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

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.

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.

Abstract 1612: Pharmacological Postconditioning Effect of G-csf Is Mediated through Activation of Pi3k-akt-enos Pathway and Opening the Mitochondrial Katp Channels in a Rabbit Model of Myocardial Infarction

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Shohei Sumi ◽  
Masamitsu Iwasa ◽  
Hiroyuki Kobayashi ◽  
Shinji Yasuda ◽  
Takahiko Yamaki ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Infarct Size ◽  
Myocardial Infarct ◽  
Rabbit Model ◽  
Katp Channels ◽  
Saline Control ◽  
Control Group ◽  
Myocardial Infarct Size ◽  
Risk Area ◽  
Mitochondrial Katp Channels

It has been reported that granulocyte-colony-stimulating factor(G-CSF) improves cardiac function after myocardial infarction (MI). However, its direct effect on the myocardium and its signaling pathway remain unclear. We examined the acute beneficial effect of G-CSF on myocardial infarct size and its precise mechanisms in a rabbit model of myocardial infarction. In 80 Japanese white rabbits, MI was induced by 30 min of ischemia and 48 hours of reperfusion. Rabbits were intravenously injected with 10 μg/kg of G-CSF (G-CSF group, n=10) or saline (control group, n=10) immediately after reperfusion. The G-CSF+5HD group (n=10) was injected with 5-HD(5-hydroxydecanoate, a mitochondrial KATP channel blocker) 5 min before G-CSF injection. The G-CSF +wortmaninn group (n=10) was injected wortmaninn (0.6mg/kg) 5 min before G-CSF injection. G-CSF+L-NAME group (n=10) was injected with L-NAME (10mg/kg) 5 min before G-CSF injection. The 5HD alone (n=10), wortmannin alone (n=10), L-NAME alone (n=10) groups were respectively injected 5HD, wortmannin and L-NAME immediately after reperfusion. Myocardial infarct size was calculated as a percentage of the risk area of the left ventricle. Western blot analysis was performed to examine the Akt and phospho-Akt and phospho-eNOS in the ischemic myocardium at 48 hours of reperfusion. The infarct size was significantly smaller in the G-CSF group (26.7±2.7%) than in the control group (42.3±4.6%). The infarct size-reducing effect of G-CSF was completely blocked by 5-HD (42.5±1.66%), wortmaninn(44.7±4.81) and L-NAME (42.1±4.2%). Wortmannin, L-NAME or 5HD alone did not affect the infarct size. Western blotting showed higher expression of phospho-Akt and phosho-eNOS in the infarct area in the G-CSF group than in the control group. G-CSF administered immediately after reperfusion reduces myocardial infarct size via activation of PI3K, Akt, eNOS and opening the mitochondrial KATP channels.

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.

Abstract 3213: Acarbose, an α -glucosidase Inhibitor, Reduces Myocardial Infarct Size in Rabbits via Stimulation of GLP-1 Receptors, Opening Mitochondrial KATP Channels, and Preventing Hydroxyl Radical Production

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Shinya Minatoguchi ◽  
Hiroaki Ushikoshi ◽  
Narantuya Bao ◽  
Hiroyuki Kobayashi ◽  
Shinji Yasuda ◽  
...  
Keyword(s):  
Infarct Size ◽  
Hydroxyl Radical ◽  
Myocardial Infarct ◽  
Katp Channels ◽  
Myocardial Infarct Size ◽  
Control Groups ◽  
Glucosidase Inhibitor ◽  
Radical Production ◽  
Mitochondrial Katp Channels ◽  
Stimulation Of

Background: Acarbose, an anti-diabetic drug, is an α– glucosidase inhibitor that can inhibit glucose absorption in the intestine. A recent large-scale clinical trial, STOP-NIDDM, showed that acarbose reduces the risk of myocardial infarction. We examined whether acarbose reduces myocardial infarct size and investigated its mechanisms. Methods and Results: Rabbits were fed with one of four diets in this study: normal chow, 30 mg acarbose/100 g chow, 8 g sucrose/100 g chow, or 30 mg acarbose plus 8 g sucrose/100 g chow for 7 days. Rabbits were assigned randomly to one of eight groups: control (n=10), acarbose (n=10), sucrose (n=10), acarbose+sucrose (n=10), acarbose+i.v. 5-hydroxydecanoate (5HD, a mitochondrial KATP channel blocker, 5 mg/kg) (n=10), 5HD (i.v. 5 mg/kg, n=10), acarbose+exendin(9 –39) (n=10, a Glucagon-Like Peptide-1(GLP-1) receptor blocker, 3 nmol/l) (45.4±1.2%) and exendin(9 –39)(n=10). Rabbits then underwent 30 min of coronary occlusion followed by 48 h reperfusion. Postprandial blood glucose levels were highest in the sucrose group and higher in the control groups, but decreased in the acarbose and sucrose+acarbose groups. The infarct size as a percentage of the left ventricular area at risk was reduced significantly in the acarbose (19.4±2.3%) and sucrose+acarbose groups (19.0±5.6%) as compared with the sucrose (47.4±4.2%) and control groups (42.8±5.4%). The infarct size-reducing effect of acarbose was abolished by 5HD (43.4±4.7%) and exendin(9 –39) (45.4±1.2%). The 5HD and exendin(9 –39) by itself did not affect the infarct size. Myocardial interstitial 2,5-DHBA levels, an indicator of hydroxyl radicals, increased during reperfusion after 30 min of ischemia but this increase was inhibited in the acarbose group. Conclusions: Acarbose reduces myocardial infarct size via stimulation of GLP-1 receptors, opening mitochondrial KATP channels, and preventing hydroxyl radical production.

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