Comparison of two sulfonylureas with high and low myocardial KATP channel affinity on myocardial infarct size and metabolism in a rat model of type 2 diabetes

Abstract

Aims/hypothesis Sulfonylureas (SUs) may impair outcome in patients with acute coronary syndrome. Most experimental studies of the myocardial effects of SU treatment are performed in non-diabetic models. We compared the effect of two widely used SUs, glibenclamide (gb) and gliclazide (gc), with high and low myocardial K ATP channel affinity, respectively, at therapeutic concentrations on infarct size, left ventricular (LV) function and myocardial glycogen, lactate and alanine content before and after ischaemia/ reperfusion (I/R). Methods Non-diabetic Wistar and diabetic Goto-Kakizaki rat hearts were investigated in a Langendorff preparation. Gb (0.1 μmol/l) and gc (1.0 μmol/l) were administrated throughout the study. Infarct size was evaluated after 120 min of reperfusion. Myocardial metabolite content was measured before and after ischaemia.Results Infarct size was smaller in diabetic hearts than in non-diabetic hearts (0.33±0.03 vs 0.51±0.05, p<0.05). Gb increased infarct size (0.54±0.04 vs 0.33±0.03, p<0.05) and reduced post-ischaemic LV developed pressure (60±3 vs 76±3 mmHg, p<0.05) and coronary flow (4.9±0.5 vs 7.1±0.4 ml min -1 g -1 , p<0.05) in gb-treated diabetic rats compared with untreated diabetic rats. On comparing gb-treated diabetic rats with untreated diabetic rats, glycogen content was reduced before (9.1 ±0.6 vs 13.6 ± 1.0 nmol/mg wet weight, p<0.01) and after ischaemia (0.9±0.2 vs 1.8±0.2 nmol/mg wet weight, p<0.05), and lactate (4.8±0.4 vs 3.2±0.3 nmol/mg wet weight, p<0.01) and alanine (1.38±0.12 vs 0.96±0.09 nmol/mg wet weight, p < 0.05) contents were increased during reperfusion. Gc-treatment of diabetic and non-diabetic rats did not affect any of the measured variables. Conclusions/interpretations Gb, but not gc, exacerbates I/R injury and deteriorates LV function in diabetic hearts. These effects of gb on diabetic hearts may be due to detrimental effects on myocardial carbohydrate metabolism.

Diabetic cardiomyopathy: pathophysiology and clinical features

“…[153]  GK rat: Refs. [153, 154] No change in infarct size  STZ (±alloxan)-induced DM (dog, rabbit, rat, mouse): Refs. [147, 149, 150, 155–165]  GK rat: Refs.…”

Effects of diabetes on myocardial infarct size and cardioprotection by preconditioning and postconditioning

“…With a few exceptions [30,31], DM models with obesity and hyperinsulinemia showed increased myocardial susceptibility to ischemia/reperfusion-induced necrosis [32-41]. In contrast, high glucose level induced simply by glucose or dextrose infusion did not affect infarct size in the majority of studies, including two recent studies [42,43] (Table 2).…”

“…However, since they used a PC protocol with multiple cycles of ischemia/reperfusion only, the change in the threshold for inducing PC protection might have been missed in their study. In fact, impairment of PC by DM has been observed in multiple species (rats, rabbits and dogs) and different models of DM (STZ-induced type 1 DM and genetic models of type 2 DM) [30,37,50-54]. Mimetics of ischemic PC and PostC (diazoxide, erythropoietin, [D-Ala 2 , D-Leu 5 -enkephalin acetate [DADLE] and isoflurane) were also ineffective for limitation of infarct size in DM hearts [33,34,37,55-59], confirming that DM impairs intracellular signaling mechanisms relevant to myocardial protection.…”

Comparative cardiovascular safety of insulin secretagogues following hospitalization for ischemic heart disease among type 2 diabetes patients: a cohort study

“…The extra-pancreatic cardiovascular effects of glyburide and repaglinide may potentially increase the risk of adverse cardiovascular events. In contrast, gliclazide appears to be more selective for SUR1, which may confer a better cardiovascular prognosis during acute ischemic events (Abdelmoneim et al, 2012;Kristiansen et al, 2011). Indeed, we have shown previously that gliclazide use is associated with a lower risk of acute coronary syndrome-related morbidity and mortality compared to glyburide use (Abdelmoneim et al, 2014).…”

“…Some IS, like glyburide and the non-sulfonylurea IS repaglinide, will bind to both SUR1 and SUR2 isoforms when given at usual therapeutic doses and therefore also inhibit K ATP channels located in the myocardium and vascular smooth muscle cells (Abdelmoneim et al, 2012). Animal models have shown that cardiac K ATP channel opening is protective during ischemia-reperfusion injury and that K ATP channel activity is essential for ischemic conditioning, an endogenous protective mechanism that promotes salvage of myocardial tissue during ischemia-reperfusion injury (Kristiansen et al, 2011;Tang et al, 2006). The extra-pancreatic cardiovascular effects of glyburide and repaglinide may potentially increase the risk of adverse cardiovascular events.…”