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First published online on April 11, 2003.
 Copyright © 2003 by The Physiological Society
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Received February 20, 2003
Accepted after revision March 19, 2003

Ischaemic preconditioning inhibits opening of mitochondrial permeability transition pores in the reperfused rat heart

Sabzali A. Javadov1, Samantha Clarke2, Manika Das2, Elinor J. Griffiths2, Kelvin H.H. Lim3, and A. P. Halestrap4*

1 Department of Biochemistry, Azerbaijan Medical University, Bakykhanov Street 23, Baku, Azerbaijan
2 Department of Biochemistry, University of Bristol, Bristol BS8 1TD, UK
3 The Bristol Heart Institute, Bristol Royal Infirmary, Malborough Street, Bristol BS2 8HW, UK
4 Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK

* To whom correspondence should be addressed. E-mail: a.halestrap{at}bristol.ac.uk.

Opening of the mitochondrial permeability transition pore (MPTP) is thought to be a critical event in mediating the damage to hearts that accompanies their reperfusion following prolonged ischaemia. Protection from reperfusion injury occurs if the prolonged ischaemic period is preceded by short ischaemic periods followed by recovery. Here we investigate whether such ischaemic preconditioning (IPC) is accompanied by inhibition of MPTP opening. MPTP opening in Langendorff-perfused rat hearts was determined by perfusion with 2-deoxy[3H]glucose ([3H]DOG) and measurement of mitochondrial [3H]DOG entrapment. We demonstrate that IPC inhibits initial MPTP opening in hearts reperfused after 30 min global ischaemia, and subsequently enhances pore closure as hearts recover. However, MPTP opening in mitochondria isolated from IPC hearts occurred more readily than control mitochondria, implying that MPTP inhibition by IPC in situ was secondary to other factors such as decreased calcium overload and oxidative stress. Hearts perfused with cyclosporin A or sanglifehrin A, powerful inhibitors of the MPTP, also recovered better from ischaemia than controls (improved haemodynamic function and less lactate dehydrogenase release). However, the mitochondrial DOG entrapment technique showed these agents to be less effective than IPC at preventing MPTP opening. Our data suggest that protection from reperfusion injury is better achieved by reducing factors that induce MPTP opening than by inhibiting the MPTP directly.




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