Ischaemic preconditioning and a mitochondrial KATP channel opener both produce cardioprotection accompanied by F1F0-ATPase inhibition in early ischaemia

Ischaemic preconditioning gives powerful protection against prolonged ischaemia affecting several intracellular regulatory and messenger pathways, although their mutual importance is far from established. Protective, preconditioning-like effects have been reported for K-ATP channel openers, and most of the evidence points to the mitochondrial K-ATP channels. We show here that the K-ATP channel opener diazoxide, which acts selectively on the mitochondrial channel, causes potentiation of ischaemic inhibition of mitochondrial ATP synthase (F1F0-ATPase) along with cardioprotection. These effects are comparable with that of ischaemic preconditioning. The administration of diazoxide did not affect the cellular energy state as monitored with P-31 NMR. The actions of both diazoxide and ischaemic preconditioning were prevented by 5-hydroxydecanoate, a specific inhibitor of the mitochondrial K-ATP channel. Thus mitochondrial K-ATP channel opening and ischaemic preconditioning must share common mechanisms of action involving mitochondrial F1F0-ATPase, although involvement of the energy state in protection could not be proved.