Sarcolemmal Versus Mitochondrial ATP-Sensitive K ⁺ Channels and Myocardial Preconditioning

Abstract

Ischemic preconditioning (IPC) is the phenomenon whereby brief periods of ischemia have been shown to protect the myocardium against a sustained ischemic insult. The result of IPC may be manifest as a marked reduction in infarct size, myocardial stunning, or incidence of arrhythmias. While many substances and pathways have been proposed to play a role in the signal transduction mediating the cardioprotective effect of IPC, overwhelming evidence indicates an intimate involvement of the ATP-sensitive potassium channel (K ATP channel) in this process. Initial hypotheses suggested that the surface or sarcolemmal K ATP (sarcK ATP) channel mediated the cardioprotective effects of IPC. However, much research has subsequently supported a major role for the mitochondrial K ATP channel (mitoK ATP) as the one involved in IPC-mediated cardioprotection. This review presents evidence to support a role for the sarcK ATP or the mitoK ATP channel as either triggers and/or downstream mediators in the phenomenon of IPC.

Nitrite confers protection against myocardial infarction: Role of xanthine oxidoreductase, NADPH oxidase and KATP channels

“…Our data show that the sarcolemmal K ATP channel appears to act as trigger and the mitochondrial K ATP channel as an effector of nitriteinduced cardioprotection. There is evidence to suggest that opening either channel may be important in producing cardioprotection, although the bulk of evidence suggests that it is the mito K ATP channel that is responsible for mediating the protective effect of ischemic preconditioning [39,40]. The role of additional components in the signaling pathway by which the heart is protected by nitrite against injury remains unknown.…”

Role of epoxyeicosatrienoic acids in protecting the myocardium following ischemia/reperfusion injury

“…sarc K ATP is activated during cardiac ischemia when cytoplasmic ATP is depleted and this affects membrane excitability. Activation leads to shortening of the cardiac action potential and reduced intracellular calcium overload [59,60]. Although there are no selective sarc K ATP openers, a number of drugs known to open this channel have been shown to produce beneficial effects in the myocardium in animal models of ischemia/reperfusion injury, and several non-selective inhibitors of sarc K ATP (such as glibenclamide) block ischemic PC [59,60].…”

“…Activation leads to shortening of the cardiac action potential and reduced intracellular calcium overload [59,60]. Although there are no selective sarc K ATP openers, a number of drugs known to open this channel have been shown to produce beneficial effects in the myocardium in animal models of ischemia/reperfusion injury, and several non-selective inhibitors of sarc K ATP (such as glibenclamide) block ischemic PC [59,60]. In spite of these findings, the strongest evidence for a role of sarc K ATP channels in ischemic PC has been demonstrated in the KiR 6.2 knockout mouse where ischemic PC could not be produced [60].…”

“…Although there are no selective sarc K ATP openers, a number of drugs known to open this channel have been shown to produce beneficial effects in the myocardium in animal models of ischemia/reperfusion injury, and several non-selective inhibitors of sarc K ATP (such as glibenclamide) block ischemic PC [59,60]. In spite of these findings, the strongest evidence for a role of sarc K ATP channels in ischemic PC has been demonstrated in the KiR 6.2 knockout mouse where ischemic PC could not be produced [60]. The EETs have been shown to be potent openers of sarc K ATP by reducing channel sensitivity to ATP in isolated rat myocytes using the inside-out patch clamp technique; however, the exact site on the channel that interacts with EETs remains unknown [30,61].…”

Cardioprotection and mitochondrial S-nitrosation: Effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia–reperfusion injury

“…Despite numerous studies the precise mechanisms of IPC are still under debate, but the preservation of mitochondrial function is believed to be an important end-point in IPC signaling. Several protective IPC mechanisms are intrinsic to mitochondria, including opening of K + ATP channels [6][7][8], activation of uncoupling proteins (UCPs) [9][10][11], modulation of ROS generation [12], or regulation of signaling pathways that impact on the PT pore [13,14]. The complex interplay between these mitochondrial IPC end-points and the upstream cytosolic signals that control them is an area of acute interest.…”