Glimepiride Treatment Facilitates Ischemic Preconditioning in the Diabetic Heart

Abstract

Aims: The diabetic heart is resistant to the myocardial infarct-limiting effects of ischemic preconditioning (IPC). This may be in part due to the downregulation of the phosphatidylinositol 3 0 -kinase-Akt pathway, an essential component of IPC protection. We hypothesized that treating the diabetic heart with the sulfonylurea, glimepiride, which has been reported to activate Akt, may lower the threshold required to protect the diabetic heart by IPC. Methods: Goto-Kakizaki rats (a type II lean model of diabetes) received glimepiride (20 mg/kg per d, by oral gavage) or vehicle for (a) 3 months (chronic treatment) or (b) 24 hours (subacute treatment). In the third group, glimepiride (10 mmol/L) was administered only to the isolated hearts on the Langendorff apparatus (acute treatment). All hearts were subjected to 35 minutes ischemia and 120 minutes reperfusion ex vivo, at the end of which infarct size was determined by tetrazolium staining. Preconditioning treatment comprised 1 (IPC-1) or 3 (IPC-3) cycles of 5 minutes global ischemia and 10 minutes reperfusion. Results: The diabetic heart was found to be resistant to IPC such that 3-IPC cycles, instead of the usual 1-IPC cycle, were required for cardioprotection. However, pretreatment with glimepiride lowered the threshold for IPC such that both 1 and 3 cycles of IPC elicited cardioprotection: chronic glimepiride treatment (IPC-1 31.9% + 3.8% and IPC-3 33.5% + 2.4% vs 43.9% + 1.4% control, P < .05; N > 6 per group); subacute glimepiride treatment (IPC-1 31.1% + 3.0% and IPC-3 29.3% + 3.3% vs 42.2% + 2.3% control, P < .05 N > 6 per group); and acute glimepiride treatment (IPC-1 28.2% + 3.7% and IPC-3 24.6% + 5.4% vs 41.9% + 5.4% control, P < .05; N > 6 per group). This effect of glimepiride was independent of changes in blood glucose. Conclusions: We report for the first time that glimepiride treatment facilitates the cardioprotective effect elicited by IPC in the diabetic heart.

Pro- and Antiarrhythmic Actions of Sulfonylureas: Mechanistic and Clinical Evidence

“…Interestingly, in a recent study of diabetic rat hearts resistant to IPC, glimepiride was able to elicit cardioprotection. [44] Studies of sulfonylurea effects on IPC in humans are equally difficult to interpret, but also generally demonstrate that glyburide abolishes while glimepiride preserves IPC; very little is known of glipzide’s effects (Table 2). Despite this body of work, it is unknown whether long-term sulfonylurea exposure in persons with T2DM has clinically meaningful effects on IPC or related endpoints.…”

Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning

“…Gu et al (2008) found that simvastatin treatment was able to restore cardioprotection elicited by ischemic preconditioning in the presence of hyperglycemia, and this effect was associated with the generation of NO. Pretreatment of diabetic Goto-Kakizaki rats with the antidiabetic sulfonylurea glimepiride (which did not reduce infarct size itself) was demonstrated to restore the sensitivity of the myocardium to ischemic preconditioning, such that one cycle instead of three cycles of ischemic preconditioning was sufficient to limit infarct size (Hausenloy et al, 2013c). However, this effect of glimepiride in lowering the threshold for ischemic preconditioning appeared to be independent of serum glucose levels, because the latter remained unchanged with glimepiride treatment (Hausenloy et al, 2013c).…”

“…Pretreatment of diabetic Goto-Kakizaki rats with the antidiabetic sulfonylurea glimepiride (which did not reduce infarct size itself) was demonstrated to restore the sensitivity of the myocardium to ischemic preconditioning, such that one cycle instead of three cycles of ischemic preconditioning was sufficient to limit infarct size (Hausenloy et al, 2013c). However, this effect of glimepiride in lowering the threshold for ischemic preconditioning appeared to be independent of serum glucose levels, because the latter remained unchanged with glimepiride treatment (Hausenloy et al, 2013c). Finally, chronic insulin treatment increases cardiac adiponectin and restores cardioprotective AMPK signaling .…”

Cardiomyocyte changes in the metabolic syndrome and implications for endogeneous protective strategies

“…Sulfonylureas have been shown to inhibit protection of ischemic preand postconditioning by blocking the ATP-sensitive K + channel in cardiomyocytes, but the effects on pre-and postconditioning are actually not uniform across sulfonylureas [125]. Recently, glimepiride treatment has shown to facilitate the cardioprotective effect elicited by ischemic preconditioning in the diabetic heart [126], while ACE inhibition and food restriction have shown to restore delayed preconditioning in diabetic mice [118].…”