alexa ATP sensitive potassium channel and myocardial preconditioning.

Journal of Pharmacokinetics & Experimental Therapeutics

Author(s): Day YJ, Gao Z, Tan PC, Linden J, Day YJ, Gao Z, Tan PC, Linden J

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Abstract KATP channels play an important role in physiology and pathophysiology of many tissues. As in the pancreatic beta 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 KATP 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 KATP 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. The dualistic behavior of KATP 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 KATP channel as both a trigger and as an end effector of both acute and delayed ischemic PC. The persistent activation of KATP 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 A1 receptor coupled with Gi protein can open the KATP 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 KATP 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 KATP 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 KATP 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 L-arginine to dilate cerebral arterioles. This suggests that there may be an amino acid binding site inside the KATP channel and nitric oxide can open the KATP 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 KATP channel openers in need of additional characterization are the Type III KCOs (nicorandiol). They open the KATP 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". (ABSTRACT TRUNCATED)
This article was published in Acta Anaesthesiol Sin and referenced in Journal of Pharmacokinetics & Experimental Therapeutics

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