title: 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.
authors.affiliation: Department of Cardiovascular, Metabolic and Endocrine Diseases, Pfizer Global Research and Development, Pfizer Inc., Groton, CT 06340, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Flynn
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Smith
authors.forename: Judith L
authors.initials: JL
authors.lastname: Treadway
authors.forename: Carolyn B
authors.initials: CB
authors.lastname: Levy
authors.forename: Walter C
authors.initials: WC
authors.lastname: Soeller
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Boettner
authors.forename: Peter
authors.initials: P
authors.lastname: Wisniecki
authors.forename: David R
authors.initials: DR
authors.lastname: Plowchalk
authors.forename: Steve S
authors.initials: SS
authors.lastname: Gernhardt
authors.forename: W Ross
authors.initials: WR
authors.lastname: Tracey
authors.forename: Delvin R
authors.initials: DR
authors.lastname: Knight
mesh_terms: D000818:Animals; D005913:Glipizide / Q000008:administration & dosage / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006993:Hypnotics and Sedatives; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D019157:Ischemic Preconditioning, Myocardial; D007649:Ketamine; D008297:Male; D023421:Models, Animal; D009203:Myocardial Infarction / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D011817:Rabbits; D014991:Xylazine
chemical_list: D006993:Hypnotics and Sedatives; D007004:Hypoglycemic Agents; D007328:Insulin; D014991:Xylazine; D007649:Ketamine; D005905:Glyburide; D005913:Glipizide