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1 Department of Integrative Physiology, University of Colorado Cardiovascular Institute, University of Colorado at Boulder, Boulder, CO 80309, USA
2 Division of Endocrinology, Department of Medicine, University of Colorado at Denver Health Sciences Center and Denver VA Medical Center, Denver, CO 80112, USA
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Abstract |
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(Received 1 August 2005;
accepted after revision 10 October 2005;
first published online 13 October 2005)
Corresponding author R. L. Moore: Department of Integrative Physiology, 202D Carlson Gymnasium, Campus Box 354, Boulder, CO 80309 USA. Email: russell.moore{at}colorado.edu
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Introduction |
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A single bout of exercise training has been shown to protect the myocardium against ischaemia–reperfusion (I–R) damage in a biphasic manner (Yamashita et al. 1999) consistent in amplitude and temporal onset as that afforded by other PC stimuli (Bolli, 2000; Yellon & Downey, 2003). Subsequent to the findings of Yamashita et al. (1999), our laboratory and others have demonstrated that the delayed phase of PC following exercise can be sustained after days (Yamashita et al. 2001; Hamilton et al. 2003; Brown et al. 2005) or months (Brown et al. 2003) of training. Other than chronic moderate ethanol consumption (Kehl et al. 2003), exercise training is the only stimulus demonstrated to sustain myocardial protection against infarction over such an extended period of time. This finding continues to be extremely relevant from a clinical standpoint, as myocardial infarction affects over 1 million Americans annually (National Health and Nutrition Examination Survey III, 2000), and size of infarction correlates inversely with chance of both short-term (Miller et al. 1995) and long-term survival (Herlitz et al. 1988).
Our previous work indicated that 20 weeks of exercise training significantly reduced myocardial infarct size after ex vivo I–R 24–36 h after the last bout of exercise (Brown et al. 2003). We postulated that improved vascular reactivity and increased manganese superoxide dismutase protein expression were responsible for the infarct sparing that was observed following exercise, although subsequent experiments have demonstrated that protection from infarction can be accomplished in the absence of improvements in these variables following short-term exercise (Brown et al. 2005). While the tissue-salvaging effect of exercise seems evident, the terminal mechanism(s) evoking this protective phenotype remain(s) to be elucidated.
The role of cardiac ATP-sensitive potassium (KATP) channels in preconditioning has received much attention over the last 10 years, with investigations exploring the protective role of both the sarcolemmal (sarcKATP) and the mitochondrial (mitoKATP) isoforms of this channel (for review see O'Rourke, 2000; Baxter & Ferdinandy, 2001; Yellon & Downey, 2003; O'Rourke, 2004). Several investigations have implicated a distal role for the KATP channel in delayed protection afforded by a variety of stimuli (Bolli, 2000); however, only one study has examined the role of the KATP channels in exercise-induced protection from infarction. Data from our laboratory indicated that short-term exercise led to reduced infarct size following I–R, with the delayed protection correlating closely with increased expression of the sarcKATP channel in both males and females (Brown et al. 2005). Although we observed a close relationship between sarcKATP protein expression and protection from I–R injury, pharmacological blockade of this channel population to confirm the postulated channel-mediated cardioprotection was not performed in our previous work (Brown et al. 2005). In the present study, we hypothesized that the increased sarcKATP channel expression would be sustained following months of training, and that pharmacological blockade of this channel population would abolish the protection from infarction afforded by training.
There is also evidence from the literature that delayed PC induced by a variety of stimuli is comprehensively abolished by 5-hydroxydecanoic acid (5HD), a putative mitochondrial ATP-sensitive K+ (mitoKATP) channel antagonist, administered minutes before index ischaemia (Pell et al. 1997; Baxter & Yellon, 1999; Bernardo et al. 1999, ; Fryer et al. 1999; Ockaili et al. 2001, 2002). These experiments provide compelling evidence for a role of the mitoKATP channel as a distal mediator of protection from infarction. As such, our interest in exercise-induced PC led us to hypothesize that mitoKATP channels may also be integrally involved in delayed protection following exercise training, and that administration of 5HD would abrogate training-induced reductions in myocardial infarct size following I–R. Therefore, the present study sought to determine if blockade of either the sarcolemmal and/or mitochondrial isoforms of the KATP channel abolished the protection afforded by chronic exercise training.
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Methods |
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Adult female Sprague–Dawley rats (Harlan; n= 103 total animals) were used in the study. Experiments were conducted with prior approval from the Institutional Animal Care and Use Committee at the University of Colorado at Boulder, and in accordance with guidelines established by the American Physiological Society.
I–R protocol
Animals were trained for 
12 weeks, as previously described (Brown et al. 2003). At the time of death, animals were anaesthetized with sodium pentobarbital (35 mg kg–1; I.P. injection) and hearts were excised and very rapidly hung by the aorta to a cannula of a modified Langendorff apparatus. Both left and right adrenal glands were removed and weighed, and plantaris muscle was dissected for analysis of citrate synthase activity (Brown et al. 2003). Retrograde perfusion was initiated using an established buffer (Brown et al. 2003, 2005), and a 3-F pressure-transducing catheter (Millar) was simultaneously inserted into the left ventricle (LV) via the aortic valve for the collection of left-ventricular developed pressure (LVDP) waveforms as previously described (Brown et al. 2003, 2005). All chemicals were obtained from Sigma-Aldrich unless otherwise noted. After a 10 min equilibration period, baseline measurements of LVDP were obtained. Following the baseline measurements, hearts from trained and sedentary animals were divided further into a total of six groups (animal numbers represent numbers used in data analysis): hearts to be perfused for the duration of the protocol with control buffer containing no KATP channel blocker (Sed and Tr; n= 19 Sed and 15 Tr), hearts to be perfused for the duration of the protocol with sarcolemmal KATP blocker (30 µM HMR 1098; a gift from Dr Heinz Gögelein, Aventis Pharma, Deutschland) in the perfusate (SedHMR and TrHMR; n= 9 each), and hearts perfused with mitochondrial KATP blocker (100 µM 5HD) for the duration of the protocol (Sed5HD and Tr5HD; n= 14 Sed5HD 13 Tr5HD). The concentrations of HMR 1098 and 5HD were previously used in both Langendorff-perfused rat heart (Chen et al. 2003; D'Souza et al. 2003; Kristiansen et al. 2005) and single-cell experiments (Light et al. 2001), and this concentration of 5HD was effective in abolishing the infarct-sparing effects of classic ischaemic preconditioning. A separate group of hearts underwent three bouts of 5 min alternating regional I–R before index ischaemia, and the reduction in infarct size following ischaemic preconditioning (5.4 ± 2.6% of the zone at risk) was abolished when hearts received 5HD during the ischaemic preconditioning (IPC) stimulus (22.6 ± 2.7% of the zone at risk; P < 0.05). LVDP measurements were taken after five additional minutes of exposure to KATP channel blockers (or control buffer) before regional ischaemia was initiated. The I–R protocol, infarct size assessment, and haemodynamic measurement time points were identical to methods previously described by our laboratory (Brown et al. 2003, 2005).
Non-ischaemic time controls
We subjected a separate group of hearts to the 3 h perfusion protocol in the absence of ischaemia to determine the effect of the crystalloid perfusate and pharmacological agents on haemodynamic parameters and infarct size.
Western blotting
A separate group of Tr and Sed animals (n= 9 Tr and 9 Sed) were anaesthetized and hearts were excised. LV free wall was isolated and rinsed in saline (4°C), and homogenized and probed for Kir6.2, SUR2a, Akt, p-Akt, glycogen synthase kinase (GSK)-3ß, and p-GSK-3ß as previously described (Brown et al. 2003, 2005; and Watson et al. manuscript currently in review).
Intracellular Ca2+ content
A separate group of hearts from Tr and Sed animals (n= 36 total) were exposed to a truncated I–R protocol (30 min each) in the presence or absence of the experimental drugs, and subsequently analysed for intracellular Ca2+ content as previously described (Alto & Dhalla, 1979). This abbreviated I–R protocol did not elicit measurable infarct sizes in experimental hearts (data not shown).
Exclusion criteria
Data were omitted from analysis if one of the following criteria were met: unclear resolution of heart slice images precluded analysis of infarction (n= 1); coronary flow did not decrease at the onset of ischaemia or increase at the onset of reperfusion (indicative of inefficient suture placement; n= 14); or hearts did not complete the I–R protocol due to excessive fibrillation or technical difficulty (n= 8). One animal died of natural causes during the course of the study.
Statistical analyses
Data are presented as means ± standard error. All statistical analyses were performed using SPSS Software, and 
-level was predetermined to be P < 0.05. A priori confirmatory comparisons of infarct size and LVDP between Sed and Tr groups were performed with a two-tailed Student's t test. All other infarct size comparisons were performed with a 2 x 3 ANOVA (training group x drug). The LV, body, spleen and adrenal gland weights, and citrate synthase activity data, were pooled according to training status and analysed with a two-tailed Student's t test (all Tr versus all Sed). A repeated-measures ANOVA was employed for analysis of LVDP during ischaemia and again following the onset of reperfusion. Main effects of drug were analysed at each time point using a one-way ANOVA with a Bonferroni correction for post hoc comparisons.
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Results |
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Morphological data are presented in Table 1. Rats in the Tr group had significantly greater body weights, LV weights, and plantaris muscle citrate synthase activity than Sed animals (P < 0.05). A resting bradycardia was observed following chronic training, with Tr animals having a lower resting heart rate than Sed prior to the onset of ischaemia. There were no differences in adrenal weights between the groups, and there was a subtle increase in spleen weight with training, indicating that the exercise protocol did not elicit classic markers of a systemic stress response (Selye, 1998; Moraska et al. 2000).
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Infarct sizes and representative images are presented in Fig. 1. The mean zone at risk (ZAR) for each experimental group ranged from 42 to 46% of the LV, with no between-group differences present (P= NS). Chronic exercise training led to a significant reduction in infarct size, with the Tr and Sed animals having infarct sizes of 35.4 ± 2.3 and 44.7 ± 3.0, respectively (P < 0.01, Sed versus Tr). Exercise-induced reductions in infarct size persisted in the presence of 5HD, with Tr5HD and Sed5HD groups having infarct sizes of 30.0 ± 3.4 and 38.0 ± 2.6, respectively (P < 0.05). Importantly, the addition of HMR 1098 abolished the infarct size difference between Tr and Sed, with the TrHMR hearts showing a trend for increased infarct size versus SedHMR (P= 0.088). The presence of HMR 1098 led to significant increases in infarct size in both the TrHMR (71.2 ± 3.3%) and SedHMR (64.0 ± 2.4%) groups when compared with respective controls (P < 0.001), with the magnitude of the increase from control being much greater in the TrHMR when compared to SedHMR (100% increase in infarct size in Tr versus 43% increase in Sed). Administration of either drug alone did not induce significant infarction, with non-ischaemic time controls having infarct sizes of 2.5 ± 0.6, 2.4 ± 0.4 and 3.7 ± 1.5% of the ZAR for the control, 5HD and HMR groups, respectively. There were no differences in infarct size between the non-ischaemic time-control groups.
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Protein expression of KATP channel subunits is presented in Fig. 2. Expression of the pore-forming subunit Kir6.2 increased by 58% in the Tr groups (P < 0.05; Fig. 2A). Protein content of the sulphonylurea receptor (SUR) subunit was increased by 75% in hearts of animals that were trained (P < 0.05; Fig. 2B).
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LVDP data are presented in Fig. 3. Hearts from Tr animals maintained LVDP better than Sed animals from 30 min into ischaemia through the first 5 min of reperfusion (Fig. 3). A significant main effect of drug was observed both during ischaemia and through the course of reperfusion. LVDP dropped quickly and significantly in hearts exposed to 5HD when compared with all other groups, with a significant difference at 15 min of ischaemia that lasted throughout the protocol (P < 0.05). As there were no differences in systolic pressure between groups from baseline (–5 min) throughout the duration of the protocol, all changes in LVDP can be explained by significant increases in LV minimum pressure generation (Fig. 4A).
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Intracellular Ca2+ content data are presented in Fig. 4B. A significant effect of drug on intracellular Ca2+ content was observed, with no effect of training. Accordingly, data were pooled as a function of perfused drug for presentational clarity. There was no difference in intracellular Ca2+ content between hearts exposed to control buffer (2.1 ± 0.1 µmol Ca2+ (g dry weight)–1) or HMR 1098 (2.0 ± 0.1 µmol Ca2+ (g dry weight)–1). The presence of 5HD in the perfusate caused a significant increase in intracellular Ca2+ content following I–R (4.3 ± 0.6 µmol Ca2+ (g dry weight)–1); P < 0.05 when compared with control and HMR 1098).
Akt and GSK-3ß phosphorylation
pAkt/Akt and pGSK-3ß/GSK-3ß data are presented in Fig. 6A and B, respectively. There were no differences in content or phosphorylation of either Akt or GSK-3ß between Tr and Sed hearts (P= NS).
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Discussion |
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This study was conducted to determine the influence of KATP channels on exercise-induced reductions in myocardial infarct size and improvements in haemodynamic variables. Our previous work (Brown et al. 2003) indicated that 20 weeks of chronic exercise training caused a 25% reduction in myocardial infarct size in female rats. The present findings corroborate our previous observation, with the Tr animals having a 21% reduction in myocardial infarct size when compared to hearts from Sed animals (Fig. 1).
While the terminal mechanisms underlying exercise induced protection from infarction are unidentified, we speculated that the involvement of myocardial KATP channels was central to the protective phenotype. MitoKATP blockade with 5HD minutes before ischaemia has been shown to negate the delayed phase of preconditioning afforded by a number of stimuli (see Table 2). Since exercise-induced PC has been proposed to share common pathways with other triggers of delayed PC (Bolli, 2000), we hypothesized that the cellular pathway(s) would be similar (i.e. also involve the activity of the mitoKATP channel). In the present study, 5HD was effective in reversing the infarct-sparing effect of ‘classic’ ischaemic preconditioning (see Methods); however, it did not abolish acquired protection from infarction in the exercised animals (Fig. 1). Training-induced infarct sparing was conserved in the presence of 5HD, indicating that unlike all other known stimuli of delayed PC, protection mediated by chronic exercise cannot be ascribed to mitoKATP channel activity. This finding is novel insofar as it is the first demonstration that delayed preconditioning can be conserved in the presence of mitoKATP blockade, and may reflect a novel mechanism for delayed cardioprotection that is also sustainable over time.
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A cytoprotective role for sarcKATP channels is confirmed by pharmacological blockade of the channels with HMR 1098, a specific sarcKATP channel antagonist (Gogelein et al. 1998). Administration of HMR 1098 during the I–R protocol completely abolished training-induced reductions in infarct size and led to dramatic increases in infarcted area regardless of training status (Fig. 1). Infarct size in Tr animals doubled with sarcKATP blockade and increased by 43% in Sed animals, implicating an important role for sarcKATP channel opening in myocardial protection during I–R. While few other studies have examined the role of sarcKATP channels in mediating delayed protection from infarction, these channels cannot be discounted in many protocols of acquired protection where glibenclamide, a non-specific channel antagonist, was administered minutes before the onset of ischaemia (see Table 2) and abolished the prophylactic phenotype. Furthermore, as pharmacological agents may have non-specific effects, it is important to note that the findings of this study are consistent with observations from genetic knockout studies where Kir6.2-deficient mice lacking intact sarcKATP channels display severe intolerance and myocardial injury following the metabolic stress of chronic exercise training (Zingman et al. 2002; Kane et al. 2004, 2005).
To the best of our knowledge, chronic ethanol ingestion is the only other stimulus besides exercise training that provides sustainable (over months) protection against myocardial I–R injury (Pagel et al. 2000, 2002). Interestingly, a cardioprotective role of the sarcKATP channel was also confirmed in previous experiments using both specific (Pagel et al. 2002) and non-specific (Pagel et al. 2000) sarcKATP channel blockers to eliminate the protection afforded by ethanol consumption. In order to further elucidate mechanistic homology between sustainable protection afforded by ethanol and exercise training, we examined the constitutive phosphorylation of Akt and its substrate GSK-3ß. While significant increases in basal Akt and GSK-3ß activity have been observed following months of ethanol consumption (Zhou et al. 2002), there was no difference in Akt or GSK-3ß expression or phosphorylation following exercise training (Fig. 6). These data indicate that both forms of sustainable protection rely on the activity of sarcKATP channels, and that other potential mediators such as activated Akt (Zhou et al. 2002) or mitoKATP channel activity (Pagel et al. 2002) may be model specific and are not obligatory for sustainable protection per se.
Although the precise mechanism by which a training-induced increase in sarcKATP channels would lead to tissue salvage is not known, several possibilities exist. The increased channel expression may improve the metabolic-sensing capability of the cell. During times of metabolic stress (i.e. ischaemia), increased channel number may help the cell better maintain energetic status. Genetic knockout of Kir6.2 has previously been shown to hinder preconditioning-mediated protection of myocardial bioenergetics following I–R (Gumina et al. 2003; Alekseev et al. 2005). Furthermore, the physical association of several enzymes, including adenlyate kinase (Carrasco et al. 2001), creatine kinase (Crawford et al. 2002b), glyceraldehyde 3-phosphate dehydrogenase (Jovanovic et al. 2005), and lactate dehydrogenase (Crawford et al. 2002a), with sarcKATP channels has been previously observed. Increased channel–enzyme complexes may provide increased sensitivity for maintaining cellular energy status, with improved communication between the cell surface and the mitochondria through the creatine kinase signalling system (Dzeja & Terzic, 1998; Sasaki et al. 2001; Alekseev et al. 2005). An increase in channel expression following exercise (Brown et al. 2005; herein) may be related to better preservation of ATP levels during ischaemia (Jew & Moore, 2001) as well as prolonged time course for KATP current expression (Jew & Moore, 2002) in hearts from trained animals, both of which were previously observed by our laboratory. Another possibility is that the sarcKATP channel may be a part of a pro-survival kinase pathway transduction system that decreases the likelihood of the permeability transition pore opening and the onset of apoptosis (Hausenloy & Yellon, 2004; Hausenloy et al. 2004, 2005). Obviously, the precise role of such protective mechanisms in exercise-induced increases in sarcKATP channels and protection from infarction warrants further investigation.
LVDP
Our observation of training-induced preservation of mechanical pressure development during I–R (Fig. 3) confirms findings from a well-documented body of literature (Scheuer & Stezoski, 1972; Bowles et al. 1992; Powers et al. 1998; Moore & Palmer, 1999; Brown et al. 2003; Hamilton et al. 2003), although the precise mechanisms involved in this phenomenon are not known. Another novel aspect of the present study was that training-induced improvements in LVDP (Fig. 3) were completely abolished with 5HD, implicating a potential role of the mitoKATP channel as a mediator of sustained ischaemic myocardial function in tissue outside of the ZAR in trained animals (as ischaemic tissue generates diminutive amounts of mechanical force). Since the molecular identity of the myocardial mitoKATP channel is not known, there could be a number of hypothetical mechanisms explaining how exercise-induced sustenance of LVDP involves the activity of this channel. Recent evidence indicates that the mitoKATP channel may belong to a multiprotein mitochondrial complex containing succinate dehydrogenase (Ardehali et al. 2004). Training-induced alterations in mitochondrial energy metabolism may underlie the improved ischaemic function that was abolished by 5HD. Obviously a scenario such as this is purely speculative at present, and requires much more investigation into both the basic molecular identity of this channel, as well as channel involvement in training-induced protection from mechanical dysfunction during I–R.
The fact that 5HD diminished LVDP so profoundly across groups warrants comment. The decrease in LVDP with the addition of 5HD can be explained by our observation that this drug significantly increased LV minimum pressure generation whether hearts were exposed to ischaemia (Fig. 4A) or not (Fig. 5). A plausible explanation for this drug-related impaired myocardial relaxation is that intracellular Ca2+ content was significantly increased only in hearts exposed to 5HD during I–R (Fig. 4B). Despite the observation that 5HD completely abolished LVDP from 15 min of ischaemia throughout the duration of the protocol, the drug did not influence infarct size or abolish training-induced protection against infarction. One possible explanation is as follows: during ischaemia, when a significant part of the LV (approx 45%) becomes ischaemic, the part of the heart receiving flow generates the vast majority of pressure. Although the presence of 5HD did not influence the tissue in the ZAR (since training-induced reductions in infarct size were maintained with 5HD), it drastically reduced the pressure-generating capability of the non-ischaemic region of the heart (as well as in non-ischaemic hearts; Fig. 5). Notwithstanding non-specific targets of 5HD (addressed below), these findings may implicate a role of mitoKATP channels in normoxic excitation–contraction coupling.
The observation that 5HD did not uniformly abrogate both training-induced infarct sparing and protection from mechanical dysfunction is consistent with results from other laboratories (Takano et al. 2000). Similarly, blockade of sarcolemmal KATP channels did not influence pressure generation in tissue outside of the ZAR, but had a very deleterious effect on tissue survival in the ischaemic region. Collectively, these data indicate that separate pathways may be involved in infarct sparing versus protection from stunning in delayed cardioprotection as suggested by Bolli (2000). Also of interest was our finding that 5HD caused a twofold increase in intracellular Ca2+ content that correlated with impaired relaxation, yet in spite of these changes in intracellular Ca2+ infarct size was not affected by 5HD. Furthermore, HMR 1098 in the perfusate caused marked increases in infarct size without affecting cellular Ca2+ homeostasis. While both Kir6.2-genetic-knockout (Zingman et al. 2002) and channel-blockade (Light et al. 2001; Ranki et al. 2002) studies propose that sarcKATP channels are obligatory for protection against I–R-induced Ca2+ overload and subsequent tissue injury, previous work has shown that increases in intracellular Ca2+ alone are not sufficient to cause irreversible tissue damage (Wagenknecht et al. 1994). It is likely that confounding factors such as decreased pH or adenine nucleotide depletion, as well as intracellular Ca2+ compartmentation, may explain the tissue damage that we observed with sarcKATP blockade in the absence of elevated intracellular Ca2+ content.
Potential limitations
One putative limitation of the current study involves the use of 5HD to block mitoKATP channels. While 5HD has been extensively used over the last 
10 years as a mitochondria-specific KATP channel blocker (see reviews O'Rourke, 2000, 2004; Yellon & Downey, 2003), recent evidence questions the pharmacological specificity of this channel antagonist (Hanley et al. 2002, 2003, 2004; Lim et al. 2002). In a series of studies, Hanley et al. (Hanley et al. 2002, 2003, 2004) demonstrated that 5HD can be metabolized in heart mitochondria and may have important effects on substrate utilization independent of KATP channel activity. As suggested by these studies, 5HD may create a ‘bottle neck’ in the mitochondria and impair fatty acid metabolism. Decreased substrate availability would then reduce the capacity of the myocardium to perform work. This theory is supported by the observation that the same concentration of 5HD that was used herein also inhibited respiration in isolated mitochondria (Lim et al. 2002). Despite the possible non-specificity of 5HD, previous work has shown this drug to be effective at abrogating the beneficial effects of delayed preconditioning in a wide variety of protocols (see Table 2). A major finding of the present study is that chronic exercise training sustained delayed cardioprotection even in the presence of 5HD. To the best of our knowledge this is the first preconditioning stimulus where the ‘second window’ of protection from infarction is not ‘closed’ by 5HD.
In summary, we have demonstrated that chronic exercise training reduces myocardial infarct size following I–R in rat heart, and that this cardioprotective phenotype is characterized by an increased expression of the sarcKATP channel. Pharmacological blockade of the sarcKATP channels abrogated the training-induced protection from infarction, while mitochondrial KATP channel blocker had no effect on myocardial infarct size or training-induced preservation of LV tissue after I–R. These data indicate that the activity and/or expression of the sarcolemmal KATP channel is an obligatory part of a mechanism conferring protection from I–R injury, and that exercise training reduces myocardial infarct size by manipulating this mechanism and further increasing sarcolemmal KATP channel expression. These findings may have important clinical implications in that we have identified a cardioprotective stimulus that confers protection that is sustainable over long periods of time. Further investigation will be needed to determine the cardioprotective efficacy of an exercise intervention on a diseased population, specifically on patients who are taking sulphonylurea medication or who have genetically defective sarcKATP channels.
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, trained control hearts (no channel blocker in the buffer); 
and 
, sedentary and trained hearts, respectively, exposed to buffer with 5HD, a mitochondrial KATP channel blocker. #P < 0.05 versus sedentary control hearts, *P < 0.05 versus all other hearts exposed to either no drug or HMR 1098, a selective sarcolemmal KATP channel antagonist. Since there were no differences in developed pressure between control hearts and those that received HMR 1098, LVDP for hearts exposed to HMR 1098 are presented as lines for sedentary (dashed line) and trained (dotted line) animals in the interest of presentational clarity. Inset, LVDP for the first 15 min of reperfusion on an expanded time scale.
), and mitochondrial KATP blocker 5HD (