Journal Logo

Original Article

Effects of KATP Channel Modulation on Myocardial Glycogen Content, Lactate, and Amino Acids in Nonischemic and Ischemic Rat Hearts

Kristiansen, Steen B MD; Nielsen-Kudsk, Jens Erik MD; Bøtker, Hans Erik MD; Nielsen, Torsten Toftegaard MD

Author Information
Journal of Cardiovascular Pharmacology: May 2005 - Volume 45 - Issue 5 - p 456-461
doi: 10.1097/01.fjc.0000159045.35241.95
  • Free


Ischemic myocardial preconditioning (IPC) is the phenomenon whereby preceding episodes of ischemia protect the heart against sustained ischemia.1 ATP-sensitive potassium (KATP) channels are extensively involved in the mechanisms underlying IPC because blockade of KATP channels abolishes the cardioprotective effect of IPC.2 The KATP channel is a heterooctameric complex of 2 subunits: a Kir 6.x subunit, which forms the potassium-conducting pore, and a SUR1 or SUR2 subunit, belonging to the ATP-binding cassette (ABC) protein superfamily that confers sensitivity to sulfonylureas.3-5 Glibenclamide, a sulfonylurea used in the treatment of type 2 diabetes mellitus, blocks KATP channels and abolishes the cardioprotective effects of IPC. IPC can be mimicked by pharmacological KATP activators such as diazoxide.6 KATP channels open during ischemia when the intracellular ATP concentration decreases, and physiological KATP modulation is generally believed to be secondary to intracellular metabolic alterations. However, KATP channel openers are previously reported to reduce the rate of ATP hydrolysis and preserve the cardiac adenine nucleotide energy pool during ischemia.7-10

Myocardial glycogen stores are an essential endogenous source of ATP formation, enabling the myocytes to maintain ion pump activity and cellular integrity during no-flow ischemia.11,12 However, uncontrolled glycogenolysis during ischemia may lead to lactate accumulation, intracellular acidosis, and cell death.13 The mechanisms behind the cardioprotective effects of IPC are not fully understood but may include preischemic myocardial glycogen depletion, decreased glycogen depletion during ischemia, and increased glycogen synthesis during reperfusion.14

The aim of the present study was to investigate whether a KATP opener, diazoxide, and KATP blocker, glibenclamide, modulate myocardial glycogen content before and during ischemia and if so whether they influence lactate accumulation during ischemia. Furthermore, because glutamate is metabolized during ischemia, leading to production of alanine and contributing to energy production during this condition,15 we investigated the effects of KATP modulation on myocardial glutamate and alanine content before and after ischemia.


Animals and Study Design

The rats were handled according to National guidelines in Denmark and the guidelines of American Heart Association for animal research. Male Wistar rats (300-350 g) obtained from M&B Taconic, Eiby, Denmark, were provided with ad libitum access to food and water in a room maintained at 23°C and 50% humidity with a 12-hour light/dark cycle. Animals were divided into 4 groups: (1) control (DMSO), (2) diazoxide, (3) glibenclamide, and (4) diazoxide + glibenclamide.

Isolated Heart Preparation and Perfusion Protocol

An isolated perfused rat heart preparation was used as previously described.16 Briefly, rats were anesthetized with midazolam 0.25 mg/kg body weight IM (Dormicum®, Roche, Basel, Switzerland) and fluanisone, 0.5 mg/kg body weight IM (Hypnorm®, Janssen-Cilag, Beerse, Belgium). A tracheotomy was made, and respiration was controlled by a mechanical ventilator (Zoovent, Newport Pagnell, UK). Subsequently, a laparotomy and a thoracotomy were performed, and the heart dissected from surrounding structures. A bolus of 1000 IE/kg heparin (Leo Pharma, Copenhagen, Denmark) was given through the femoral vein. The heart was cannulated in situ, mounted in a Langendorf apparatus, and perfused retrogradely with Krebs-Henseleit solution (NaCl 118.5 mmol/L, KCl 4.7 mmol/L, NaHCO3 25.0 mmol/L, glucose monohydrate 11.1 mmol/L, MgSO4·7H2O 1.2 mmol/L, CaCl2 2.4 mmol/L, and KH2PO4 1.2 mmol/L) (Sigma, St Louis, MO) at a pressure of 100 cm H2O. The perfusion solution was fully oxygenated with 95% O2 and 5% CO2 and kept at 37°C. The hearts were allowed to stabilize for 30 minutes and then subjected to global ischemia for 25 minutes and 45 minutes of reperfusion. Diazoxide (30 μM) (Sigma, St Louis, MO) and glibenclamide (10 μM) (Sigma, St Louis, MO) was dissolved in 1 mL dimethyl sulfoxide (DMSO) and administered during the last 15 minutes of the stabilization period. Controls received an equivalent dose of DMSO during the last 15 minutes of stabilization. The final concentration of DMSO was <0.1%.

Evaluation of Left Ventricular Function

A latex balloon (Hugo Sachs Elektronic, March-Hugstetten, Germany) was placed in the left ventricle through an incision in the left atrium and kept in place by the mitral valve. The volume in the balloon was adjusted to obtain an end-diastolic pressure of 7 cm H2O. A pressure transducer (Baxter Cardiovascular Group, Irvine, CA) was connected to the latex balloon, allowing recording of left ventricular pressure (LVP). The analog signal from the transducer was converted (AD-converter, MP100 system, BioPAC Systems Inc, Goleta, USA) and stored on a PC. Coronary flow was monitored continuously by a flow meter (Transonic, Maastricht, The Netherlands).

Assessment of Myocardial Metabolites

At the end of stabilization, ischemia, and reperfusion, hearts were frozen within 2 seconds in liquid nitrogen (−196°C) using precooled Wollenberger clamps.

Total glycogen was measured in triplicate from homogenates of frozen biopsies after degradation to glucose using the filter-paper technique and spectrophotometric detection at 340 nm.17,18 Lactate, glutamate, and alanine were measured from the same homogenates using enzymatic analyses and spectrophotometric detection.19

Statistics and Calculations

All values are expressed as mean ± SEM. Left ventricular developed pressure (LVDP) was calculated as PLV,systolic − PLV,diastolic. Groups were compared using 2-way ANOVA with repeated measures. SPSS 10 (SPSS Inc, US) was used for statistical calculations and P < 0.05 was considered statistically significant.



A total of 98 animals were used. We studied 33 animals after stabilization (diazoxide, n = 8; control, n = 8; glibenclamide, n = 9; and glib + diaz, n = 8), 34 animals after ischemia (diazoxide, n = 8; control, n = 9; glibenclamide, n = 9; and glib + diaz, n = 8), and 31 animals after 45 minutes of reperfusion (diazoxide, n = 8; control, n = 7; glibenclamide, n = 8; and glib + diaz, n = 8).

Effects of Diazoxide, Glibenclamide, and Their Interaction on Myocardial Function

Left ventricular developed pressure (LVDP) did not differ between groups before ischemia (P = 0.79) (Fig. 1). During reperfusion LVDP was increased in the diazoxide group compared with control (P < 0.05). The enhancement of myocardial contractile function induced by diazoxide was abolished by coinfusion with glibenclamide (P < 0.05). Glibenclamide itself did not influence LVDP during reperfusion compared with control (P = 0.28). Heart rate did not differ between groups before (P = 0.34) or after ischemia (0.79).

Left ventricular developed pressure (LVDP) did not differ between groups before ischemia. Diazoxide (▪) significantly increased LVDP during reperfusion compared with controls (□); however, this effect was abolished with coinfusion of glibenclamide (▵). Glibenclamide (○) itself did not influence LVDP compared with control. Mean ± SEM. *P < 0.05 compared with control.

Effects of KATP Modulators on Coronary Flow in Nonischemic and Ischemic Hearts

Coronary flow (mL/min/g) before ischemia was not altered in diazoxide- (12.7 ± 1.1, P = 0.44) or glibenclamide-treated (10.8 ± 1.0, P = 0.57) hearts compared with controls (11.6 ± 0.6). During reperfusion coronary flow was not altered in diazoxide- (6.8 ± 0.6, P = 0.79) and glibenclamide-treated (6.0 ± 0.7, P = 0.67) hearts compared with controls (6.5 ± 0.9).

Effects of KATP Modulators on Myocardial Metabolism in Nonischemic and Ischemic Hearts

Diazoxide did not influence myocardial glycogen (nmol/mg wet weight) content before ischemia (11.3 ± 0.6, P = 0.50) (Fig. 2). However, compared with control (11.8 ± 0.8), coinfusion of diazoxide and glibenclamide (8.7 ± 0.2, P < 0.01) or of glibenclamide alone (8.9 ± 0.4, P < 0.01) reduced myocardial glycogen (nmol/mg) content before ischemia.

Myocardial glycogen content before ischemia (black columns) was significantly reduced in glibenclamide and glibenclamide + diazoxide-treated hearts compared with controls. After 25 minutes of global ischemia (gray columns), myocardial glycogen content was increased in diazoxide-treated hearts compared with controls; however, this effect was abolished by glibenclamide coinfusion. Glibenclamide-treated hearts had significantly reduced myocardial glycogen content compared with controls after ischemia. After 45 minutes of reperfusion (white columns), there were no differences between groups. Mean ± SEM. *P < 0.05 compared with control; †P < 0.01 compared with control; ‡P < 0.01 compared with diazoxide.

After 25 minutes of global no-flow ischemia, myocardial glycogen content was increased 50% in diazoxide-treated hearts compared with control (2.7 ± 0.3 versus 1.8 ± 0.3, P < 0.05). This effect was abolished with coinfusion of glibenclamide (0.9 ± 0.1, P < 0.01 versus diazoxide alone). Glibenclamide decreased myocardial glycogen content 45% after ischemia (1.0 ± 0.1, P < 0.05 versus control). After 45 minutes of reperfusion, there was no difference between groups in myocardial glycogen content (diazoxide, 2.5 ± 0.3; glibenclamide, 1.9 ± 0.2; diaz + glib, 1.9 ± 0.2; control, 2.1 ± 0.2, P = 0.12).

Diazoxide did not influence myocardial lactate content (nmol/mg wet weight) before ischemia compared with control (0.9 ± 0.1 and 1.0 ± 0.1, P = 0.59) (Fig. 3). However, coinfusion of diazoxide and glibenclamide (1.6 ± 0.2, P < 0.05) or glibenclamide alone (1.7 ± 0.2, P < 0.05) increased myocardial lactate content before ischemia compared with controls. After ischemia, lactate content was decreased in diazoxide-treated hearts (21.7 ± 0.7) compared with control (25.3 ± 0.7, P < 0.05). This effect was abolished with coinfusion of glibenclamide (P < 0.05). Myocardial lactate content did not differ between groups after 45 minutes of reperfusion (diazoxide, 2.3 ± 0.3; glibenclamide, 3.2 ± 0.4; diaz + glib, 2.9 ± 0.4; control, 3.9 ± 0.5, P = 0.93).

Myocardial lactate content before ischemia (black columns) was significantly increased in glibenclamide- and glibenclamide + diazoxide-treated hearts compared with controls. After 25 minutes of global ischemia (gray columns), myocardial lactate content was decreased in diazoxide-treated hearts compared with controls; however, this effect was abolished by glibenclamide coinfusion. After 45 minutes of reperfusion (white columns), there were no differences between groups. Mean ± SEM. *P < 0.05 compared with control; ‡P < 0.05 compared with diazoxide.

Myocardial glutamate content tended to be reduced in glibenclamide- (P = 0.06) and glibenclamide + diazoxide-treated hearts before ischemia (P = 0.09), but there was no differences after ischemia (P = 0.62) or after 45 minutes of reperfusion (P = 0.26) between groups (Fig. 4). Myocardial alanine content was increased in glibenclamide- (P < 0.05) and glibenclamide + diazoxide-treated hearts (P < 0.05) compared with control before ischemia. Alanine content did differ between groups after ischemia (P = 0.88) or reperfusion (P = 0.28) (Fig. 5).

Myocardial glutamate content before ischemia (black columns) tended to be increased in glibenclamide- (P = 0.06) and glibenclamide + diazoxide-treated hearts (P = 0.09) compared with controls. After 25 minutes of global ischemia (gray columns) and 45 minutes of reperfusion (white columns), there were no differences between groups. Mean ± SEM.
Myocardial alanine content before ischemia (black columns) was significantly increased in glibenclamide- and glibenclamide + diazoxide-treated hearts compared with controls. After 25 minutes of global ischemia (gray columns) and 45 minutes of reperfusion there were no differences between groups. Mean ± SEM. P < 0.05 compared with control.


The major findings of the present study are that KATP channel opening induced by diazoxide before ischemia reduced myocardial glycogen depletion and lactate accumulation during ischemia and improved left ventricular function during reperfusion. The effects were blocked by glibenclamide, which had metabolic effects itself by reducing myocardial glycogen content before and after ischemia and increasing myocardial lactate content in the nonischemic myocardium.

Changes in the status of the KATP channels are generally considered secondary to metabolic alterations.20 KATP channels are opened by decreased intracellular concentrations of ATP. The impact of KATP opening and blocking on myocardial content of glycogen, lactate, and amino acids has not previously been studied. Because the myocardial concentrations of these compounds were modified by alterations in the opening of KATP channels, the present study provides evidence that KATP modulation per se alters cardiac metabolism.

Myocardial glycogen content is an important source of energy during ischemia and secures maintenance of ion homeostasis and cellular integrity.21 However, during ischemia myocardial oxidative metabolism is depressed, and glycolysis becomes an important source of ATP generation.22 In the face of impaired glucose oxidation, the increased glycolytic rate leads to proton accumulation and downstream activation of pathways that result in Ca2+ overload, impaired contractile function, and cell death.23 Consequently, it has been considered whether preischemic depletion of myocardial glycogen stores, which is an inherent feature of IPC, may be cardioprotective during ischemia-reperfusion because the source of lactate accumulation is restricted. However, the results have been conflicting.24-29 Our data do not support the hypothesis of a cardioprotective effect of preischemic glycogen depletion. Diazoxide did not alter myocardial glycogen content before ischemia in spite of improved ventricular function during reperfusion. In contrast, glibenclamide reduced myocardial glycogen content before ischemia without improving ventricular function after ischemia. During no-flow ischemia, diazoxide decreased myocardial glycogen depletion and lactate accumulation, which is also seen with IPC.14 This is supported by the findings of Morticello et al, who microscopically found that glycogen stores were preserved during ischemia after treatment with the KATP channel opener BMS-180448.30 The effect was abolished by coinfusion of glibenclamide. These results suggest that preischemic glycogen depletion yields no protection against ischemia-reperfusion. A component in the mechanisms behind cardioprotection during ischemia-reperfusion may rather be a reduction of the rate of glycogen depletion and lactate accumulation during ischemia. In the nonischemic hearts glibenclamide decreased myocardial glycogen in accordance with studies of peroxide-induced toxicity.31 Furthermore, glibenclamide increased myocardial lactate content before ischemia, suggesting that glibenclamide impairs aerobic metabolism in the nonischemic myocardium. Despite these metabolic alterations we did not detect any influence of glibenclamide on myocardial function in the nonischemic heart after 20 minutes of infusion. This may be because of a short exposure of the compound in the heart.

The importance of myocardial amino acid metabolism during ischemia-reperfusion is only sparsely described. We16 and others32-34 have previously found beneficial effects of glutamate supplementation during ischemia-reperfusion. In the present study no exogenous amino acids were added, and the intrinsic stores of glutamate and alanine were investigated. In accordance with the well-known intracellular regulatory mechanism, intracellular lactate accumulation by glibenclamide appeared to be limited by transamination of pyruvate to alanine by glutamate.35 As a consequence, not only was there increased myocardial lactate content, glibenclamide also increased myocardial alanine content and tended to decrease myocardial glutamate content before ischemia. These findings indicate that the intracellular signaling pathways remain preserved during KATP modulation in the absence of ischemia. Although myocardial lactate content was decreased after ischemia in diaxozide-treated hearts, neither alanine nor glutamate contents differed between the study groups. These findings indicate that transamination of pyruvate by glutamate was not significantly activated by KATP activation during ischemia.36 Consequently, KATP activation appears to reduce glycogen depletion rather than redirecting intermediary substrate pathways during ischemia.

Despite concerns about possible cardiovascular adverse effects, sulfonylureas, with glibenclamide the most widely used in the United States, are still a cornerstone of the treatment of type 2 diabetes mellitus (T2DM).37 The mechanism behind the detrimental effects of sulfonylureas on myocardial ischemia-reperfusion injury is thought to be attenuation of ischemic preconditioning. However, we have recently found that hearts of T2DM animals are not amenable to protection afforded by ischemic preconditioning, indicating that other mechanisms could be involved.38

The limitations of the present study are mainly related to the use of the isolated perfused heart model. We chose this model to avoid alteration in circulating glucose and free fatty acids levels, which are factors known to influence myocardial responses to ischemia-reperfusion.39-41 Glibenclamide is a nonspecific KATP inhibitor, blocking both sarcolemmal and mitochondrial KATP channels, which in the present study does not allow any conclusion about the relative importance of blocking sarcolemmal or mitochondrial KATP channels. The biologic significance of the effects of KATP channel modulation on myocardial metabolite content is unclear and seems small relative to the changes observed in the vehicle control group. However, it is conceivable that the 50% increase in myocardial glycogen content afforded by diazoxide may be of great importance to sustain vital cellular functions.


In conclusion, KATP modulation interferes with essential components in myocardial metabolism. KATP opening decreased myocardial glycogen depletion and lactate accumulation during ischemia and improved postischemic left ventricular function. KATP blocking with glibenclamide reduced myocardial glycogen stores and increased myocardial lactate content in the nonischemic myocardium.


We appreciate technical assistance by Eva Sparrewath and Bente Jacobsen.


1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124-1136.
2. Gross GJ, Peart JN. KATP channels and myocardial preconditioning: an update. Am J Physiol Heart Circ Physiol. 2003;285:H921-H930.
3. Aguilar-Bryan L, Nichols CG, Wechsler SW, et al. Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science. 1995;268:423-426.
4. Sakura H, Ammala C, Smith PA, et al. Cloning and functional expression of the cDNA encoding a novel ATP-sensitive potassium channel subunit expressed in pancreatic beta-cells, brain, heart and skeletal muscle. FEBS Lett. 1995;377:338-344.
5. Tucker SJ, Gribble FM, Zhao C, et al. Truncation of Kir6.2 produces ATP-sensitive K+ channels in the absence of the sulphonylurea receptor. Nature. 1997;387:179-183.
6. Garlid KD, Paucek P, Yarov-Yarovoy V, et al. Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection. Circ Res. 1997;81:1072-1082.
7. Dos SP, Kowaltowski AJ, Laclau MN, et al. Mechanisms by which opening the mitochondrial ATP- sensitive K(+) channel protects the ischemic heart. Am J Physiol Heart Circ Physiol. 2002;283:H284-H295.
8. Grover GJ, Newburger J, Sleph PG, et al. Cardioprotective effects of the potassium channel opener cromakalim: stereoselectivity and effects on myocardial adenine nucleotides. J Pharmacol Exp Ther. 1991;257:156-162.
9. Grover GJ, Sleph PG, Dzwonczyk S, et al. Glyburide-reversible cardioprotective effects of BMS-180448: functional and energetic considerations. J Cardiovasc Pharmacol. 1997;29:28-38.
10. McPherson CD, Pierce GN, Cole WC. Ischemic cardioprotection by ATP-sensitive K+ channels involves high-energy phosphate preservation. Am J Physiol. 1993;265:H1809-H1818.
11. Eberli FR, Weinberg EO, Grice WN, et al. Protective effect of increased glycolytic substrate against systolic and diastolic dysfunction and increased coronary resistance from prolonged global underperfusion and reperfusion in isolated rabbit hearts perfused with erythrocyte suspensions. Circ Res. 1991;68:466-481.
12. Weiss J, Hiltbrand B. Functional compartmentation of glycolytic versus oxidative metabolism in isolated rabbit heart. J Clin Invest. 1985;75:436-447.
13. Neely JR, Grotyohann LW. Role of glycolytic products in damage to ischemic myocardium. Dissociation of adenosine triphosphate levels and recovery of function of reperfused ischemic hearts. Circ Res. 1984;55:816-824.
14. Bradamante S, Marchesani A, Barenghi L, et al. Glycogen turnover and anaplerosis in preconditioned rat hearts. Biochim Biophys Acta. 2000;1502:363-379.
15. Wiesner RJ, Deussen A, Borst M, et al. Glutamate degradation in the ischemic dog heart: contribution to anaerobic energy production. J Mol Cell Cardiol. 1989;21:49-59.
16. Kristiansen SB, Henning O, Nielsen-Kudsk JE, et al. Effects of L-glutamate supplementation mimic effects of fasting in the ischemic heart. APMIS Suppl. 2003;109:117-121.
17. Solling H, Esmann V. A sensitive method of glycogen determination in the presence of interfering substances utilizing the filter-paper technique. Anal Biochem. 1975;68:664-668.
18. Botker HE, Randsbaek F, Hansen SB, et al. Superiority of acid extractable glycogen for detection of metabolic changes during myocardial ischaemia. J Mol Cell Cardiol. 1995;27:1325-1332.
19. Hohorst HH. L-(+)-Lactate determination with lactic dehydrogenase and DPN, In: Bergmeyer HU, ed. Metoden der enzymatischen Analyse. Weinheim: Verlag Chemie, 1962, p 262.
20. Edwards G, Weston AH. The pharmacology of ATP-sensitive potassium channels. Annu Rev Pharmacol Toxicol. 1993;33:597-637.
21. Stanley WC, Hall JL, Stone CK, et al. Acute myocardial ischemia causes a transmural gradient in glucose extraction but not glucose uptake. Am J Physiol. 1992;262:H91-H96.
22. Kubler W, Spieckermann PG. Regulation of glycolysis in the ischemic and the anoxic myocardium. J Mol Cell Cardiol. 1970;1:351-377.
23. King LM, Opie LH. Glucose and glycogen utilisation in myocardial ischemia-changes in metabolism and consequences for the myocyte. Mol Cell Biochem. 1998;180:3-26.
24. Schaefer S, Carr LJ, Prussel E, et al. Effects of glycogen depletion on ischemic injury in isolated rat hearts: insights into preconditioning. Am J Physiol. 1995;268:H935-H944.
25. Goodwin GW, Taegtmeyer H. Metabolic recovery of isolated working rat heart after brief global ischemia. Am J Physiol. 1994;267:H462-H470.
26. King LM, Opie LH. Does preconditioning act by glycogen depletion in the isolated rat heart? J Mol Cell Cardiol. 1996;28:2305-2321.
27. Allard MF, Emanuel PG, Russell JA, et al. Preischemic glycogen reduction or glycolytic inhibition improves postischemic recovery of hypertrophied rat hearts. Am J Physiol. 1994;267:H66-H74.
28. Barbosa V, Sievers RE, Zaugg CE, et al. Preconditioning ischemia time determines the degree of glycogen depletion and infarct size reduction in rat hearts. Am Heart J. 1996;131:224-230.
29. McNulty PH, Darling A, Whiting JM. Glycogen depletion contributes to ischemic preconditioning in the rat heart in vivo. Am J Physiol. 1996;271:H2283-H2289.
30. Monticello TM, Sargent CA, McGill JR, et al. Amelioration of ischemia/reperfusion injury in isolated rats hearts by the ATP-sensitive potassium channel opener BMS-180448. Cardiovasc Res. 1996;31:93-101.
31. Gan XT, Cook MA, Moffat MP, et al. Protective effects against hydrogen peroxide-induced toxicity by activators of the ATP-sensitive potassium channel in isolated rat hearts. J Mol Cell Cardiol. 1998;30:33-41.
32. Khogali SE, Pringle SD, Weryk BV, et al. Is glutamine beneficial in ischemic heart disease? Nutrition. 2002;18:123-126.
33. Engelman RM, Rousou JA, Flack JE III, et al. Reduction of infarct size by systemic amino acid supplementation during reperfusion. J Thorac Cardiovasc Surg. 1991;101:855-859.
34. Lazar HL, Buckberg GD, Manganaro AJ, et al. Reversal of ischemic damage with amino acid substrate enhancement during reperfusion. Surgery. 1980;88:702-709.
35. Thomassen A, Bagger JP, Nielsen TT, et al. Altered global myocardial substrate preference at rest and during pacing in coronary artery disease with stable angina pectoris. Am J Cardiol. 1988;62:686-693.
36. Thomassen AR, Nielsen TT, Bagger JP, et al. Myocardial exchanges of glutamate, alanine and citrate in controls and patients with coronary artery disease. Clin Sci (Lond). 1983;64:33-40.
37. Riddle MC. Editorial: sulfonylureas differ in effects on ischemic preconditioning-is it time to retire glyburide? J Clin Endocrinol Metab. 2003;88:528-530.
38. Kristiansen SB, Lofgren B, Stottrup NB, et al. Ischaemic preconditioning does not protect the heart in obese and lean animal models of type 2 diabetes. Diabetologia. 2004;47(10):1716-1721.
39. Tanira MO, Furman BL. The in vivo interaction between gliclazide and glibenclamide and insulin on glucose disposal in the rat. Pharmacol Res. 1999;39:349-356.
40. Vik-Mo H, Mjos OD, Neely JR, et al. Limitation of myocardial infarct size by metabolic interventions that reduce accumulation of fatty acid metabolites in ischemic myocardium. Am Heart J. 1986;111:1048-1054.
41. Libby P, Maroko PR, Braunwald E. The effect of hypoglycemia on myocardial ischemic injury during acute experimental coronary artery occlusion. Circulation. 1975;51:621-626.

ischemia; reperfusion; KATP channels; glycogen; glutamate

© 2005 Lippincott Williams & Wilkins, Inc.