KATP Channel Openers Have Opposite Effects on Mitochondrial Respiration Under Different Energetic Conditions

Mitochondrial (m) K ATP channel opening has been implicated in triggering cardiac preconditioning. Its consequence on mitochondrial respiration, however, remains unclear. We investigated the effects of two different K ATP channel openers and antagonists on mitochondrial respiration under two different energetic conditions. Oxygen consumption was measured for complex I (pyruvate/malate) or complex II (succinate with rotenone) substrates in mitochondria from fresh guinea pig hearts. One of two mK ATP channel openers, pinacidil or diazoxide, was given before adenosine diphosphate in the absence or presence of an mK ATP channel antagonist, glibenclamide or 5-hydroxydecanoate. Without ATP synthase inhibition, both mK ATP channel openers differentially attenuated mitochondrial respiration. Neither mK ATP channel antagonist abolished these effects. When ATP synthase was inhibited by oligomycin to decrease [ATP], both mK ATP channel openers accelerated respiration for both substrate groups. This was abolished by mK ATP channel blockade. Thus, under energetically more physiological conditions, the main effect of mK ATP channel openers on mitochondrial respiration is differential inhibition independent of mK ATP channel opening. In contrast, under energetically less physiological conditions, mK ATP channel opening can be evidenced by accelerated respiration and blockade by antagonists. Therefore, the effects of mK ATP channel openers on mitochondrial function likely depend on the experimental conditions and the cell's underlying energetic state.