Calcium preconditioning, but not ischemic preconditioning, bypasses the adenosine triphosphate-dependent potassium (KATP) channel.
BACKGROUND
Recent evidence has implicated the KATP channel as an important mediator of ischemic preconditioning (IPC). Indeed, patients taking oral sulfonylurea hypoglycemic agents (i.e., KATP channel inhibitors) for treatment of diabetes mellitus are resistant to the otherwise profoundly protective effects of IPC. Unfortunately, many cardiopulmonary bypass patients, who may benefit from IPC, are chronically exposed to these agents. Calcium preconditioning (CPC) is a potent form of similar myocardial protection which may or may not utilize the KATP channel in its mechanism of protection. The purpose of this study was to determine whether CPC may bypass the KATP channel in its mechanism of action. If so, CPC may offer an alternative to IPC in patients chronically exposed to these agents.


METHODS
Isolated rat hearts (n = 6-8/group) were perfused (Langendorff) and received KATP channel inhibition (glibenclamide) or saline vehicle 10 min prior to either a CPC or IPC preconditioning stimulus or neither (ischemia and reperfusion, I/R). Hearts were subjected to global warm I/R (20 min/40 min). Postischemic myocardial functional recovery was determined by measuring developed pressure (DP), coronary flow (CF), and compliance (end diastolic pressure, EDP) with a MacLab pressure digitizer.


RESULTS
Both CPC and IPC stimuli protected myocardium against postischemic dysfunction (P < 0.05 vs I/R; ANOVA with Bonferroni/Dunn): DP increased from 52 +/- 4 (I/R) to 79 +/- 2 and 83 +/- 4 mmHg; CF increased from 11 +/- 0.7 to 17 +/- 2 and 16 +/- 1 ml/min; and EDP decreased (compliance improved) from 50 +/- 7 to 27 +/- 5 and 31 +/- 7 mmHg. However, KATP channel inhibition abolished protection in hearts preconditioned with IPC (P < 0.05 vs IPC alone), but not in those preconditioned with CPC (P > 0.05 vs CPC alone).


CONCLUSIONS
(1) Both IPC and CPC provide similar myocardial protection; (2) IPC and CPC operate via different mechanisms; i.e., IPC utilizes the KATP channel whereas CPC does not; and (3) CPC may offer a means of bypassing the deleterious effects of KATP channel inhibition in diabetic patients chronically exposed to oral sulfonylurea hypoglycemic agents.
Meldrum
D R
DR
Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado, 80262, USA. danmeldrum@netscape.net
Cain
B S
BS
Meng
X
X
Cleveland
J C
JC
Shames
B D
BD
Donnahoo
K K
KK
Banerjee
A
A
Harken
A H
AH
D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000502:physiology; D006321:Heart / Q000503:physiopathology; D066298:In Vitro Techniques; D007511:Ischemia / Q000503:physiopathology; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D015221:Potassium Channels / Q000378:metabolism*; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley
D015221:Potassium Channels; D000255:Adenosine Triphosphate; D002118:Calcium