Objective: We compared the effects of two sulphonylureas, glibenclamide and gliclazide, on ischaemic preconditioning (IPC) and nicorandil-induced protection in the in-vivo rat. We also studied the effects of these agents on the membrane potential of isolated rat mitochondria. Methods: Anaesthetised male Sprague-Dawley rats were used in an open chest model of myocardial infarction. Animals were randomly assigned to receive one of the following drugs: (1) saline control, (2) glibenclamide, 0.3 mg/kg, or (3) gliclazide, 1 mg/kg i.v. bolus. Each was then further randomised to one of the following treatments: (a) control, (b) IPC (consisting of 2 × 5 mins of regional ischaemia and 5 minutes reperfusion) or (c) nicorandil (50 ug/kg/min i.v). infusion. Each group then underwent 25 mins regional ischaemia and 2 hrs reperfusion. Infarct to risk zone ratio (%) was calculated by computerised planimetry of tetrazolium stained heart slices. The membrane potential of mitochondria isolated from rat ventricles was measured using flow cytometry. Comparisons were made between groups in control medium, nicorandil alone, and nicorandil with either glibenclamide or gliclazide. Results: Infarct size was significantly reduced with IPC (15.0 ± 1.1%,) and nicorandil (25.5 ± 4.2%), versus control (44.1 ± 3.2%), p < 0.005. Glibenclamide abolished IPC (40.8 ± 4.6%) and nicorandil-induced protection completely (39.5 ± 5.1%). Gliclazide had no adverse effect on IPC (20.4 ± 1.9%) or nicorandil-induced protection (23.6 ± 2.2%), p < 0.005. Nicorandil caused a partial depolarisation of the mitochondrial membrane potential (−14.92 ± 2.34%), which was abolished by glibenclamide (+2.03 ± 0.53%), but not gliclazide (−16.47 ± 3.36%), p < 0.01. Conclusion: Both IPC and nicorandil-induced protection are abolished by glibenclamide but not gliclazide in-vivo. These results may have important clinical implications in type II diabetic patients at risk of acute coronary syndromes.
|Number of pages||7|
|Journal||Cardiovascular Drugs and Therapy|
|Publication status||Published - Mar 2004|