Delayed Preconditioning Induced by Lipoteichoic Acid From B. Subtilis and S. Aureus Is Not Blocked by Administration of 5-Hydroxydecanoate : Shock

Secondary Logo

Journal Logo

Basic Science Studies

Delayed Preconditioning Induced by Lipoteichoic Acid From B. Subtilis and S. Aureus Is Not Blocked by Administration of 5-Hydroxydecanoate

Zacharowski, Kai*; Chatterjee, Prabal K.; Thiemermann, Christoph

Author Information
  • Free


Bacterial walls contain lipopolysaccharide (LPS), lipoteichoic acid (LTA), or peptidoglycan. Pretreatment of rats with low doses of LPS (from E. coli) or LTA (from S. aureus, a pathogenic gram-positive bacterium) for 16–24 h reduces myocardial infarct size caused by a subsequent period of myocardial ischemia-reperfusion. This phenomenon of enhanced tolerance to an ischemic insult has been termed delayed preconditioning (DP). The aim of this study was to investigate whether LTA from B. subtilis (a nonpathogenic gram-positive bacterium) induces DP when administered 16 h before left anterior descending coronary artery (LAD) occlusion-reperfusion in the rat. Furthermore, we investigated whether the specific mitochondrial KATP (mitoKATP) channel inhibitor 5-hydroxydecanoate (5-HD, 5 mg/kg) blocks DP afforded by LTA of both strains of bacteria. Male Wistar rats were subjected to LAD occlusion-reperfusion (25–120 min) and infarct size was determined. In rats pretreated with saline (1 mL/kg i.p.), LAD occlusion-reperfusion resulted in an infarct size of 58%. Pretreatment of animals with LTA (S. aureus, 1 mg/kg i.p.) or LTA (B. subtilis, 1 mg/kg i.p.) reduced infarct size by 22% or 33%, respectively. Administration of 5-HD 10 min before LAD occlusion-reperfusion did not abolish DP afforded by LTA from S. aureus or B. subtilis, respectively. These results imply that late (after 16 h) opening of the mitoKATP channel is not part of the signaling pathway of LTA-induced DP.


In classic ischemic preconditioning (IPC), brief periods of coronary artery occlusion-reperfusion, transiently (10–120 min) protects the myocardium against subsequent lethal ischemia-reperfusion injury (1). After dissipation of this acute protection, a second window of protection (2) or delayed preconditioning (DP) appears 12–24 h later, which lasts up to 72 h. In addition to reducing myocardial infarct size (2–5), DP enhances the resistance of the myocardium against myocardial stunning (6), arrhythmias (7), and post-ischemic endothelial dysfunction (8).

Several triggers induce pharmacological DP in the heart including wall fragments of gram-positive bacteria such as lipoteichoic acid (LTA) (5), wall fragments of gram-negative bacteria such as lipopolysaccharide (LPS or endotoxin) (4,9), the structurally related monophosphoryl lipid A (MLA) (10), or the novel glycolipid RC-552 (11,12). LPS, MLA, and RC-552 contain the lipid A moiety, which mediates many of the biological effects of LPS. Although RC-552 is less toxic than MLA (and MLA is many times less toxic than LPS), recent data from knockout mice has provided evidence that RC-552 is still an immunomodulator, which causes upregulation of the inducible nitric oxide synthase (iNOS) (12).

Gram-positive organisms, however, do not contain lipid A or LPS, which is the cell wall component of gram-negative bacteria responsible for the initiation of septic shock. Gram-positive bacteria such as S. epidermidis can also cause septic shock and multiple organ failure without causing endotoxemia (13), and endotoxin is not always found in the serum of patients with septic shock (14). The cell wall of gram-positive bacteria contains LTA and peptidoglycan (PepG), a large polymer, which provides stress resistance and shape-determining properties to bacterial cell walls. LTA is a macroamphiphile molecule, which is equivalent to LPS in gram-negative bacteria (15). The predominant type of LTA contains a 1,3-linked poly-(glycerophosphate) chain attached by a phosphodiester bond to a glycolipid or phosphatidyl-glycolipid, which is a characteristic membrane lipid of gram-positive bacteria (15). The lipid moiety on the LTA renders LTA amphiphilic and enables it to anchor to the cytoplasmic membrane by hydrophobic interaction. The glycolipids differ in structure among gram-positive bacteria, usually in a genus-specific manner, and the glycolipid moieties of LTA that are derived from them vary accordingly (15). S. aureus is a major cause of nosocomial infections and gram-positive septic shock (14), whereas B. subtilis is a nonpathogenic gram-positive bacterium (16,17). The molecular structures of LTA from S. aureus and B. subtilis are very similar, except that the glycosylation and alanine substitution of the poly-glycerophosphate backbone is higher in S. aureus (15). This substitution changes the chemical features of LTA. The wall fragment is more lipophilic and much more toxic in several different disease models compared with the LTA derived from B. subtilis.

Since the discovery in 1983 of the mitochondrial KATP (mitoKATP) channel in isolated pig ventricular myocytes (18), numerous studies have investigated the effects of drugs that open or close this channel in conditions associated with myocardial ischemia (for review see Refs. 19 and 20). Today, we know that mitoKATP channels are involved in the beneficial effects of IPC. Inhibitors of the mitoKATP channel, such as glibenclamide (inhibitor of sarcolemmal and mitochondrial KATP channels) or 5-hydroxydecanoate acid (5-HD, inhibitor of mitoKATP channels), abolish the cardioprotective effects of IPC, whereas openers of mitoKATP channels, such as diazoxide, aprikalim, or bimakalim, mimick the beneficial effects of IPC (for review see Ref. 20). Activation of transmembrane receptors, such as adenosine (21) or opioid (22), causes the opening of mitoKATP channels and cardioprotection. The mechanism by which opening of mitoKATP channels protects the myocardium against ischemic injury is not entirely clear.

Because it was shown that MLA produces a similar reduction in infarct size as IPC, it was hypothesized that the mitoKATP channel might be an important effector of IPC and/or DP. Therefore, by using glibenclamide and/or 5-HD it was shown that the cardioprotective effects of MLA were abolished in the late phase of preconditioning (23). In fact, MLA also induces iNOS with enhanced release of NO, which directly activates mitoKATP channels and may cause cardioprotection (24,25). There is also evidence that mitoKATP channels are involved in the delayed cardioprotective effect of adenosine A1 receptor activation (21). Most investigators used the specific mitoKATP channel inhibitor 5-HD (at a dose of 5 mg/kg i.v.) to study the role of mitoKATP channels in IPC and/or DP (21,26).

Currently, not much is known about DP induced by bacterial wall fragments in the heart (5). Therefore, we investigated the delayed cardioprotective effects of LTA derived from the nonpathogenic gram-positive bacterium B. subtilis in the rat in vivo. Furthermore, we studied whether DP afforded by LTA from nonpathogenic and pathogenic strains of gram-positive bacteria is mediated by late opening of mitoKATP channels.


Male Wistar rats (200–330g) were obtained from Tuck (Rayleigh, Essex, UK) and cared for according to AAALAC guidelines and Guide for the Care and Use of Laboratory Animals (Department of Health and Human Services, National Institutes of Health, Publication No. 86-23). Animals were housed for at least 3 days in a stress-free environment after transportation from the supplier. All procedures were conducted in accordance with the Home Office Guidance on the Operation of Animals (Scientific Procedures) Act 1986 published by HMSO, London.

Myocardial ischemia-reperfusion in the rat

Myocardial injury was caused by occlusion-reperfusion (25–120 min) of the left anterior descending coronary artery (LAD). Rats were randomly allocated into the groups described in Table 1 and injected IP either 16 h before 1) no occlusion of the LAD (sham) or 2) LAD occlusion-reperfusion (I-R). The technique used to produce LAD occlusion was identical to that described previously (4,5). Rats were anesthetized by using sodium thiopentone (120 mg/kg i.p.). The trachea was cannulated and artificial respiration was maintained by using a Harvard ventilator. The right carotid artery was cannulated to monitor mean arterial blood pressure (MAP) and heart rate (HR). Pressure rate index (PRI), a relative indicator of myocardial oxygen consumption (27), was calculated as the product of MAP and HR and expressed in mmHg/(min · 103). The right jugular vein was cannulated for the administration of drugs. The chest was opened by a left-side thoracotomy, the pericardium was incised, and an atraumatic needle and occluder were placed around the LAD. After completion of the surgical procedure, the animals were allowed to stabilize for 30 min before LAD ligation. After 25 min of acute myocardial ischemia, the occluder was released, allowing the reperfusion of the previously ischemic myocardium for 2 h. After re-occluding the LAD, Evans blue dye (1 mL of 2% wt/vol) was administered i.v. to distinguish between ischemic (area at risk [AR]) and nonischemic myocardium (area not at risk). Subsequently, the heart was cut into horizontal slices and then into small pieces. The AR was separated from the area not at risk and then incubated with p- nitro-blue tetrazolium (0.5 mg/mL, 20 min at 37°C) to distinguish between ischemic and infarcted tissue (28), whereas the area not at risk was incubated with saline. The AR and infarct size were calculated after weighing the respective tissue samples and expressed as percent of the AR.

Table 1:
Animal groups exposed to bacterial products followed by occlusion-reperfusion (25–120 min) of the left anterior descending coronary artery (LAD) or sham surgery


Unless otherwise stated, all compounds were obtained from Sigma Chemical Co. (St. Louis, MO). LTA was obtained by a phenolic extraction procedure from S. aureus or B. subtilis (29). Intraval (sodium thiopentone) was obtained from May & Baker Ltd.

Statistical analysis

Data are reported as means ± SEM of n observations. ANOVA followed by a Dunnett's post test was used to compare data. A value of P < 0.05 was considered statistically significant.


Effects of bacterial wall fragments on myocardial infarct size

The mean values for the AR were similar in all animal groups studied and ranged from 44 to 53% (P > 0.05, data not shown). In rats pretreated with saline, LAD occlusion-reperfusion (25–120 min) resulted in an infarct size of approximately 60% of the AR. Compared with saline, administration of LTA from S. aureus or B. subtilis 16 h before coronary artery ligation caused significant reductions in myocardial infarct size (P < 0.05;Fig. 1). Compared with LTA (both strains of bacteria) treatment alone, 5-HD did not inhibit the infarct size reduction afforded by LTA. Sham operation with saline, 5-HD, LTA (S. aureus), or LTA (B. subtilis) alone did not result in a significant degree of infarction in any of the animal groups studied (<3% of the AR, P > 0.05, data not shown).

Fig. 1:
Myocardial injury caused by occlusion-reperfusion (25 min-2 h) of the left anterior descending coronary artery (LAD). Rats received saline (1 mL/kg i.p.) or LTA from either S. aureus (1 mg/kg) or B. subtilis (1 mg/kg) 16 h before LAD occlusion-reperfusion (I-R). 5-hydroxydecanoate (5-HD, 5 mg/kg) was administered i.v. 10 min before I-R. Infarct size is expressed as percent of the area at risk (AR). Data are expressed as means ± SEM of n observations. ANOVA followed by a Dunnett's post test was used to compare data. * P < 0.05 compared with saline control.

Hemodynamic data from rats subjected to myocardial ischemia-reperfusion

Hemodynamic data, e.g., MAP, HR, and PRI measured during the course of the experiments were similar in all groups studied (P > 0.05;Table 2). In sham-operated rats (no LAD occlusion), injection of either saline, 5-HD, LTA (S. aureus), or LTA (B. subtilis) did not cause any significant effects on MAP, HR, or PRI (P > 0.05, data not shown). In rats subjected to LAD occlusion-reperfusion, which were subjected to either saline, 5-HD, LTA (S. aureus) or LTA (B. subtilis) treatment, mean values for MAP and PRI fell throughout the experiment (P < 0.05;Table 2).

Table 2:
Mean arterial blood pressure (MAP), heart rate (HR), and pressure rate index (PRI) measured during myocardial ischemia-reperfusion


This study shows for the first time that pretreatment (16 h before LAD occlusion-reperfusion) with LTA from the nonpathogenic gram-positive bacterium B. subtilis protects the heart against a subsequent period of regional ischemia-reperfusion. We used LTA from the pathogenic gram-positive bacterium S. aureus (1 mg/kg) as a recognized control with which to induce DP (5). Recently, we showed that the effects of LTA from S. aureus are time dependent and accompanied by a reduction of cardiac troponin T release into the plasma and a reduction in the histological signs of necrosis in this model of myocardial ischemia-reperfusion (5). LTA from B. subtilis (1 mg/kg i.p.) reduced myocardial infarct size to the same degree as LTA from S. aureus (∼60% reduction in infarct size). B. subtilis is a less pathogenic gram-positive bacterium than S. aureus and, therefore, may offer a new therapeutic approach to exploit DP.

Clearly, in all groups studied, there were no significant differences in body weight, heart weight, AR, or hemodynamic parameters such as MAP or HR, suggesting that the beneficial effects of the different bacterial wall fragments were not related to differences in the amount of myocardial tissue sampled nor to changes in myocardial oxygen demand. What, then, are the mechanisms by which bacterial wall fragments induce DP in the rat heart in vivo? We and others recently reported that different pathways, e.g., NO (30–32), iNOS (33), antioxidative enzymes (5), or protein kinase C (34) are involved in DP. For instance, LPS causes a release of cytokines such as tumor necrosis factor (TNFα) or interleukin (IL-1β) and, hence, an upregulation of the Mn-SOD gene (5). In contrast, the same study showed that LTA from S. aurues was not sufficient to induce the Mn-SOD gene.

However, in this study we investigated whether the mitoKATP channel is an important end effector in DP afforded by LTA from S. aureus or B. subtilis. Opening of mitoKATP channels is protective in ischemic heart, and the mechanism of cardioprotection is under active investigation in several laboratories (20). There is evidence that mitoKATP channels are involved in the mechanism of IPC (35,36). Furthermore, the mitoKATP channel has also been suggested as a possible end effector in the mechanism of DP afforded by adenosine A1-receptor activation (21), δ1-opioid receptor stimulation (37), or heat stress (26). Mei et al. (23) showed that the delayed cardioprotective effects of MLA, which contains the same moiety of lipid A as LPS, are abolished by blocking the mitoKATP channel with 5-HD. These findings encouraged us to investigate whether DP afforded by LTA from S. aureus or LTA from B. subtilis is also mediated by the mitoKATP channel.

It is surprising that late administration of 5-HD did not affect the delayed cardioprotective effects of LTA from either strain of bacteria. The dose (5 mg/kg i.v.) and administration regimen (10 min before LAD ischemia-reperfusion) of 5-HD used in this study was previously shown to abolish the cardioprotective effects of different prostanoids in identical models of coronary artery occlusion-reperfusion (38–40). Similarly, others have shown that 5-HD (5–10 mg/kg i.v.) or glibenclamide administered (5–20 min) before coronary artery occlusion blocks DP afforded by a range of other treatments (21,23,41,42). For these data and other studies, many investigators have used 5-HD only as a selective blocker of mitoKATP channels. Although our laboratory has extensive experience with 5-HD, we cannot exclude in this study that 5-HD did not reach the mitoKATP channel in vivo for some reasons. In conclusion, the inability of 5-HD to abolish DP afforded by LTA from either S. aureus or B. subtilis does not support a role for the mitoKATP channel as the end effector involved.


KZ is supported by the Deutsche Herzstiftung.


1. Murry CE, Jennings RB, Reimer KA: Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136, 1986.
2. Baxter GF, Marber MS, Patel VC, Yellon DM: Adenosine receptor involvement in a delayed phase of myocardial protection 24 hours after ischemic preconditioning. Circulation 90:2993–3000, 1994.
3. Marber MS, Latchman DS, Walker JM, Yellon DM: Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation 88:1264–1272, 1993.
4. Zacharowski K, Otto M, Hafner G, Chatterjee PK, Thiemermann C: Endotoxin induces a second window of protection in the rat heart as determined by using p-nitro-blue tetrazolium staining, cardiac troponin T release, and histology. Arterioscler Thromb Vasc Biol 19:2276–2280, 1999.
5. Zacharowski K, Frank S, Otto M, Chatterjee PK, Cuzzocrea S, Hafner G, Pfeilschifter J, Thiemermann C: Lipoteichoic acid induces delayed protection in the rat heart: a comparison with endotoxin. Arterioscler Thromb Vasc Biol 20:1521–1528, 2000.
6. Tang XL, Qiu Y, Park SW, Sun JZ, Kalya A, Bolli R: Time course of late preconditioning against myocardial stunning in conscious pigs. Circ Res 79:424–434, 1996.
7. Vegh A, Papp JG, Parratt JR: Prevention by dexamethasone of the marked antiarrhythmic effects of preconditioning induced 20 h after rapid cardiac pacing. Br J Pharmacol 113:1081–1082, 1994.
8. Kaeffer N, Richard V, Thuillez C: Delayed coronary endothelial protection 24 hours after preconditioning: role of free radicals. Circulation 96:2311–2316, 1997.
9. Brown JM, Grosso MA, Terada LS, Whitman GJ, Banerjee A, White CW, Harken AH, Repine JE: Endotoxin pretreatment increases endogenous myocardial catalase activity and decreases ischemia-reperfusion injury of isolated rat hearts. Proc Natl Acad Sci USA 86:2516–2520, 1989.
10. Yao Z, Auchampach JA, Pieper GM, Gross GJ: Cardioprotective effects of monophosphoryl lipid A, a novel endotoxin analogue, in the dog. Cardiovasc Res 27:832–838, 1993.
11. Elliott GT, Sowell CG, Walker EB, Weber PA, Moore J, Gross GJ: The novel glycolipid RC-552 attenuates myocardial stunning and reduces infarct size in dogs. J Mol Cell Cardiol 32:1327–1339, 2000.
12. Xi L, Salloum F, Tekin D, Jarrett NC, Kukreja RC: Glycolipid RC-552 induces delayed preconditioning-like effect via iNOS-dependent pathway in mice. Am J Physiol 277:H2418–H2424, 1999.
13. Wakabayashi G, Gelfand JA, Jung WK, Connolly RJ, Burke JF, Dinarello CA: Staphylococcus epidermidis induces complement activation, tumor necrosis factor and interleukin-1, a shock-like state and tissue injury in rabbits without endotoxemia: comparison to Escherichia coli. J Clin Invest 87:1925–1935, 1991.
14. Bone RC: Gram-positive organisms and sepsis. Arch Intern Med 154:26–34, 1994.
15. Fischer W: Physiology of lipoteichoic acids in bacteria. Adv Microb Physiol 29:233–302, 1988.
16. Himanen JP, Pyhala L, Olander RM, Merimskaya O, Kuzina T, Lysyuk O, Pronin A, Sanin A, Helander IM, Sarvas M: Biological activities of lipoteichoic acid and peptidoglycan-teichoic acid of Bacillus subtilis 168 (Marburg). J Gen Microbiol 139:2659–2665, 1993.
17. Himanen JP, Sarvas M, Helander IM: Assessment of non-protein impurities in potential vaccine proteins produced by Bacillus subtilis. Vaccine 11:970–973, 1993.
18. Noma A: ATP-regulated K+ channels in cardiac muscle. Nature 305:147–148, 1983.
19. Gross GJ, Kersten JR, Warltier DC: Mechanisms of postischemic contractile dysfunction. Ann Thorac Surg 68:1898–1904, 1999.
20. Grover GJ, Garlid KD: ATP-Sensitive potassium channels: a review of their cardioprotective pharmacology. J Mol Cell Cardiol 32:677–695, 2000.
21. Baxter GF, Yellon DM: ATP-sensitive K+ channels mediate the delayed cardioprotective effect of adenosine A1 receptor activation. J Mol Cell Cardiol 31:981–989, 1999.
22. Liang BT, Gross GJ: Direct preconditioning of cardiac myocytes via opioid receptors and KATP channels. Circ Res 84:1396–1400, 1999.
23. Mei DA, Elliott GT, Gross GJ: KATP channels mediate late preconditioning against infarction produced by monophosphoryl lipid A. Am J Physiol 271:H2723–H2729, 1996.
24. Sasaki N, Sato T, Ohler A, O'Rourke B, Marban E: Activation of mitochondrial ATP-dependent potassium channels by nitric oxide. Circulation 101:439–445, 2000.
25. Xi L, Jarrett NC, Hess ML, Kukreja RC: Essential role of inducible nitric oxide synthase in monophosphoryl lipid A-induced late cardioprotection: evidence from pharmacological inhibition and gene knockout mice. Circulation 99:2157–2163, 1999.
26. Hoag JB, Qian YZ, Nayeem MA, D'Angelo M, Kukreja RC: ATP-sensitive potassium channel mediates delayed ischemic protection by heat stress in rabbit heart. Am J Physiol 273:H2458–H2464, 1997.
27. Baller D, Bretschneider HJ, Hellige G: A critical look at currently used indirect indices of myocardial oxygen consumption. Basic Res Cardiol 76:163–181, 1981.
28. Weisman HF, Bartow T, Leppo MK, Marsh Jr, HC, Carson GR, Concino MF, Boyle MP, Roux KH, Weisfeldt ML, Fearon DT: Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis. Science 249:146–151, 1990.
29. Fischer W, Koch HU, Haas R: Improved preparation of lipoteichoic acids. Eur J Biochem 133:523–530, 1983.
30. Qiu Y, Rizvi A, Tang XL, Manchikalapudi S, Takano H, Jadoon AK, Wu WJ, Bolli R: Nitric oxide triggers late preconditioning against myocardial infarction in conscious rabbits. Am J Physiol 273:H2931–H2936, 1997.
31. Bolli R, Manchikalapudi S, Tang XL, Takano H, Qiu Y, Guo Y, Zhang Q, Jadoon AK: The protective effect of late preconditioning against myocardial stunning in conscious rabbits is mediated by nitric oxide synthase: evidence that nitric oxide acts both as a trigger and as a mediator of the late phase of ischemic preconditioning. Circ Res 81:1094–1107, 1997.
32. Takano H, Tang XL, Qiu Y, Guo Y, French BA, Bolli R: Nitric oxide donors induce late preconditioning against myocardial stunning and infarction in conscious rabbits via an antioxidant-sensitive mechanism. Circ Res 83:73–84, 1998.
33. Guo Y, Jones WK, Xuan YT, Tang XL, Bao W, Wu WJ, Han H, Laubach VE, Ping P, Yang Z, Qiu Y, Bolli R: The late phase of ischemic preconditioning is abrogated by targeted disruption of the inducible NO synthase gene. Proc Natl Acad Sci USA 96:11507–11512, 1999.
34. Yamashita N, Nishida M, Hoshida S, Kuzuya T, Hori M, Taniguchi N, Kamada T, Tada M: Induction of manganese superoxide dismutase in rat cardiac myocytes increases tolerance to hypoxia 24 hours after preconditioning. J Clin Invest 94:2193–2199, 1994.
35. Grover GJ: Pharmacology of ATP-sensitive potassium channel (KATP) openers in models of myocardial ischemia and reperfusion. Can J Physiol Pharmacol 75:309–315, 1997.
36. Garlid KD, Paucek P, Yarov-Yarovoy V, Murray HN, Darbenzio RB, D'Alonzo AJ, Lodge NJ, Smith MA, Grover GJ: Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels: possible mechanism of cardioprotection. Circ Res 81:1072–1082, 1997.
37. Fryer RM, Hsu AK, Eells JT, Nagase H, Gross GJ: Opioid-induced second window of cardioprotection: potential role of mitochondrial KATP channels. Circ Res 84:846–851, 1999.
38. Zacharowski K, Olbrich A, Piper J, Hafner G, Kondo K, Thiemermann C: Selective activation of the prostanoid EP(3) receptor reduces myocardial infarct size in rodents. Arterioscler Thromb Vasc Biol 19:2141–2147, 1999.
39. Zacharowski K, Olbrich A, Otto M, Hafner G, Thiemermann C: Effects of the prostanoid EP3-receptor agonists M&B 28767 and GR 63799X on infarct size caused by regional myocardial ischaemia in the anaesthetized rat. Br J Pharmacol 126:849–858, 1999.
40. Hide EJ, Thiemermann C: Sulprostone-induced reduction of myocardial infarct size in the rabbit by activation of ATP-sensitive potassium channels. Br J Pharmacol 118:1409–1414, 1996.
41. Takashi E, Wang Y, Ashraf M: Activation of mitochondrial K(ATP) channel elicits late preconditioning against myocardial infarction via protein kinase C signaling pathway. Circ Res 85:1146–1153, 1999.
42. Pell TJ, Yellon DM, Goodwin RW, Baxter GF: Myocardial ischemic tolerance following heat stress is abolished by ATP-sensitive potassium channel blockade. Cardiovasc Drugs Ther 11:679–686, 1997.

LTA; mitochondrial KATP channel; myocardial infarct size; 5-HD; rat; bacteria

© 2002 Lippincott Williams & Wilkins, Inc.