Sulfonylurea Effects On Myocardial Protection Afforded By Ischemic Preconditioning

Objective: To compare the effect of different sulfonylureas(glibenclamide, glimepirde,gliclamide and glipizide) on the isolated rat heart myocardial protection afforded byischemic preconditioning, and observe their inhibition of ATP-sensitve potassiumcurrent of rat myocyte.Materials and Method: The isolated male S-D rat heart was perfused usingLangendorff perfusion system, and randomly divided into the following sixgroups:(1). ischemia group; (2). ischemic preconditioning group, 3 cycle of 5 minuteischemia/5 minute perfusion was applied to every heart followed by 30 minuteischemia and 120 minute reperfusion; (3).ischemic preconditioning+glibenclamide(10μM); (4).ischemic preconditioning+glimepiride (10μM); (5).ischemicpreconditioning+gliclazide(50μM); (6).ischemic preconditioning+glipizide (10μM,3μM,1μM and 0.1μM). Record the heamodynamic indexes during the perfusion andmeasure infarct size of each isolated heart after the perfusion. The membraneATP-sensitive potassium current was induced by simulated ischemia and recordedwith single-pipette whole-cell voltage clamp. Observe the inhibition effct ofglibenclamide(10μM), glimepiride(1μM), gliclazide(1μM) and glipizide(1μM) on theventricular myocyte membrane ATP-sensitive potassium current.Results: Under the conditions of our test, the infarct size of isolated hearts in IPC,IPC+GLM and IPC+GLC groups was significantly reduced compared with isolatedhearts in CON group(23.7±1.3％,24.6±1.0％and 33.1±1.3％vs 43.3±1.8％,P＜0.01, n=6), the infarct size of isolated hearts in IPC+GLB and IPC+GLC groupswas significantly increased compared with isolated hearts in IPC group(40.4±1.4％and 33.1±1.3％vs 23.7±1.3％, P＜0.01, n=6). Simulated ischemia significantlyincrease the membrane ATP-sensitive potassium channel current in every group(P＜0.05), glibenclamide inhibited I_KATP, decreasing 112.9％(P＜0.05, n=6), theinhibition of glimepiride has no statistical significance, the inhibition of gliclazideand glipizide was 93.7％and 91.2％respectively(P＜0.05, n=4). Conclusion: Ischemic preconditioning significantly reduced the infarct size affordedby sublethal ischemia, glimepiride did not abolish the myocardial protection affordedby ischemic preconditioning while glibencalmide completely abolish it, the effect ofgliclazide on ischemic preconditioning is between glibenclamide and glimepiride.The heart function of isolated hearts in glipizide groups did not recover after 30minute ischemia, it was probably due to the glipizide effect on vascular or theischemic preconditioning protocol of our study was not proper for examine theglipizide effect on ischemic preconditioning. Simulated ischemia could induce IK_ATp;the current density after glibenclamide inhibition was lower than the backgroundlevel, indicating the 10μM glibenclamide inhibition was not selectively forATP-sensitive potassium current; glimiperide inhibition of IK_ATP had no statisticalsignificance; the inhibition effect of gliclazide and glipizide were similar. Theinhibition on IK_ATp with other concentrations of these sulfonylureas needs furtherexamination.