The K
+
ATP channel in the inner membrane is inhibited by ATP and activated by protein kinase C (PKC)-ε and PKG. The exact molecular composition of the K
+
ATP channel and the participation of the sulfonylurea receptor subunit 2A (SUR2A) and the potassium channel proteins Kir6.1 and 6.2 remain elusive. A purified inner membrane fraction, including the adenine nucleotide transporter and succinate dehydrogenase, confers K
+
ATP channel activity and is targeted by K
+
ATP agonist/antagonist drugs [
64]. Mitochondrial K
+
ATP channels are causally involved in ischemic preconditioning and postconditioning [
65,
66]. Sasaki et al. found that NO directly activates mitochondrial K
+
ATP channels and potentiates the ability of diazoxide to open these channels [
67]. Bell et al. demonstrated that nitric oxide can mediate cardioprotection in a dose-dependent fashion by an effect that may be related to mitochondrial membrane potential. Both cardioprotection and changes of mitochondrial membrane potential are sensitive to 5-hydroxy decanoate (5-HD), selective inhibitor of K
+
ATP channel, and the cardioprotection appears independent of free radical synthesis [
68]. Thus, on the basis of these results, it appears that the mitochondrial K
+
ATP channel is a pivotal target for the protective effects of nitric oxide. Mitochondrial calcium overload is pathognomic of irreversible ischemia-reperfusion injury - the calcium paradox [
69,
70]. Interestingly, mitochondrial K
+
ATP channel openers attenuate the calcium paradox [
71] and limit calcium accumulation in mitochondria by altering mitochondrial calcium homeostasis [
72]. Given that opening of the mitochondrial permeability transition pore (PTP) is associated with triggering of apoptotic cell death cascades and that high calcium leads to opening of the PTP [
73,
74], the finding that low-dose exogenous nitric oxide attenuates both the calcium paradox and the opening of the PTP is of great interest [
75]. Since exogenous nitric oxide has been demonstrated to increase the open probability of mitochondrial K
+
ATP channels [
67], it is attractive to postulate that cardioprotective low-dose nitric oxide is initial mediated via the mitochondrial K
+
ATP channel.