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.

Adenosine-enhanced ischemic preconditioning: adenosine receptor involvement during ischemia and reperfusion

2001 ◽  
Vol 280 (2) ◽  
pp. H591-H602 ◽  
Author(s):  
James D. McCully ◽  
Yoshiya Toyoda ◽  
Masahisa Uematsu ◽  
Robert D. Stewart ◽  
Sidney Levitsky
Keyword(s):  
Infarct Size ◽  
Functional Recovery ◽  
Ischemic Preconditioning ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Ischemia And Reperfusion ◽  
Infarct Size Reduction

Adenosine-enhanced ischemic preconditioning (APC) extends the cardioprotection of ischemic preconditioning (IPC) by both significantly decreasing myocardial infarct size and significantly enhancing postischemic functional recovery. In this study, the role of adenosine receptors during ischemia-reperfusion was determined. Rabbit hearts ( n = 92) were used for Langendorff perfusion. Control hearts were perfused for 180 min, global ischemia hearts received 30-min ischemia and 120-min reperfusion, and IPC hearts received 5-min ischemia and 5-min reperfusion before ischemia. APC hearts received a bolus injection of adenosine coincident with IPC. Adenosine receptor (A1, A2, and A3) antagonists were used with APC before ischemia and/or during reperfusion. GR-69019X (A1/A3) and MRS-1191/MRS-1220 (A3) significantly increased infarct size in APC hearts when administered before ischemia and significantly decreased functional recovery when administered during both ischemia and reperfusion ( P < 0.05 vs. APC). DPCPX (A1) administered either before ischemia and/or during reperfusion had no effect on APC cardioprotection. APC-enhanced infarct size reduction is modulated by adenosine receptors primarily during ischemia, whereas APC-enhanced postischemic functional recovery is modulated by adenosine receptors during both ischemia and reperfusion.

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.

scholarly journals Mechanisms of myocardial ischemic preconditioning are age related: PKC-ϵ does not play a requisite role in old rabbits

2003 ◽  
Vol 95 (6) ◽  
pp. 2563-2569 ◽  
Author(s):  
Karin Przyklenk ◽  
Guohu Li ◽  
Boris Z. Simkhovich ◽  
Robert A. Kloner
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Myocardial Infarct ◽  
Control Period ◽  
Size Reduction ◽  
Myocardial Infarct Size ◽  
Age Related ◽  
Specific Subset ◽  
Infarct Size Reduction

Data obtained from adult cohorts have implicated activation/translocation of protein kinase C (PKC)-ϵ as an important cellular mediator of myocardial infarct size reduction with ischemic preconditioning (PC). Age-related alterations in cellular signaling may, however, confound the extrapolation of mechanistic insight derived from adults to the aging population, the specific subset in which cardioprotection is undoubtedly most relevant. Accordingly, our aim was to investigate the role of PKC-ϵ as a mediator of infarct size reduction with PC in old vs. adult rabbits. In protocol 1, we assessed the effect of PKC-ϵ translocation inhibitor peptide (PKC-ϵ-TIP) and the pan-PKC inhibitor chelerythrine on infarct size reduction with PC in adult and ∼4-yr-old rabbits, a population previously shown to exhibit definitive hallmarks of cardiovascular aging. Rabbits received 5 min of PC ischemia or a matched control period followed by 30 min of coronary artery occlusion and 3 h of reperfusion, with infarct size (delineated by tetrazolium staining) serving as the primary endpoint. In protocol 2, we obtained insight (by Western immunoblotting) into the subcellular redistribution of PKC-ϵ in response to the 5-min PC stimulus in adult and old rabbits. In adults, infarct size reduction with PC was abrogated by both PKC-ϵ-TIP and chelerythrine. However, in old rabbits, 1) PC-induced cardioprotection was maintained despite inhibitor treatment and 2) brief PC ischemia was not associated with activation/translocation of PKC-ϵ. Thus the mechanisms responsible for PC are age related in the rabbit heart, with no apparent, requisite role of PKC-ϵ in aging animals.

Cellular Mechanisms of Infarct Size Reduction with Ischemic Preconditioning: Role of Calcium?

1999 ◽  
Vol 874 (1 HEART IN STRE) ◽  
pp. 192-210 ◽  
Author(s):  
KARIN PRZYKLENK ◽  
BORIS Z. SIMKHOVICH ◽  
BARBARA BAUER ◽  
KATSUYA HATA ◽  
LIN ZHAO ◽  
...  
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Size Reduction ◽  
Cellular Mechanisms ◽  
Infarct Size Reduction

Reduction of infarct size with d-myo-inositol trisphosphate: role of PI3-kinase and mitochondrial KATP channels

2006 ◽  
Vol 290 (2) ◽  
pp. H830-H836 ◽  
Author(s):  
Karin Przyklenk ◽  
Michelle Maynard ◽  
Peter Whittaker
Keyword(s):  
Infarct Size ◽  
Katp Channels ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Additional Treatment ◽  
Pi3 Kinase ◽  
Mitochondrial Katp Channels ◽  
Tetrazolium Staining ◽  
Sparing Effect

Prophylactic treatment with d- myo-inositol 1,4,5-trisphosphate hexasodium [d- myo-Ins(1,4,5)P3], the sodium salt of the endogenous second messenger Ins(1,4,5)P3, triggers a reduction of infarct size comparable in magnitude to that seen with ischemic preconditioning (PC). However, the mechanisms underlying d- myo-Ins(1,4,5)P3-induced protection are unknown. Accordingly, our aim was to investigate the role of four archetypal mediators implicated in PC and other cardioprotective strategies (i.e., PKC, PI3-kinase/Akt, and mitochondrial and/or sarcolemmal KATP channels) in the infarct-sparing effect of d- myo-Ins(1,4,5)P3. Fifteen groups of isolated buffer-perfused rabbit hearts [5 treated with d- myo-Ins(1,4,5)P3, 5 treated with PC, and 5 control cohorts] underwent 30 min of coronary artery occlusion and 2 h of reflow. One set of control, d- myo-Ins(1,4,5)P3, and PC groups received no additional treatment, whereas the remaining sets were infused with chelerythrine, LY-294002, 5-hydroxydecanoate (5-HD), or HMR-1098 [inhibitors of PKC, PI3-kinase, and mitochondrial and sarcolemmal ATP-sensitive K+ (KATP) channels, respectively]. Infarct size (delineated by tetrazolium staining) was, as expected, significantly reduced in both d- myo-Ins(1,4,5)P3- and PC-treated hearts versus controls. d- myo-Ins(1,4,5)P3-induced cardioprotection was blocked by 5-HD but not HMR-1098, thereby implicating the involvement of mitochondrial, but not sarcolemmal, KATP channels. Moreover, the benefits of d- myo-Ins(1,4,5)P3 were abrogated by LY-294002, whereas, in contrast, chelerythrine had no effect. These latter pharmacological data were corroborated by immunoblotting: d- myo-Ins(1,4,5)P3 evoked a significant increase in expression of phospho-Akt but had no effect on the activation/translocation of the cardioprotective ε-isoform of PKC. Thus PI3-kinase/Akt signaling and mitochondrial KATP channels participate in the reduction of infarct size afforded by prophylactic administration of d- myo-Ins(1,4,5)P3.

Transgenic overexpression of cardiac A1adenosine receptors mimics ischemic preconditioning

2000 ◽  
Vol 279 (3) ◽  
pp. H1071-H1078 ◽  
Author(s):  
R. Ray Morrison ◽  
Rachael Jones ◽  
Anne M. Byford ◽  
Alyssa R. Stell ◽  
Jason Peart ◽  
...  
Keyword(s):  
Infarct Size ◽  
Functional Recovery ◽  
Ischemic Preconditioning ◽  
Adenosine Receptors ◽  
Myocardial Function ◽  
Wild Type ◽  
Beneficial Effects ◽  
Pressure Development ◽  
Ldh Release

The role of A1adenosine receptors (A1AR) in ischemic preconditioning was investigated in isolated crystalloid-perfused wild-type and transgenic mouse hearts with increased A1AR. The effect of preconditioning on postischemic myocardial function, lactate dehydrogenase (LDH) release, and infarct size was examined. Functional recovery was greater in transgenic versus wild-type hearts (44.8 ± 3.4% baseline vs. 25.6 ± 1.7%). Preconditioning improved functional recovery in wild-type hearts from 25.6 ± 1.7% to 37.4 ± 2.2% but did not change recovery in transgenic hearts (44.8 ± 3.4% vs. 44.5 ± 3.9%). In isovolumically contracting hearts, pretreatment with selective A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine attenuated the improved functional recovery in both wild-type preconditioned (74.2 ± 7.3% baseline rate of pressure development over time untreated vs. 29.7 ± 7.3% treated) and transgenic hearts (84.1 ± 12.8% untreated vs. 42.1 ± 6.8% treated). Preconditioning wild-type hearts reduced LDH release (from 7,012 ± 1,451 to 1,691 ± 1,256 U · l−1 · g−1 · min−1) and infarct size (from 62.6 ± 5.1% to 32.3 ± 11.5%). Preconditioning did not affect LDH release or infarct size in hearts overexpressing A1AR. Compared with wild-type hearts, A1AR overexpression markedly reduced LDH release (from 7,012 ± 1,451 to 917 ± 1,123 U · l−1 · g−1 · min−1) and infarct size (from 62.6 ± 5.1% to 6.5 ± 2.1%). These data demonstrate that murine preconditioning involves endogenous activation of A1AR. The beneficial effects of preconditioning and A1AR overexpression are not additive. Taken with the observation that A1AR blockade equally eliminates the functional protection resulting from both preconditioning and transgenic A1AR overexpression, we conclude that the two interventions affect cardioprotection via common mechanisms or pathways.

scholarly journals Investigating the role of GSK3beta kinase as a molecular target for myocardial infarct size reduction by using novel pharmacological inhibitors

2013 ◽  
Vol 34 (suppl 1) ◽  
pp. 777-777
Author(s):  
I. Andreadou ◽  
A. Lazari ◽  
S. I. Bibli ◽  
N. Gaboriaud-Kolar ◽  
A. L. Skaltsounis ◽  
...  
Keyword(s):  
Infarct Size ◽  
Myocardial Infarct ◽  
Molecular Target ◽  
Size Reduction ◽  
Myocardial Infarct Size ◽  
Infarct Size Reduction

Persistent beneficial effect of postconditioning against infarct size: role of mitochondrial KATP channels during reperfusion

2008 ◽  
Vol 103 (5) ◽  
pp. 472-484 ◽  
Author(s):  
James Mykytenko ◽  
James G. Reeves ◽  
Hajime Kin ◽  
Ning-Ping Wang ◽  
Amanda J. Zatta ◽  
...  
Keyword(s):  
Beneficial Effect ◽  
Infarct Size ◽  
Katp Channels ◽  
Mitochondrial Katp Channels

Sarcolemmal KATP channel triggers delayed ischemic preconditioning in rats

2005 ◽  
Vol 288 (1) ◽  
pp. H445-H447 ◽  
Author(s):  
Hemal H. Patel ◽  
Eric R. Gross ◽  
Jason N. Peart ◽  
Anna K. Hsu ◽  
Garrett J. Gross
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Size Reduction ◽  
Sprague Dawley ◽  
Area At Risk ◽  
Sprague Dawley Rats ◽  
Rat Hearts ◽  
Opioid Administration ◽  
Infarct Size Reduction ◽  
Prior Administration

Previous work from our laboratory has shown that the sarcolemmal KATP channel (sKATP) is required as a trigger for delayed cardioprotection upon exogenous opioid administration. We also established that the mitochondrial KATP (mKATP) channel is not required for triggering delayed δ-opioid-induced infarct size reduction. Because mechanistic differences have been found among δ-opioids and that due to ischemic preconditioning (IPC), we determined whether the triggering mechanism of delayed IPC-induced infarct size reduction involves either the sKATP or mKATP. Male Sprague-Dawley rats received either sham surgery or IPC (3- to 5-min cycles of ischemia and reperfusion) 24 h before being subjected to 30 min of ischemia and 2 h of reperfusion. Infarct size was determined and expressed as a percentage of the area at risk, with significance compared with sham reported at P ≤ 0.001. A subset of both sham and IPC-treated rats received either the selective sKATP channel antagonist, HMR-1098 (6 mg/kg), or the selective mKATP channel antagonist, 5-hydroxydeconoic acid (5-HD; 10 mg/kg), given 5 min before IPC. Rats subjected to IPC demonstrated a significant reduction in infarct size compared with sham (29.2 ± 4.7 vs. 59.3 ± 2.5%, respectively; P ≤ 0.001). Prior administration of HMR-1098, but not 5-HD, abolished IPC-induced infarct size reduction (48.8 ± 2.9 and 28.8 ± 4.0%, respectively; P ≤ 0.001). Furthermore, administration of HMR 24 h after IPC, before index ischemia, did not abrogate IPC-induced infarct size reduction (33.0 ± 5.0 vs. 29.2 ± 4.7%, respectively; P ≤ 0.001). These data suggest that the sKATP channel is required as a trigger but not a mediator for delayed IPC-induced infarct size reduction in rat hearts.

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