Objective: We propose that ischemic preconditioning (IPC) and mitochondrial KATP channel activation protect the myocardium by inhibiting mitochondrial permeability transition pore (MPTP) opening at reperfusion. Methods: Isolated rat hearts were subjected to 35 min ischemia/120 min reperfusion and assigned to the following groups: (1) control; (2) IPC of 2×5 min each of preceding global ischemia; (3,4,5) 0.2 μmol/l cyclosporin A (CsA, which inhibits MPTP opening), 5 μmol/l FK506 (which inhibits the phosphatase calcineurin without inhibiting MPTP opening), or 20 μmol/l atractyloside (Atr, a MPTP opener) given at reperfusion; (6,7) pre-treatment with 30 μmol/l diazoxide (Diaz, a mitochondrial KATP channel opener) or 200 nmol/l 2 chloro-N6-cyclopentyl-adenosine (CCPA, an adenosine A1 receptor agonist); (8) IPC+Atr; (9) Diaz+Atr; (10) CCPA+Atr. The effect of mitochondrial KATP channel activation on calcium-induced MPTP opening in isolated calcein-loaded mitochondria was also assessed. Results: IPC, CsA when given at reperfusion, and pre-treatment with diazoxide or CCPA all limited infarct size (19.9±2.6% in IPC; 24.6±1.9% in CsA, 18.0±1.7% in Diaz, 20.4±3.3% in CCPA vs. 44.7±2.0% in control, P<0.0001). Opening the MPTP with atractyloside at reperfusion abolished this cardio-protective effect (47.7±1.8% in IPC+Atr, 42.3±3.2% in Diaz+Atr, 51.2±1.6% in CCPA+Atr). Atractyloside and FK506, given at reperfusion, did not influence infarct size (45.7±2.1% in Atr and 43.1±3.6% in FK506 vs. 44.7±2.0% in control, P = NS). Diazoxide (30 μmol/l) was shown to reduce calcium-induced MPTP opening by 52.5±8.0% in calcein-loaded mitochondria. 5-Hydroxydecanoic acid (100 μmol/l) was able to abolish the cardio-protective effects of both diazoxide and IPC. Conclusion: One interpretation of these data is that IPC and mitochondrial KATP channel activation may protect the myocardium by inhibiting MPTP opening at reperfusion.
Bibliographical noteThe full text of this item is not available from the repository.
- K-ATP channel
- Membrane permeability/physics
Hausenloy, D. J., Maddock, H. L., Baxter, G. F., & Yellon, D. M. (2002). Inhibiting mitochondrial permeability transition pore opening: A new paradigm for myocardial preconditioning? Cardiovascular Research, 55(3), 534-543. https://doi.org/10.1016/S0008-6363(02)00455-8