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.

KATP channels mediate late preconditioning against infarction produced by monophosphoryl lipid A

1996 ◽  
Vol 271 (6) ◽  
pp. H2723-H2729 ◽  
Author(s):  
D. A. Mei ◽  
G. T. Elliott ◽  
G. J. Gross
Keyword(s):  
Infarct Size ◽  
Lipid A ◽  
Katp Channels ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Cardioprotective Effect ◽  
Monophasic Action Potential ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid

The cardioprotective effect of myocardial preconditioning (PC) to reduce infarct size has been shown to last approximately 90 min (early PC), and then a second window of protection (SWOP or late PC) appears 24 h later. Although much work has been done to characterize early PC, little has been done to investigate potential mediators of SWOP. To that end, we have used monophosphoryl lipid A (MLA), a nontoxic endotoxin derivative, to produce SWOP and have examined the role of ATP-sensitive potassium (KATP) channels in mediating its cardioprotection. Adult mongrel dogs were given MLA (3, 10, or 35 micrograms/kg i.v.) 24 h before a 60-min left anterior descending coronary artery occlusion and 3 h of reperfusion. After reperfusion, the hearts were stained for myocardial infarction with triphenyltetrazolium. MLA produced a dose-dependent reduction in infarct size that was associated with an enhanced shortening of the monophasic action potential duration during early ischemia. To further examine the role of KATP channels, animals were treated with MLA (35 micrograms/kg) and 24 h later were administered either glibenclamide (0.3 mg/kg i.v.) or 5-hydroxydecanoate (7.5 mg/kg intracoronary over 20 min), two structurally distinct KATP-channel antagonists. Both glibenclamide and 5-hydroxydecanoate abolished the cardioprotection produced by MLA. These results demonstrate that the cardioprotective effect of late PC produced by MLA is dependent on functional KATP channels and is the first study to suggest that late PC may be the result of an increased KATP current during ischemia.

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.

Myocardial temperature in acute myocardial infarction: protection with mild regional hypothermia

1997 ◽  
Vol 273 (1) ◽  
pp. H220-H227 ◽  
Author(s):  
S. L. Hale ◽  
R. A. Kloner
Keyword(s):  
Infarct Size ◽  
Myocardial Infarct ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Control Group ◽  
Myocardial Infarct Size ◽  
Local Cooling ◽  
Risk Zone ◽  
Myocardial Temperature

This study tests the hypothesis that a 2-4 degrees C reduction in myocardial temperature, obtained by using topical regional hypothermia (TRH), reduces infarct size. Anesthetized rabbits received coronary artery occlusion and reperfusion. We cooled hearts in the TRH group by applying an ice bag directly over the risk zone; the control group received no intervention. Risk zone myocardial temperature (MT) in the TRH group was reduced at occlusion by 2 degrees C from baseline and after 5 min of occlusion by 3.6 degrees C. In the control group, MT in the risk region remained within 0.3 degree C of baseline. The ischemic area was similar in both groups, yet infarct size in the TRH group was reduced by an average of 65% compared with the control group. Infarct size closely correlated with MT in the risk region at the time of occlusion. In a second protocol in which all hearts were paced, infarct size was 21% of the risk region in TRH hearts compared with 44% in controls. These results strongly support the important role of MT in the progression of necrosis and demonstrate that the application of local cooling to the risk region profoundly reduces myocardial infarct size.

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

Movement of necrotic wavefront after coronary artery occlusion in rabbit

1982 ◽  
Vol 243 (5) ◽  
pp. H682-H690 ◽  
Author(s):  
C. Connelly ◽  
W. M. Vogel ◽  
Y. M. Hernandez ◽  
C. S. Apstein
Keyword(s):  
Coronary Artery ◽  
Left Ventricle ◽  
Infarct Size ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Early Reperfusion ◽  
Transmural Extent ◽  
Circumferential Extent ◽  
Tetrazolium Staining ◽  
Four Levels

Movement of the necrotic wavefront after coronary artery occlusion (CAO) was defined in rabbits by comparing transient CAO (15, 30, or 60 min) and reperfusion to permanent CAO (n = 5-9/group). At 24 h after CAO the area of necrosis was determined by nitro-blue tetrazolium staining, and the transmural and circumferential extent of necrosis was evaluated at four levels from ligation to apex. Infarct size after permanent CAO for 24 h was 27 +/- 2 (SE) % of the left ventricle. Reperfusion at 60, 30, or 15 min after CAO reduced the infarct size to 24 +/- 3 (P = NS vs. 24 h), 14 +/- 2, and 8 +/- 1% (P less than 0.05 vs. 60 min), respectively. Reperfusion at 15 and 30 min after CAO decreased transmural extent by 49 and 38% (P less than 0.001 vs. 24 h), whereas the circumferential extent was reduced by only 10 and 12%, respectively (P = NS). After 60 min of CAO, reperfusion did not significantly reduce either transmural or circumferential necrosis. Thus early reperfusion reduced infarct size by converting potentially transmural infarcts into subendocardial infarcts but did not significantly reduce the lateral or circumferential extent of necrosis.

KATP channels are common mediators of ischemic and calcium preconditioning in rabbits

1998 ◽  
Vol 274 (4) ◽  
pp. H1106-H1112 ◽  
Author(s):  
Ichiro Kouchi ◽  
Tomoyuki Murakami ◽  
Ryuzo Nawada ◽  
Masaharu Akao ◽  
Shigetake Sasayama
Keyword(s):  
Infarct Size ◽  
Channel Blocker ◽  
Myocardial Infarct ◽  
Katp Channels ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Myocardial Infarct Size ◽  
Area At Risk ◽  
Channel Activation ◽  
Calcium Infusion

Calcium preconditioning (CPC), like ischemic preconditioning (IPC), reduces myocardial infarct size in dogs and rats. ATP-sensitive potassium (KATP) channels induce cardioprotection of IPC in these animals. To determine whether KATP channels mediate both IPC and CPC, pentobarbital sodium-anesthetized rabbits received 30 min of coronary artery occlusion followed by 180 min of reperfusion. IPC was elicited by 5 min of occlusion and 10 min of reperfusion, and CPC was elicited by two cycles of 5 min of calcium infusion with an interval period of 15 min. Infarct size expressed as a percentage of the area at risk was 38 ± 3% (mean ± SE) in controls. IPC, CPC, and pretreatment with a KATP channel opener, cromakalim, all reduced infarct size to 13 ± 2, 17 ± 2, and 12 ± 3%, respectively ( P < 0.01 vs. controls). Glibenclamide, a KATP channel blocker administered 45 min (but not 20 min) before sustained ischemia, attenuated the effects of IPC and CPC (31 ± 4 and 41 ± 6%, respectively). Thus KATP channel activation appears to contribute to these two types of cardioprotection in rabbits.

scholarly journals Sevoflurane Confers Additional Cardioprotection after Ischemic Late Preconditioning in Rabbits

2003 ◽  
Vol 99 (3) ◽  
pp. 624-631 ◽  
Author(s):  
Jost Müllenheim ◽  
Dirk Ebel ◽  
Mirco Bauer ◽  
Florian Otto ◽  
André Heinen ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Infarct Size ◽  
Katp Channels ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Area At Risk ◽  
Late Preconditioning ◽  
Infarct Size Reduction ◽  
Artery Disease ◽  
Conscious Animals

Background Sevoflurane exerts cardioprotective effects that mimic the early ischemic preconditioning phenomenon (EPC) by activating adenosine triphosphate-sensitive potassium (KATP) channels. Ischemic late preconditioning (LPC) is an important cardioprotective mechanism in patients with coronary artery disease. The authors investigated whether the combination of LPC and sevoflurane-induced preconditioning results in enhanced cardioprotection and whether opening of KATP channels plays a role in this new setting. Methods Seventy-three rabbits were instrumented with a coronary artery occluder. After recovery for 10 days, they were subjected to 30 min of coronary artery occlusion and 120 min of reperfusion (I/R). Controls (n = 14) were not preconditioned. LPC was induced in conscious animals by a 5-min period of coronary artery occlusion 24 h before I/R (LPC, n = 15). Additional EPC was induced by a 5-min period of myocardial ischemia 10 min before I/R (LPC+EPC, n = 9). Animals of the sevoflurane (SEVO) groups inhaled 1 minimum alveolar concentration of sevoflurane for 5 min at 10 min before I/R with (LPC+SEVO, n = 10) or without (SEVO, n = 15) additional LPC. The KATP channel blocker 5-hydroxydecanoate (5-HD, 5 mg/kg) was given intravenously 10 min before sevoflurane administration (LPC+SEVO+5-HD, n = 10). Results Infarct size of the area at risk (triphenyltetrazolium staining) was reduced from 45 +/- 16% (mean+/-SD, control) to 27 +/- 11% by LPC (P &lt; 0.001) and to 27 +/- 17% by sevoflurane (P = 0.001). Additional sevoflurane administration after LPC led to a further infarct size reduction to 14 +/- 8% (LPC+SEVO, P = 0.003 vs. LPC; P = 0.032 vs. SEVO), similar to the combination of LPC and EPC (12 +/- 8%; P = 0.55 vs. LPC+SEVO). Cardioprotection induced by LPC+SEVO was abolished by 5-HD (LPC+SEVO+5-HD, 41 +/- 19%, P = 0.001 vs. LPC+SEVO). Conclusions Sevoflurane administration confers additional cardioprotection after LPC by opening of KATP channels.

Differential role of KATP channels in late preconditioning against myocardial stunning and infarction in rabbits

2000 ◽  
Vol 279 (5) ◽  
pp. H2350-H2359 ◽  
Author(s):  
Hitoshi Takano ◽  
Xian-Liang Tang ◽  
Roberto Bolli
Keyword(s):  
Infarct Size ◽  
Myocardial Stunning ◽  
Late Phase ◽  
Katp Channels ◽  
Wall Thickening ◽  
Late Preconditioning ◽  
End Effectors ◽  
Sparing Effect ◽  
Systolic Wall Thickening

The role of ATP-sensitive potassium (KATP) channels in the late phase of ischemic preconditioning (PC) remains unclear. Furthermore, it is unknown whether KATP channels serve as end effectors both for late PC against infarction and against stunning. Thus, in phase I of this study, conscious rabbits underwent a 30-min coronary occlusion (O) followed by 72 h of reperfusion (R) with or without ischemic PC (6 4-min O/4-min R cycles) 24 h earlier. Late PC reduced infarct size ∼46% versus controls. The KATPchannel blocker 5-hydroxydecanoic acid (5-HD), given 5 min before the 30-min O, abrogated the infarct-sparing effect of late PC but did not alter infarct size in non-PC rabbits. In phase II, rabbits underwent six 4-min O/4-min R cycles for 3 consecutive days ( days 1, 2, and 3). In controls, the total deficit of systolic wall thickening (WTh) after the sixth reperfusion was reduced by 46% on day 2 and 54% on day 3compared with day 1, indicating a late PC effect against myocardial stunning. Neither 5-HD nor glibenclamide, given on day 2, abrogated late PC. The KATP channel opener diazoxide, given on day 1, attenuated stunning, and this effect was completely blocked by 5-HD. Thus the same dose of 5-HD that blocked the antistunning effect of diazoxide failed to block the antistunning effects of late PC. Furthermore, when diazoxide was administered in PC rabbits on day 2, myocardial stunning was further attenuated, indicating that diazoxide and late PC have additive anti-stunning effects. We conclude that KATP channels play an essential role in late PC against infarction but not in late PC against stunning, revealing an important pathogenetic difference between these two forms of cardioprotection.

First molecular evidence that inositol trisphosphate signaling contributes to infarct size reduction with preconditioning

2006 ◽  
Vol 291 (4) ◽  
pp. H2008-H2012 ◽  
Author(s):  
Karin Przyklenk ◽  
Michelle Maynard ◽  
Peter Whittaker
Keyword(s):  
Infarct Size ◽  
Treatment Phase ◽  
Size Reduction ◽  
Receptor Protein ◽  
Molecular Evidence ◽  
Infarct Size Reduction ◽  
Tetrazolium Staining ◽  
Sparing Effect ◽  
To Receive

Considerable attention has focused on the role of protein kinase C (PKC) in triggering the profound infarct-sparing effect of ischemic preconditioning (PC). In contrast, the involvement of inositol 1,4,5-trisphosphate [Ins( 1 , 4 , 5 )P3], the second messenger generated in parallel with the diacylglycerol-PKC pathway, remains poorly understood. We hypothesized that, if Ins( 1 , 4 , 5 )P3signaling [i.e., release of Ins( 1 , 4 , 5 )P3and subsequent binding to Ins( 1 , 4 , 5 )P3receptors] contributes to PC-induced cardioprotection, then the reduction of infarct size achieved with PC would be attenuated in mice that are deficient in Ins( 1 , 4 , 5 )P3receptor protein. To test this concept, hearts were harvested from 1) B6C3Fe- a/a-Itpr-1opt+/−/J mutants displaying reduced expression of Ins( 1 , 4 , 5 )P3receptor-1 protein, 2) Itpr-1opt+/+wild types from the colony, and 3) C57BL/6J mice. All hearts were buffer-perfused and randomized to receive two 5-min episodes of PC ischemia, pretreatment with d- myo-Ins( 1 , 4 , 5 )P3[sodium salt of native Ins( 1 , 4 , 5 )P3], the mitochondrial ATP-sensitive K+channel opener diazoxide, or no intervention (controls). After the treatment phase, all hearts underwent 30-min global ischemia followed by 2 h of reperfusion, and infarct size was delineated by tetrazolium staining. In both wild-type and C57BL/6J cohorts, area of necrosis in hearts that received PC, d- myo-Ins( 1 , 4 , 5 )P3, and diazoxide averaged 28–35% of the total left ventricle (LV), significantly smaller than the values of 52–53% seen in controls ( P < 0.05). In contrast, in Itpr-1opt+/−mutants, protection was only seen with diazoxide: neither PC nor d- myo-Ins( 1 , 4 , 5 )P3limited infarct size (52–58% vs. 56% of the LV in mutant controls). These data provide novel evidence that Ins( 1 , 4 , 5 )P3signaling contributes to infarct size reduction with PC.

Diabetes and hyperglycemia impair activation of mitochondrial KATP channels

2001 ◽  
Vol 280 (4) ◽  
pp. H1744-H1750 ◽  
Author(s):  
Judy R. Kersten ◽  
Matthew W. Montgomery ◽  
Tannaz Ghassemi ◽  
Eric R. Gross ◽  
Wolfgang G. Toller ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Infarct Size ◽  
Myocardial Infarct ◽  
Katp Channels ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
High Dose ◽  
Myocardial Infarct Size ◽  
Area At Risk ◽  
Triphenyltetrazolium Chloride

Hyperglycemia is an important predictor of cardiovascular mortality in patients with diabetes. We investigated the hypothesis that diabetes or acute hyperglycemia attenuates the reduction of myocardial infarct size produced by activation of mitochondrial ATP-regulated potassium (KATP) channels. Acutely instrumented barbiturate-anesthetized dogs were subjected to a 60-min period of coronary artery occlusion and 3 h of reperfusion. Myocardial infarct size (triphenyltetrazolium chloride staining) was 25 ± 1, 28 ± 3, and 25 ± 1% of the area at risk (AAR) for infarction in control, diabetic (3 wk after streptozotocin-alloxan), and hyperglycemic (15% intravenous dextrose) dogs, respectively. Diazoxide (2.5 mg/kg iv) significantly decreased infarct size (10 ± 1% of AAR, P < 0.05) but did not produce protection in the presence of diabetes (28 ± 5%) or moderate hyperglycemia (blood glucose 310 ± 10 mg/dl; 23 ± 2%). The dose of diazoxide and the degree of hyperglycemia were interactive. Profound (blood glucose 574 ± 23 mg/dl) but not moderate hyperglycemia blocked the effects of high-dose (5.0 mg/kg) diazoxide [26 ± 3, 15 ± 3 ( P < 0.05), and 11 ± 2% ( P < 0.05), respectively]. There were no differences in systemic hemodynamics, AAR, or coronary collateral blood flow (by radioactive microspheres) between groups. The results indicate that diabetes or hyperglycemia impairs activation of mitochondrial KATP channels.

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