel opening.


CONCLUSIONS
Transient selective mitochondrial K(ATP) channel opening protects both viability and function of human myocardium against I/R injury, although prolonged opening of the mitochondrial K(ATP) channel does not. These results reinforce the concept of preconditioning as a transient event that must be completed before the onset of ischemia.
Pomerantz
B J
BJ
Department of Surgery, University of Colorado Health Sciences Center, Denver 80262, USA.
Robinson
T N
TN
Heimbach
J K
JK
Calkins
C M
CM
Miller
S A
SA
Banerjee
A
A
Harken
A H
AH
D000255:Adenosine Triphosphate / Q000378:metabolism; D002315:Cardiopulmonary Bypass; D003238:Connective Tissue / Q000502:physiology / Q000503:physiopathology; D001026:Coronary Artery Bypass; D003402:Creatine Kinase / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D006325:Heart Atria / Q000187:drug effects / Q000503:physiopathology; D006339:Heart Rate; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D019157:Ischemic Preconditioning, Myocardial; D008929:Mitochondria, Heart / Q000502:physiology*; D015425:Myocardial Reperfusion; D015221:Potassium Channels / Q000502:physiology*
D015221:Potassium Channels; D000255:Adenosine Triphosphate; D003402:Creatine Kinase; D003981:Diazoxide