Diazoxide Pharmacological Postconditioning And The Mechanisms Underling It

With increasing application of PTCA, CABG, intracoronary thrombolisis in acute myocardial infarction in recent years, myocardial ischemic and reperfusion injury has attracted considerable attention. Ischemic preconditioning has been proved to exert extensive protection to ischemic and reperfusion myocardium, including attenuation of myocardial cell death or apoptosis. However, as its name implies, ischemic preconditioning must be applied before an ischemic event to be protective, thus limiting its utility. It is of great encourage that Zhao et al first reported in 2003 that multiple brief periods reperfusion and ischemic intervention before reperfusion, called ischemic postconditioning, significantly reduced infarct size in dog heart model. The ischemic postconditioning phenomenon was also confirmed by Kin in rat model and Yan in rabbit model in the following research. Because ischemic postconditionong was applied after an ischemic event, it has greatly clinical appeal. After ischemic postconditioning phenomenon was recognized, it is of great significance to establish effective pharmacological postconditioning and explore possible mechanisms underling it . Considerating that mitochondrial KATP(mito KATP) channels have a critical role in cardioprotection of ischemic preconditioning and that diazoxide, which is a selected agonist of mito KATP, can be applied to clinical treatment, the present study intends to firstly establish diazoxide pharmacological postconditioning Furthermore,we explore the mechanism. underling the diazoxide pharmacological postconditioning and mimic ischemic postconditioning medicated cardioprotective effect by activation of KATP channel, which lay strong basis for future clinical study. Part ⅠProtective effect of diazoxide pharmocological postconditioning on myocardial regional ischemia/reperfusion injury in isolated rat heart Objective To test whether and how diazoxide pharmacological postconditioning might protect myocardium against ischemic and reperfusion injury. Materials and Methods An isolated myocardial regional ischemic/reperfusion rat model was established. Briefly, Wistar rat was sacrificed and heart was mounted on a Langendorff apparatus and retrogradely perfused with Tyrode's solution. Then the isolated hearts underwent regional ischemia by ligaturing the left anterior descending (LAD) coronary artery and reperfusion by releasing the ligature. All hearts were divided into 11 groups: group Ⅰ, myocardial ischemic/reperfusion group ; group Ⅱ, diazoxide pharmacological postconditioning group , which was further devided into 3 dosage groups, Ⅱa,Ⅱb and Ⅱc groups; group Ⅲ, pinacidil pharmacological postconditioning group; group Ⅳ, diazoxide pharmacological preconditioning group; groupⅤ, diazoxide+5-HD pharmacological postconditioning group; group Ⅵ, diazoxide + glybenclamide pharmacological postconditioning group ; group Ⅶ, diazoxide + glybenclamide +5-HD pharmacological postconditioning group ; group Ⅷ, diazoxide + atractyloside pharmacological postconditioning group; group Ⅸ, diazoxide + GF 109203X pharmacological postconditioning group; group Ⅹ, PMA pharmacological postconditioning group; group Ⅺ, PMA + 5-HD postconditioning group . After completing perfusion, infarct size (NBT Staining), the leakage of CK were measured, and recovery of cardiac function at the end of reperfusion was also evaluated. Result (1) In groupⅠ(myocardial ischemic reperfusion group),myocardial infarct size(myocardial infarct size/total left ventricular size)was 44.4±0.9% . Compared with group Ⅰ, infarct sizes in different pharmacological postconditioning decreased to different levels: groupⅡa (diazoxide 10μmol/Lpharmacological postconditioning group) (36.2±0.7%), groupⅡb (diazoxide30 μmol/L pharmacological postconditioning group) (32.2±0.4%), group Ⅱc (diazoxide 60μmol/L pharmacological postconditioning group)( 22.2±2.1%), group Ⅲ( pinacidil pharmacological postconditioning group)( 35.2±2.2%), group Ⅹ(PMA pharmacological postconditioning group)( 31.2 ±1.9). Each of the a...