KATP channels and memory of ischemic preconditioning in dogs: synergism between adenosine and KATP channels

1997 ◽  
Vol 272 (1) ◽  
pp. H334-H342 ◽  
Author(s):  
Z. Yao ◽  
T. Mizumura ◽  
D. A. Mei ◽  
G. J. Gross
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Katp Channels ◽  
Canine Heart ◽  
Ischemic Insult ◽  
Area At Risk ◽  
Adenosine Receptor Antagonist ◽  
Anesthetized Dogs ◽  
Drug Free ◽  
Occlusion Period

Results from numerous studies have shown that there is an important link between adenosine A1 receptors and ATP-sensitive potassium (KATP) channels in mediating the cardioprotective effects of ischemic preconditioning (PC). The major aim of the present study was to determine whether occupation of A1 receptors and/or the opening of KATP channels is involved in the time delay between the PC stimulus and the prolonged ischemic insult or the “memory” of PC to reduce infarct size. Barbital sodium-anesthetized dogs were subjected to 1 h of left anterior descending coronary artery (LAD) occlusion followed by 4 h of reperfusion. Ischemic PC was elicited by 10 min of LAD occlusion followed by 1 h of reperfusion (1-h memory) before the 1-h occlusion period. Either adenosine (800 g/min), bimakalim (3 g/min), a combination of two lower doses of each agent (400 g/min of adenosine and 0.3 g/min of bimakalim), or an equivalent volume of saline was infused into the LAD for 10 min followed by a 1-h drug-free period before the 1-h ischemic insult. In another series, glibenclamide, 8-cyclopentyl-1,3-dipropylxanthine (a selective A1-receptor blocker), or PD-115199 (a nonselective adenosine-receptor antagonist) was administered 50 min after ischemic PC (10 min before the 1-h occlusion period). Infarct size (IS) was expressed as a percentage of the area at risk. PC with 1 h of reperfusion resulted in a marked reduction in IS (8.1 +/- 6.5 vs. 29.8 +/- 5.8% in control dogs). Administration of adenosine or bimakalim followed by a 1-h drug-free period had no effect on IS; however, the simultaneous administration of adenosine and bimakalim resulted in a marked decrease in IS (11.5 +/- 2.7%). One hour after ischemic PC, administration of glibenclamide blocked the protective effect of ischemic PC, whereas 8-cyclopentyl-1,3-dipropylxanthine or PD-115199 did not affect it. These results provide evidence that the opening of myocardial KATP channels may play an important role in the memory of ischemic PC in the canine heart and also suggest that adenosine and the KATP channel may have a synergistic interaction that is important for the memory phase of PC.

Acetylcholine mimics ischemic preconditioning via a glibenclamide-sensitive mechanism in dogs

1993 ◽  
Vol 264 (6) ◽  
pp. H2221-H2225 ◽  
Author(s):  
Z. Yao ◽  
G. J. Gross
Keyword(s):  
Blood Flow ◽  
Ischemic Preconditioning ◽  
Katp Channel ◽  
Channel Blocker ◽  
Katp Channels ◽  
Protective Effects ◽  
Ischemic Insult ◽  
Area At Risk ◽  
Drug Free

The major objectives of the present study were to examine the ability of acetylcholine (ACh) to mimic ischemic preconditioning in dogs and to determine the role of cardiac ATP-sensitive potassium (KATP) channels in mediating its effects. Barbital-anesthetized open-chest dogs were subjected to 60 min of left anterior descending coronary artery (LAD) occlusion followed by 4 h of reperfusion. Preconditioning was elicited by 10 min of LAD occlusion followed by 10 min of reperfusion before the 60-min occlusion period. ACh (10 micrograms/min) or an equivalent volume of saline were infused into the LAD for 10 min followed by a 10-min drug-free period before the 60-min ischemic insult. In another group, the specific KATP channel blocker glibenclamide (0.3 mg/kg iv) was given 15 min before ACh administration. Transmural myocardial blood flow was measured at 30 min of occlusion, and infarct size (IS) was determined by triphenyltetrazolium staining and expressed as a percentage of the anatomic area at risk (AAR). There were no significant differences in hemodynamics, collateral blood flow, or AAR between groups. Preconditioning produced a marked reduction (P < 0.05) in IS (5.3 +/- 3.0 vs. 23.7 +/- 5.9% in the controls). ACh, similar to preconditioning, resulted in a dramatic decrease in IS (10.0 +/- 2.9%), whereas glibenclamide completely abolished its protective effects (20.9 +/- 4.8%). These results are the first to indicate that ACh mimics ischemic preconditioning via a cardiac KATP channel-sensitive mechanism in dogs.

Isoflurane Mimics Ischemic Preconditioning via Activation of KATPChannels 

1997 ◽  
Vol 87 (2) ◽  
pp. 361-370 ◽  
Author(s):  
Judy R. Kersten ◽  
Todd J. Schmeling ◽  
Paul S. Pagel ◽  
Garrett J. Gross ◽  
David C. Warltier
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Myocardial Infarct ◽  
Myocardial Infarct Size ◽  
Protective Effects ◽  
Hemodynamic Effects ◽  
Area At Risk ◽  
Triphenyltetrazolium Chloride ◽  
Anesthetized Dogs

Background The authors tested the hypothesis that isoflurane directly preconditions myocardium against infarction via activation of K(ATP) channels and that the protection afforded by isoflurane is associated with an acute memory phase similar to that of ischemic preconditioning. Methods Barbiturate-anesthetized dogs (n = 71) were instrumented for measurement of systemic hemodynamics. Myocardial infarct size was assessed by triphenyltetrazolium chloride staining. All dogs were subjected to a single prolonged (60 min) left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion. Ischemic preconditioning was produced by four 5-min LAD occlusions interspersed with 5-min periods of reperfusion before the prolonged LAD occlusion and reperfusion. The actions of isoflurane to decrease infarct size were examined in dogs receiving 1 minimum alveolar concentration (MAC) isoflurane that was discontinued 5 min before prolonged LAD occlusion. The interaction between isoflurane and ischemic preconditioning on infarct size was evaluated in dogs receiving isoflurane before and during preconditioning LAD occlusions and reperfusions. To test whether the cardioprotection produced by isoflurane can mimic the acute memory of ischemic preconditioning, isoflurane was discontinued 30 min before prolonged LAD occlusion and reperfusion. The mechanism of isoflurane-induced cardioprotection was evaluated in two final groups of dogs pretreated with glyburide in the presence or absence of isoflurane. Results Myocardial infarct size was 25.3 +/- 2.9% of the area at risk during control conditions. Isoflurane and ischemic preconditioning produced significant (P &lt; 0.05) and equivalent reductions in infarct size (ischemic preconditioning alone, 9.6 +/- 2.0; isoflurane alone, 11.8 +/- 2.7; isoflurane and ischemic preconditioning, 5.1 +/- 1.9%). Isoflurane-induced reduction of infarct size also persisted 30 min after discontinuation of the anesthetic (13.9 +/- 1.5%), independent of hemodynamic effects during LAD occlusion. Glyburide alone had no effect on infarct size (28.3 +/- 3.9%), but it abolished the protective effects of isoflurane (27.1 +/- 4.6%). Conclusions Isoflurane directly preconditions myocardium against infarction via activation of K(ATP) channels in the absence of hemodynamic effects and exhibits acute memory of preconditioning in vivo.

KATP channels in rat heart: blockade of ischemic and acetylcholine-mediated preconditioning by glibenclamide

1996 ◽  
Vol 271 (1) ◽  
pp. H23-H28 ◽  
Author(s):  
Y. Z. Qian ◽  
J. E. Levasseur ◽  
K. Yoshida ◽  
R. C. Kukreja
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Rat Heart ◽  
Katp Channel ◽  
Katp Channels ◽  
Ischemia And Reperfusion ◽  
Area At Risk ◽  
Specific Antagonist ◽  
Percent Area

The objective of this study was to examine if the opening of ATP-sensitive K+ (KATP) channels play an important role in ischemic preconditioning (PC) in the rat heart. A second goal was to test the role of acetylcholine (ACh) in mimicking PC and test if it could be blocked by KATP antagonist. Glibenclamide, a specific antagonist of the KATP channel, was given as two doses of 0.3 mg/kg each at 60 and 30 min before PC. Six groups of rats were subjected to ischemia and reperfusion (I/R) using these protocols: 1) control (I/R), 30-min ischemia followed by 90-min reperfusion (n = 6 rats); 2) preconditioned hearts given 5-min ischemia 10 min before I/R (n = 9 rats); 3) glibenclamide (0.3 mg/kg) treatment 60 and 30 min before PC (n = 13 rats); 4) glibenclamide treatment before I/R (n = 15 rats); 5) ACh infusion for 5 min (18 micrograms/ml) at a rate of 0.15 ml/min followed by equilibration for 10 min before I/R, n = 13 rats; and 6) glibenclamide treatment before ACh infusion followed by I/R (n = 11 rats). Preconditioning reduced the infarcted area (expressed as percent area at risk) from 42.0 +/- 4.4% in control to 8.7 +/- 6% (mean +/- SE, P < 0.05). Glibenclamide blocked the protection conferred by PC (39.1 +/- 4.5%, P < 0.05) without having a significant effect on control nonpreconditioned hearts. ACh infusion in lieu of PC also reduced infarct size to 25.0 +/- 5.63% (P < 0.05 compared with control), which was again blocked by glibenclamide (44.2 +/- 5.0%, P < 0.05). The data suggest that opening of KATP channels for ischemic and ACh-mediated preconditioning is also important in the rat heart.

Effects of selective inhibition of cytochrome P-450 ω-hydroxylases and ischemic preconditioning in myocardial protection

2006 ◽  
Vol 290 (2) ◽  
pp. H500-H505 ◽  
Author(s):  
Kasem Nithipatikom ◽  
Michael P. Endsley ◽  
Jeannine M. Moore ◽  
Marilyn A. Isbell ◽  
John R. Falck ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemic Preconditioning ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Canine Heart ◽  
Area At Risk ◽  
Cytochrome P 450

Cytochrome P-450 (CYP) ω-hydroxylases and their arachidonic acid (AA) metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE), produce a detrimental effect on ischemia-reperfusion injury in canine hearts, and the inhibition of CYP ω-hydroxylases markedly reduces myocardial infarct size expressed as a percentage of the area at risk (IS/AAR, %). In this study, we demonstrated that a specific CYP ω-hydroxylase inhibitor, N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), markedly reduced 20-HETE production during ischemia-reperfusion and reduced myocardial infarct size compared with control [19.5 ± 1.0% (control), 9.6 ± 1.5% (0.40 mg/kg DDMS), 4.0 ± 2.0% (0.81 mg/kg DDMS), P < 0.01]. In addition, 20-hydroxyeicosa-6( Z),15( Z)-dienoic acid (20-HEDE, a putative 20-HETE antagonist) significantly reduced myocardial infarct size from control [10.3 ± 1.3% (0.032 mg/kg 20-HEDE) and 5.9 ± 1.9% (0.064 mg/kg 20-HEDE), P < 0.05]. We further demonstrated that one 5-min period of ischemic preconditioning (IPC) reduced infarct size to a similar extent as that observed with the high doses of DDMS and 20-HEDE, and the higher dose of DDMS given simultaneously with IPC augmented the infarct size reduction [9.9 ± 2.8% (IPC) to 2.5 ± 1.4% (0.81 mg/kg DDMS), P < 0.05] to a greater degree than that observed with either treatment alone. These results suggest an important negative role for endogenous CYP ω-hydroxylases and their product, 20-HETE, to exacerbate myocardial injury in canine myocardium. Furthermore, for the first time, this study demonstrates that the effect of IPC and the inhibition of CYP ω-hydroxylase synthesis (DDMS) or its actions (20-HEDE) may have additive effects in protecting the canine heart from ischemia-reperfusion injury.

Cardioprotection with ischemic preconditioning and MLA: role of adenosine-regulating enzymes?

1996 ◽  
Vol 271 (3) ◽  
pp. H1004-H1014 ◽  
Author(s):  
K. Przyklenk ◽  
L. Zhao ◽  
R. A. Kloner ◽  
G. T. Elliott
Keyword(s):  
Blood Flow ◽  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Lipid A ◽  
Canine Heart ◽  
Collateral Blood Flow ◽  
Cellular Mechanisms ◽  
Monophosphoryl Lipid A ◽  
Anesthetized Dogs ◽  
Increased Activity

Both ischemic preconditioning and pretreatment with the endotoxin derivative monophosphoryl lipid A (MLA) protect the heart against infarction, yet the cellular mechanisms responsible for the cardioprotection achieved with either intervention are unknown. Using pentobarbital-anesthetized dogs, we tested the hypothesis that increased activity of 5'-nucleotidase (5'-NT), the enzyme that catalyzes the formation of adenosine from AMP, may play a role. Twenty-two dogs underwent 1 h of coronary occlusion and 4 h of reperfusion: eight controls received no intervention, seven animals were preconditioned with four 5-min episodes of brief ischemia, and seven received MLA (35 micrograms/kg iv) 24 h previously. Collateral blood flow was measured by injection of radiolabeled microspheres, infarct size was delineated by tetrazolium staining, and myocardial 5'-NT activities were measured by quantifying the release of adenosine from AMP. Despite comparable values of collateral blood flow in all groups, infarct size was reduced in preconditioned and MLA-treated dogs vs. controls. In addition, 5'-NT activities were increased throughout the heart with preconditioning and MLA treatment. However, single and multivariate regression analyses revealed no correlation between infarct size and 5'-NT activities for either treatment group. In fact, in the preconditioned cohort, animals with the highest enzyme activities developed the largest infarcts. This dissociation between infarct size and 5'-NT suggests that increased activity of 5'-NT is not the mechanism by which preconditioning or MLA treatment protects the canine heart against infarction.

Adenosine A1 receptors, KATP channels, and ischemic preconditioning in dogs

1993 ◽  
Vol 264 (5) ◽  
pp. H1327-H1336 ◽  
Author(s):  
J. A. Auchampach ◽  
G. J. Gross
Keyword(s):  
Infarct Size ◽  
Receptor Antagonist ◽  
Ischemic Preconditioning ◽  
Katp Channels ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Canine Heart ◽  
Adenosine A1 Receptors ◽  
Intracoronary Infusion ◽  
Adenosine A1

The objective of the present study was to characterize the role of adenosine in myocardial ischemic preconditioning in the canine heart. Preconditioning with 5 min of ischemia resulted in a marked reduction in infarct size after 60 min of left circumflex coronary artery occlusion and 5 h of reperfusion in barbital-anesthetized dogs compared with dogs that were not preconditioned (4.8 +/- 1.9 vs. 27.9 +/- 4.5%; P < 0.05). Pretreatment with either the nonselective adenosine receptor antagonist PD 115199 or the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine blocked this protective effect, although in the absence of preconditioning neither of the antagonists affected infarct size. Intracoronary infusion of two different doses of adenosine or dipyridamole over a 5-min period before a prolonged 60-min occlusion period did not mimic preconditioning; however, intracoronary infusion of a combination of adenosine and dipyridamole produced a significant reduction in infarct size (13.6 +/- 4.1%), which was abolished by pretreatment with the ATP-dependent potassium (KATP) channel antagonist glibenclamide. These results suggest that activation of adenosine A1 receptors produces myocardial preconditioning in the canine heart by opening KATP channels.

Ischemic preconditioning in rats: role of mitochondrial KATP channel in preservation of mitochondrial function

2000 ◽  
Vol 278 (1) ◽  
pp. H305-H312 ◽  
Author(s):  
Ryan M. Fryer ◽  
Janis T. Eells ◽  
Anna K. Hsu ◽  
Michele M. Henry ◽  
Garrett J. Gross
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion ◽  
Mitochondrial Protein ◽  
Atp Synthesis ◽  
Area At Risk ◽  
Selective Antagonist ◽  
Mitochondrial Katp Channel

We examined the role of the sarcolemmal and mitochondrial KATPchannels in a rat model of ischemic preconditioning (IPC). Infarct size was expressed as a percentage of the area at risk (IS/AAR). IPC significantly reduced infarct size (7 ± 1%) versus control (56 ± 1%). The sarcolemmal KATP channel-selective antagonist HMR-1098 administered before IPC did not significantly attenuate cardioprotection. However, pretreatment with the mitochondrial KATP channel-selective antagonist 5-hydroxydecanoic acid (5-HD) 5 min before IPC partially abolished cardioprotection (40 ± 1%). Diazoxide (10 mg/kg iv) also reduced IS/AAR (36.2 ± 4.8%), but this effect was abolished by 5-HD. As an index of mitochondrial bioenergetic function, the rate of ATP synthesis in the AAR was examined. Untreated animals synthesized ATP at 2.12 ± 0.30 μmol ⋅ min−1 ⋅ mg mitochondrial protein−1. Rats subjected to ischemia-reperfusion synthesized ATP at 0.67 ± 0.06 μmol ⋅ min−1 ⋅ mg mitochondrial protein−1. IPC significantly increased ATP synthesis to 1.86 ± 0.23 μmol ⋅ min−1 ⋅ mg mitochondrial protein−1. However, when 5-HD was administered before IPC, the preservation of ATP synthesis was attenuated (1.18 ± 0.15 μmol ⋅ min−1 ⋅ mg mitochondrial protein−1). These data are consistent with the notion that inhibition of mitochondrial KATPchannels attenuates IPC by reducing IPC-induced protection of mitochondrial function.

scholarly journals Decreased tetrahydrobiopterin and disrupted association of Hsp90 with eNOS by hyperglycemia impair myocardial ischemic preconditioning

2011 ◽  
Vol 301 (5) ◽  
pp. H2130-H2139 ◽  
Author(s):  
Nikolina Vladic ◽  
Zhi-Dong Ge ◽  
Thorsten Leucker ◽  
Anna K. Brzezinska ◽  
Jian-Hai Du ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Myocardial Infarct ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Myocardial Infarct Size ◽  
Human Coronary Artery ◽  
Area At Risk ◽  
Synthesis Inhibitor

Cardioprotection by ischemic preconditioning (IPC) is impaired during hyperglycemia, but the mechanisms underlying this phenomenon are poorly understood. This study investigated the role of hyperglycemia to adversely modulate tetrahydrobiopterin (BH4) and heat shock protein 90 (Hsp90) during cardioprotection by IPC. Rabbits or mice underwent 30 min of coronary occlusion followed by reperfusion with or without IPC in the presence or absence of hyperglycemia. IPC significantly ( P < 0.05) decreased myocardial infarct size (46 ± 1 to 19 ± 2% of the area at risk in control and IPC rabbits, respectively) and increased BH4 concentrations (HPLC; 7.6 ± 0.2 to 10.2 ± 0.3 pmol/mg protein, respectively), Hsp90-endothelial nitric oxide synthase (eNOS) association (coimmunoprecipitation and Western blotting in mice; 4.0 ± 0.3 to 5.4 ± 0.1, respectively), and the ratio of phosphorylated eNOS/total eNOS. These beneficial actions of IPC on infarct size, BH4, Hsp90/eNOS, and phosphorylated eNOS were eliminated by hyperglycemia. Pretreatment of animals with the Hsp90 inhibitor geldanamycin (0.6 mg/kg) or the BH4 synthesis inhibitor diamino-6-hydroxypyrimidine (1.0 g/kg) also eliminated cardioprotection produced by IPC. In contrast, the BH4 precursor sepiapterin (2 mg/kg iv) restored the beneficial effects of IPC on myocardial BH4 concentrations, eNOS dimerization, and infarct size during hyperglycemia. A-23871 increased Hsp90-eNOS association (0.33 ± 0.06 to 0.59 ± 0.3) and nitric oxide production (184 ± 17%) in human coronary artery endothelial cells cultured in normal (5.5 mM) but not high (20 mM) glucose media. These data indicate that hyperglycemia eliminates protection by IPC via decreases in myocardial BH4 concentration and disruption of the association of Hsp90 with eNOS. The results suggest that eNOS dysregulation may be a central mechanism of impaired cardioprotection during hyperglycemia.

Mechanisms of Isoflurane-induced Myocardial Preconditioning in Rabbits 

1999 ◽  
Vol 90 (3) ◽  
pp. 812-821 ◽  
Author(s):  
Mohamed S. Ismaeil ◽  
Igor Tkachenko ◽  
Kurt A. Gamperl ◽  
Robert F. Hickey ◽  
Brian A. Cason
Keyword(s):  
At Risk ◽  
Potassium Channels ◽  
Infarct Size ◽  
Adenosine Triphosphate ◽  
Ischemic Preconditioning ◽  
Adenosine Receptors ◽  
Coronary Occlusion ◽  
Myocardial Infarct ◽  
Myocardial Infarct Size ◽  
Area At Risk

Background Isoflurane has cardioprotective effects that mimic the ischemic preconditioning phenomenon. Because adenosine triphosphate-sensitive potassium channels and adenosine receptors are implicated in ischemic preconditioning, the authors wanted to determine whether the preconditioning effect of isoflurane is mediated through these pathways. Methods Myocardial infarct size was measured in seven groups of propofol-anesthetized rabbits, each subjected to 30 min of anterolateral coronary occlusion followed by 3 h of reperfusion. Groups differed only in the pretreatments given, and controls received no pretreatment. An ischemia-preconditioned group was pretreated with 5 min of coronary occlusion and 15 min of reperfusion. An isoflurane-preconditioned group was pretreated with 15 min end-tidal isoflurane, 1.1%, and then 15 min of washout. An isoflurane-plus-glyburide group was administered 0.33 mg/kg glyburide intravenously before isoflurane pretreatment. An isoflurane plus 8-(p-sulfophenyl)-theophylline (SPT) group received 7.5 mg/kg SPT intravenously before isoflurane. Additional groups were administered identical doses of glyburide or SPT, but they were not pretreated with isoflurane. Infarct size and area at risk were defined by staining. Data were analyzed by analysis of variance or covariance. Results Infarct size, expressed as a percentage of the area at risk (IS:AR) was 30.2+/-11% (SD) in controls. Ischemic preconditioning and isoflurane preexposure reduced myocardial infarct size significantly, to 8.3+/-5% and 13.4+/-8.2% (P&lt;0.05), respectively. Both glyburide and SPT pretreatment eliminated the preconditioning-like effect of isoflurane (IS:AR = 30.0+/-9.1% and 29.2+/-12.6%, respectively; P = not significant). Neither glyburide nor SPF alone increased infarct size (IS:AR = 33.9+/-7.6% and 31.8+/-12.7%, respectively; P = not significant). Conclusions Glyburide and SPT abolished the preconditioning-like effects of isoflurane but did not increase infarct size when administered in the absence of isoflurane. Isoflurane-induced preconditioning and ischemia-induced preconditioning share similar mechanisms, which include activation of adenosine triphosphate-sensitive potassium channels and adenosine receptors.

Differential role of sarcolemmal and mitochondrial KATP channels in adenosine-enhanced ischemic preconditioning

2000 ◽  
Vol 279 (6) ◽  
pp. H2694-H2703 ◽  
Author(s):  
Yoshiya Toyoda ◽  
Ingeborg Friehs ◽  
Robert A. Parker ◽  
Sidney Levitsky ◽  
James D. McCully
Keyword(s):  
Infarct Size ◽  
Functional Recovery ◽  
Ischemic Preconditioning ◽  
Channel Blocker ◽  
Katp Channels ◽  
Size Reduction ◽  
Ischemia And Reperfusion ◽  
Infarct Size Reduction ◽  
Mitochondrial Katp Channels

Adenosine-enhanced ischemic preconditioning (APC) extends the protection afforded by ischemic preconditioning (IPC) by both significantly decreasing infarct size and significantly enhancing postischemic functional recovery. The purpose of this study was to determine whether APC is modulated by ATP-sensitive potassium (KATP) channels and to determine whether this modulation occurs before ischemia or during reperfusion. The role of KATP channels before ischemia (I), during reperfusion (R), or during ischemia and reperfusion (IR) was investigated using the nonspecific KATP blocker glibenclamide (Glb), the mitochondrial (mito) KATP channel blocker 5-hydroxydecanoate (5-HD), and the sarcolemmal (sarc) KATPchannel blocker HMR-1883 (HMR). Infarct size was significantly increased ( P < 0.05) in APC hearts with Glb-I, Glb-R, and 5-HD-I treatment and partially with 5-HD-R. Glb-I and Glb-R treatment significantly decreased APC functional recovery ( P < 0.05 vs. APC), whereas 5-HD-I and 5-HD-R had no effect on APC functional recovery. HMR-IR significantly decreased postischemic functional recovery ( P < 0.05 vs. APC) but had no effect on infarct size. These data indicate that APC infarct size reduction is modulated by mitoKATP channels primarily during ischemia and suggest that functional recovery is modulated by sarcKATP channels during ischemia and reperfusion.

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