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Calcium preconditioning, but not ischemic preconditioning, bypasses the adenosine triphosphate-dependent potassium
D R Meldrum1, B S Cain, X Meng
1Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado, 80262, USA. danmeldrum@netscape.net
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.
Insights
Calcium preconditioning (CPC) offers myocardial protection independent of the KATP channel, unlike ischemic preconditioning (IPC). This finding is crucial for diabetic patients on sulfonylureas, who may benefit from CPC when IPC is ineffective.
Area of Science:
- Cardiology
- Cardiovascular Physiology
- Ischemic Heart Disease
Background:
- Ischemic preconditioning (IPC) protects the heart but is inhibited by sulfonylureas used by diabetic patients.
- Calcium preconditioning (CPC) is a potential alternative cardioprotective strategy.
- The mechanism of CPC and its interaction with KATP channels remain unclear.
Purpose of the Study:
- To determine if calcium preconditioning (CPC) bypasses the KATP channel in its protective mechanism.
- To investigate CPC as an alternative to IPC in patients taking KATP channel inhibitors.
Main Methods:
- Isolated rat hearts underwent KATP channel inhibition (glibenclamide) or vehicle.
- Hearts received either CPC, IPC, or no preconditioning stimulus before global warm ischemia/reperfusion (I/R).
- Myocardial functional recovery was assessed by measuring developed pressure, coronary flow, and compliance.
Main Results:
- Both CPC and IPC significantly improved post-ischemic myocardial function compared to I/R alone.
- KATP channel inhibition abolished IPC-mediated protection but did not affect CPC-induced protection.
- CPC demonstrated myocardial protection independent of KATP channel activity.
Conclusions:
- IPC and CPC provide comparable myocardial protection through distinct mechanisms.
- IPC relies on KATP channel activity, while CPC functions independently of it.
- CPC may serve as a viable cardioprotective strategy for diabetic patients on sulfonylureas, bypassing KATP channel inhibition effects.