The Sulfonylurea Glipizide Does Not Inhibit Ischemic Preconditioning in Anesthetized Rabbits

Abstract

The K(ATP) channel blocker glibenclamide inhibits cardioprotection afforded by ischemic preconditioning (IPC), raising concern about sulfonylurea use by patients with cardiovascular disease. We examined the effects of the widely prescribed sulfonylurea glipizide (Glucotrol XL(R) ) on IPC in anesthetized rabbits. Initially, in parallel studies in pentobarbital-anesthetized rabbits, we identified doses of glipizide (GLIP, 0.17 mg/kg + 0.12 mg/kg/h, IV) and glibenclamide (GLIB, 0.05 mg/kg + 0.03 mg/kg/h, IV) that produced steady-state, clinically relevant plasma levels of both drugs; these doses also significantly increased plasma insulin by 51 +/- 17% (GLIP) and by 57 +/- 17% (GLIB, both p < 0.05 vs. their respective baseline levels). Subsequent parallel studies in ketamine-xylazine-anesthetized rabbits examined the effects of these doses of GLIP and GLIB on IPC. Myocardial injury (30 min coronary occlusion/120 min reperfusion), either with or without IPC (5 min occlusion/10 min reperfusion) was induced midway during a 2 h infusion of vehicle (VEH), GLIP or GLIB (n = 10-11 each). Infarct area (IA) normalized to area-at-risk (%IA/AAR) was 62 +/- 3% in the VEH group, and was significantly reduced to 39 +/- 5% by IPC (p < 0.05 vs. VEH). Neither GLIP nor GLIB treatment had any effect on %IA/AAR in the absence of IPC (p > 0.05). IPC-induced cardioprotection was preserved in the GLIP + IPC treatment group (45 +/- 4%) when compared to VEH alone (p < 0.05), but was attenuated in the presence of GLIB (GLIB+IPC: 53 +/- 4% IA/AAR, p > 0.05 vs. VEH). Thus, at a clinically relevant plasma concentration, glipizide did not limit the cardioprotective effects of IPC, and is unlikely to increase the severity of cardiac ischemic injury.

New Drugs for the Treatment of Diabetes

“…Glipizide 52 and glimepiride 53 may be safer than glyburide and the rarely used first-generation sulfonylureas because of greater inhibition of K ATP channels on pancreatic ␤ cells (which induce membrane depolarization and insulin release) versus mitochondrial K ATP channels in cardiomyocytes, with a resultant lower likelihood of interfering with ischemic preconditioning. As a group, the newer nonsulfonylurea secretagogues (glinides) are not necessarily safer in this regard, although nateglinide 54 appears to have less affinity for K ATP channels in general than repaglinide.…”

Role of conventional oral antidiabetic drugs in management of type 2 diabetes mellitus

“…49,50 Insulin Can be added to or substituted for oral agents at any point in the disease course. When more advanced regimens are used, insulin secretagogues traditionally…”

Cardiovascular effects of anti-diabetes drugs

“…Glyburide therapy abolished the cardio-protective effect of preconditioning and demonstrated no improvements in any ischemic cardiac measures [34]. The preservation of ischemic preconditioning has been replicated in individuals receiving glimepiride [35,36], gliclazide [37] and glipizide [38]. In two studies of patients undergoing consecutive exercise treadmill stress tests, repaglinide appeared to abolish ischemic preconditioning [39,40].…”