ATP-sensitive potassium channel blockers, glimepiride and glibenclamide reduces ischemia reperfusion-induced renal injury in rats by inhibition of neutrophil aggregation: comparative study of glimepiride versus glibenclamide and diazoxide

ABSTRACT

Renal ischemia is a complex neutrophils-mediated syndrome in which ATP-sensitive potassium channels are involved. Fall in intracellular ATP concentration induces opening of these channels resulting in massive influx of neutrophils .This exerts a crucial role in the patho-physiology of post-ischemic renal failure. Our study has used the ischemia reperfusion [I/R] model to asses the role of ATP-dependant potassium channel modulation, comparing the protective effects of glimepiride and glibenclamide on renal I/R inflammatory injury and neutrophil aggregation. As this protective effect in renal I/R stands in sharp contrast to the harmful effects on the cardiac tissues, our study evaluates the harmful effects of both sulfonylurea drugs on normal hearts and on ischemic reperfused hearts subjected to ischemic preconditioning protection afforded by diazoxide. One hundred and fourteen [114] adult albino rats were used; 72 of them were used for the in renal I/R study and 42 rats for the cardiac I/R experiment. In renal I/R study, rats were unilaterally nephrectomized, then all rats except the Sham operated control group, were subjected to renal I/R by ischemia 45 min and reperfusion 4 and 24 h, then divided into five groups [1] renal ischemia-reperfusion, [2] renal I/R + solvent control, [3] renal I/R + diazoxide, [4] renal I/R + glibenclamide, [5] renal I/R + glimepiride. At the end of each reperfusion period, mean arterial pressure, urine volume, serum creatinine and urea, were measured. Then kidneys and lungs were taken for histological examination and determination of TNF-alpha levels, superoxide anion production and myloperoxidase activity. Cardiac I/R study, cardiac ischemia reperfusion model by left coronary artery ligation was used for evaluating the side effects of both sulfonylureas on both normal and ischemic preconditioning rat's hearts. Renal ischemia reperfusion induced marked renal dysfunction associated with significant increase in arterial pressure, TNF-alpha levels, superoxide anion production, and myloperoxidase activity. Treatment with glibenclamide or glemipiride, illustrated significant improvement in the reperfusion-induced injury in both kidney and lung, but glemipiride has no effect on superoxide anion production. However glibenclamide induced a significant improvement in these measurements as compared to glimepiride group. Before coronary artery ligation, neither diazoxide nor glimepiride pretreatment influenced significantly the electrocardiographic parameters [heart rates, T-waves voltages and ST segment elevation] in comparison with control group. On the other hand, glibenclamide supplementation induced a significant elevation in all these parameters. After left coronary artery ligation, reperfusion of the ischemic hearts caused a significant elevation in the measured electrocardiographic parameters. These elevations were significantly ameliorated by pretreatment with diazoxide. Administration of glibenclamide significantly abolished the protective effects of diazoxide, while pretreatment with glimepiride didn't abolish it. In conclusion, glimepiride offered some promise for therapy of renal I/R with minimizing the undesirable cardiac side effects