Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K+ channel blocker.

Abstract

BACKGROUND Brief episodes of ischemia render the heart more resistant to subsequent ischemia; this phenomenon has been called ischemic preconditioning. In some animal species, myocardial preconditioning appears to be due to activation of ATP-sensitive K+ (KATP) channels. The role played by KATP channels in preconditioning in humans remains unknown. The aim of this study was to establish whether glibenclamide, a selective KATP channel blocker, abolishes the ischemic preconditioning observed in humans during coronary angioplasty following repeated balloon inflations. METHODS AND RESULTS Twenty consecutive patients undergoing one-vessel coronary angioplasty were randomized to receive 10 mg oral glibenclamide or placebo. Sixty minutes after glibenclamide or placebo administration, patients were given an infusion of 10% dextrose (8 mL/min) to correct glucose plasma levels or, respectively, an infusion of saline at the same infusion rate. Thirty minutes after the beginning of the infusion, both patient groups underwent coronary angioplasty. The mean values (+/- 1 SD) of ST-segment shifts on the surface 12-lead ECG and the intracoronary ECG were measured at the end of the first and second balloon inflations, both 2 minutes long. In glibenclamide-treated patients, the mean ST-segment shift during the second balloon inflation was similar to that observed during the first inflation (23 +/- 13 versus 20 +/- 8 mm, P = NS), and the severity of cardiac pain was greater (55 +/- 21 versus 43 +/- 23 mm on a scale of 0 to 100, P < .05). Conversely, in placebo-treated patients the mean ST-segment shift during the second inflation was less than that during the first inflation (9 +/- 5 versus 23 +/- 13 mm, P < .001), as was the severity of cardiac pain (15 +/- 15 versus 42 +/- 19 mm, P < .01). Blood glucose levels were significantly reduced 60 minutes after glibenclamide compared with those at baseline (53 +/- 9 versus 102 +/- 10 mg/100 mL, P < .001) in the glibenclamide group; however, before coronary angioplasty, blood glucose levels increased to 95 +/- 19 mg/100 mL, a value similar to that found in placebo group (96 +/- 11 mg/100 mL, P = NS). CONCLUSIONS In humans, ischemic preconditioning during brief repeated coronary occlusions is completely abolished by pretreatment with glibenclamide, thus suggesting that it is mainly mediated by KATP channels.

Glimepiride, a Novel Sulfonylurea, Does Not Abolish Myocardial Protection Afforded by Either Ischemic Preconditioning or Diazoxide

“…There are also data from human studies in which preconditioning has been examined with surrogate end points such as ST-segment deviation during repeated intracoronary balloon inflations that support the notion that glibenclamide blunts the preconditioning response. 20 Such observations have generated concern about the safety of sulfonylurea agents in diabetic patients with concurrent ischemic heart disease, because inhibition of the endogenous preconditioning mechanism by sulfonylureas might predispose to cell death. 1 Glimepiride, a second-generation sulfonylurea, has been shown to be more specific to the pancreas than to other tissues, especially the myocardium.…”

Annexin A5 Scintigraphy of Forearm as a Novel In Vivo Model of Skeletal Muscle Preconditioning in Humans

“…Like infarct size in animal models, these surrogates for ischemiareperfusion injury are responsive to adenosine receptor antagonists and glibenclamide. 34,35 However, possible recruitment of collateral circulation, which could be reduced by the pharmacological treatment, complicates interpretation of these observations. Changes in venous lactate do not necessarily reflect differences in ischemic injury but may result from differences in ischemic load.…”

Cardiovascular Disease

“…Given this information, it is noteworthy that glyburide inhibits the beneficial effects of ischemic preconditioning in animal models of myocardial infarction (29), as well as blocking the effects of K ATP channel openers. In humans, glyburide also can be shown to prevent ischemic preconditioning (30,31).…”