ATP sensitive potassium channel and myocardial preconditioning

K_ATP channels play an important role in physiology and pathophysiology of many tissues. As in the pancreatic β cells, they couple the change of blood glucose with insulin release. The data coming from Baukrowitz et al. and Shyng and Nichols gave the possible answers to the two old enigmas of K_ATP channels, i.e., different ATP sensitivity reported in the same tissue and how the channel opened under intracellular millimolar ATP concentration, in which they showed the lipids and lipid metabolites are essential for K_ATP channel regulation by altering ATP sensitivity. This new information rises several further considerations. How does PIP₂ reduce the sensitivity of the channel to ATP? In order to clarify the possibility of direct competing or allosteric effect on the ATP binding site, competitive binding assay should be performed. Since the PIP₂ theory seems to be the key event to determine the ATP sensitivity and thus control the channel open probability, then what is the resting concentration of PIP₂ in the cell membrane? Is it sufficient to account for the difference in the ATP sensitivity of the intact cell and excised patch from different tissues? Quantitative studies either immunoblotting by PIP₂ antibody or fluorescence-labeled lipid assay may obtain some basic but useful data for further studies to answer these questions. Furthermore, the ATPi mediated restoration of activity was inhibited by antibodies against PIP₂.^la The dualistic behavior of K_ATP channels to intracellular NDPs should be reexamined with respect to PIP₂ . The vast majority of preconditioning studies has been performed in intact animals in which myocardial infarct size was used as the end point to define the cardio-protective effect of ischemic PC. These results suggest a key role for the K_ATP channel as both a trigger and as an end effector of both acute and delayed ischemic PC. The persistent activation of K_ATP channels during the early reperfusion phase is essential for a smooth and full recovery of contractile function, as well as for maintenance of electrical stability in heart that has been exposed to ischemia. Though activate adenosine A_I receptor coupled with Gi protein can open the K_ATP channels, adenosine is quickly released during ischemia and exerts potent coronary vasodilatation to maintain coronary blood flow through A₂ receptors. This adenosine-induced coronary vasodilatation could be coupled with K_ATP channels based on the evidence of the augmentation effect of KCOs. Nitric oxide may also play some role in both first and second window of myocardial protection. It is possible that rapid and reversible phosphorylation and activation of constitutive expressed myocardial NOS or by direct K_ATP channel phosphorylation and activation leads to the first window of myocardial protection. This hypothesis can be further investigated either by using site direct mutagenesis of iNOS or K_ATP channel, or by applying the dominant negative iNOS in the cell ischemic model, or by building the adenosine or iNOS knock-out mice to study the relationship of these possible mechanisms. Recently, Kontos further showed that KCOs need L-lysine or Larginine to dilate cerebral arterioles.^lb This suggests that there may be an amino acid binding site inside the K_ATP channel and nitric oxide can open the K_ATP. channel either by direct acting on the channel protein or by modulating the affinity of the amino acid binding site for L-lysine or L-arginine. Other K_ATP channel openers in need of additional characterization are the Type III KCOs (nicorandiol). They open the K_ATP channel only in the presence of elevated intracellular NDPs, which may make them specifically target to the ischemic region, because the intracellular NDP increases mostly in ischemic region. It is possible that type III KCOs can selectively improve blood flow to ischemic areas without diverting blood away to non-ischemic region, and prevents the "steal phenomenon". Such drugs may selectively protect the myocardium from ischemia-reperfusion injury, especially after cardiopulmonary bypass. Studies of anti-ischemia effect of nicorandiol in whole cardiomyocytes and in human are preliminary and need further investigation. Finally, monophosphoryl lipid A (MLA) is undergoing phase 2 clinical trials in patients undergoing cardiopulmonary bypass associated with coronary artery bypass engraftmcnt or aortic valve replacement or reconstruction. Although further clinical testing may or may not establish the utility of MLA as a cardioprotectant against ischemia-reperfusion injury in man, this agent is still very useful to understand the mechanisms of delayed cardiac preconditioning following ischemia-reperfusion injury.