scholarly journals Ecto-5′-nucleotidase is not required for ischemic preconditioning in rabbit myocardium in situ

1998 ◽  
Vol 275 (4) ◽  
pp. H1329-H1337 ◽  
Author(s):  
Takayuki Miki ◽  
Tetsuji Miura ◽  
Rolf Bünger ◽  
Katsuo Suzuki ◽  
Jun Sakamoto ◽  
...  
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Cardiovascular Responses ◽  
Adenosine Diphosphate ◽  
Rabbit Heart ◽  
Area At Risk ◽  
Inotropic Effects ◽  
And Control

This study tested the hypothesis that cardiac ecto-5′-nucleotidase (ecto-5′-NT) activity during ischemic preconditioning (PC) contributes to augmented tolerance against ischemia, thereby reducing infarct size in the rabbit heart in situ. The effects of α,β-methylene-adenosine diphosphate (AOPCP), a selective inhibitor of ecto-5′-NT, on cardiovascular responses to AMP were measured to establish in vivo activities of the enzyme and its inhibitor. Left atrial infusion of AOPCP (0.75 mg ⋅ kg−1⋅ min−1) raised AOPCP plasma levels to 138 μM; under these conditions negative chronotropic and inotropic effects of AMP were blocked, demonstrating essentially full inhibition of ecto-5′-NT in the heart in situ. This AOPCP-blocked heart in situ model was used to examine the proposed contribution of ecto-5′-NT in ischemic PC. Myocardial infarction caused by 30-min ischemia was followed by 3-h reperfusion. Infarct size (IS) was measured and expressed as a percentage of the size of the area at risk (%IS/AR). In untreated controls, %IS/AR was 38.1 ± 3.8%; PC (5-min ischemia, 5-min reperfusion) markedly reduced %IS/AR to 10.0 ± 2.0%. Essentially identical IS reductions by PC were observed in AOPCP-blocked animals (%IS/AR = 13.8 ± 2.2 and 13.3 ± 1.8% in rabbits receiving AOPCP at 0.75 and 1.50 mg ⋅ kg−1⋅ min−1, respectively); here plasma AOPCP levels were established before and during PC but not during the subsequent prolonged ischemia. As expected, AOPCP also did not affect %IS/AR in non-PC controls (%IS/AR = 35.5 ± 3.7%). In contrast but as predicted, adenosine-receptor blockade by 8-phenyltheophylline (10 mg/kg iv) substantially attenuated IS reduction by PC in both AOPCP-blocked and control hearts (%IS/AR = 25.2 ± 4.3 and 21.8 ± 2.2%, respectively; P < 0.05 vs. PC alone). The results demonstrate that cardiac ecto-5′-NT is not required for ischemic PC against infarction in the rabbit.

Endogenous myocardial norepinephrine is not essential for ischemic preconditioning in rabbit heart

1996 ◽  
Vol 270 (3) ◽  
pp. H1078-H1084 ◽  
Author(s):  
J. L. Ardell ◽  
X. M. Yang ◽  
B. A. Barron ◽  
J. M. Downey ◽  
M. V. Cohen
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Rabbit Heart ◽  
Chemical Sympathectomy ◽  
Single Cycle ◽  
Risk Zone ◽  
Regional Ischemia ◽  
Norepinephrine Content ◽  
Ischemic Period

To determine whether endogenous cardiac catecholamines mediate ischemic preconditioning (PC) in the rabbit heart, myocardial catecholamines were depleted by reserpine (5 mg/kg, 18-24 h pre-PC) or surgical sympathectomy (2 wk pre-PC). In vivo hearts were subjected to 30 min of regional ischemia and 3 h of reperfusion. PC involved either one or four cycles of 5-min ischemia and 10-min reperfusion before the 30-min ischemic period. Right ventricular norepinephrine content (pmol/mg protein), 51.4 +/- 11.1 in untreated rabbits, was reduced to 0.6 +/- 0.2 and 1.8 +/- 0.5 by surgical sympathectomy and reserpine, respectively. Infarct size (IS) was measured by tetrazolium and expressed as percentage of the risk zone. In untreated animals exposed solely to 30 min of regional ischemia IS was 35.5 +/- 1.6% and was unchanged by reserpine (43.3 +/- 5.4%) or surgical sympathectomy (33.4 +/- 3.5%). compared with infarction in the respective non-PC controls, IS in untreated (7.4 +/- 1.5%, P < 0.0001) and surgically sympathectomized (11.2 +/- 1.5%, P < 0.0001) animals was significantly diminished by a single cycle of PC, but the latter exerted less protection in reserpinized animals (27.6 +/- 3.5%, P < 0.0025). Four cycles of PC, however, reduced IS to 10.3 +/- 1.2% in reserpinized animals. Therefore, despite comparable depression of myocardial norepinephrine content, surgical and chemical sympathectomy had different effects on the level of protection afforded by ischemic PC. These data demonstrate that endogenous myocardial catecholamines are not essential for protection from PC in the rabbit.

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.

Delayed ischemic preconditioning is mediated by opening of ATP-sensitive potassium channels in the rabbit heart

1999 ◽  
Vol 276 (4) ◽  
pp. H1323-H1330 ◽  
Author(s):  
Nelson L. Bernardo ◽  
Michael D’Angelo ◽  
Shinji Okubo ◽  
Archi Joy ◽  
Rakesh C. Kukreja
Keyword(s):  
Protective Effect ◽  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Action Potential Duration ◽  
Rabbit Heart ◽  
Monophasic Action Potential ◽  
Initial Stimulus ◽  
Selective Blocker ◽  
Second Window Of Protection

Cardioprotection from preconditioning reappears 24 h after the initial stimulus. This phenomenon is called the second window of protection (SWOP). We hypothesized that opening of the ATP-sensitive potassium (KATP) channel mediates the protective effect of SWOP. Rabbits were preconditioned (PC) with four cycles of 5-min regional ischemia each followed by 10 min of reperfusion. Twenty-four hours later, the animals were subjected to sustained ischemia for 30 min followed by 180 min of reperfusion (I/R). Glibenclamide (Glib, 0.3 mg/kg ip) or 5-hydroxydecanoate (5-HD, 5 mg/kg iv) was used to block the KATP channel function. Infarct size was reduced from 41.2 ± 2.6% in sham-operated rabbits to 11.6 ± 1.0% in PC rabbits, a 71% reduction ( n = 11, P < 0.01). Treatment with Glib or 5-HD before I/R increased the infarct size to 43.4 ± 2.6 and 37.8 ± 1.9%, respectively ( P < 0.01 vs. PC group, n = 12/group). Sham animals treated with either Glib or 5-HD had an infarct size of 39.0 ± 3.4 and 37.8 ± 1.5%, respectively, which was not different from control (40.0 ± 3.8%) or sham (41.2 ± 2.6%) I/R hearts. Monophasic action potential duration (APD) at 50% repolarization significantly shortened by 28.7, 26.6, and 23.3% in sham animals during 10, 20, and 30 min of ischemia. However, no further augmentation in the shortening of APD was observed in PC hearts. Glib and 5-HD significantly suppressed ischemia-induced epicardial APD shortening, suggesting that 5-HD may not be a selective blocker of the mitochondrial KATP channel in vivo. We conclude that SWOP is mediated by a KATP channel-sensitive mechanism that may have occurred because of the opening of the sarcolemmal KATP channel in vivo.

Delayed preconditioning with adenosine is mediated by opening of ATP-sensitive K+ channels in rabbit heart

1999 ◽  
Vol 277 (1) ◽  
pp. H128-H135 ◽  
Author(s):  
Nelson L. Bernardo ◽  
Shinji Okubo ◽  
Mohammed M. Maaieh ◽  
Mark A. Wood ◽  
Rakesh C. Kukreja
Keyword(s):  
Infarct Size ◽  
Coronary Artery Occlusion ◽  
Rabbit Heart ◽  
Blue Dye ◽  
Channel Blockers ◽  
Area At Risk ◽  
Risk Area ◽  
Group I ◽  
Ischemia Group

The adenosine agonist 2-chloro- N 6-cyclopentyladenosine (CCPA) induces delayed ischemic protection in vivo. We hypothesized that this protection is mediated by opening of ATP-sensitive K+(KATP) channels and increased synthesis of 72-kDa heat shock protein (HSP 72). Six groups ( n = 9–13 animals/group) of animals were studied: group I, control rabbits that received no treatment; group II, animals given glibenclamide (0.3 mg/kg iv) 30 min before ischemia; group III, animals given 5-hydroxydecanoate (5-HD; 5 mg/kg iv) 15 min before ischemia; group IV, rabbits treated with CCPA (0.1 mg/kg iv) 24 h before ischemia; and groups V and VI, CCPA-treated animals that received the KATP-channel blockers glibenclamide or 5-HD, respectively, 30 or 15 min before ischemia. All animals were subjected to ischemia by 30 min of coronary artery occlusion followed by 3 h of reperfusion. Risk area was delineated by injection of 10% Evans blue dye, and infarct size was determined by triphenyltetrazolium staining. Action potential duration (APD) was measured with an epicardial electrode. HSP 72 was measured by Western blotting. CCPA caused a significant reduction in infarct size [12.02 ± 1.0 vs. 40.0 ± 3.8% (%area at risk) in controls, P < 0.01] that was blocked by glibenclamide (36.2 ± 3.1%, P < 0.01) and 5-HD (35.0 ± 2.9%, P < 0.01). Glibenclamide and 5-HD did not change infarct size in control rabbits. These blockers significantly suppressed ischemia-induced APD shortening in control and CCPA-treated animals. CCPA treatment did not induce HSP 72 in hearts. These data suggest that adenosine-initiated delayed protection is mediated via opening of KATP channels but does not involve the synthesis of HSP 72.

scholarly journals CRYAB and HSPB2 deficiency alters cardiac metabolism and paradoxically confers protection against myocardial ischemia in aging mice

2007 ◽  
Vol 293 (5) ◽  
pp. H3201-H3209 ◽  
Author(s):  
Ivor J. Benjamin ◽  
Yiru Guo ◽  
Sathyanarayanan Srinivasan ◽  
Sihem Boudina ◽  
Ryan P. Taylor ◽  
...  
Keyword(s):  
At Risk ◽  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Coronary Occlusion ◽  
Ex Vivo ◽  
Double Knockout ◽  
Area At Risk ◽  
Small Molecular Weight ◽  
Calcium Dependent

The abundantly expressed small molecular weight proteins, CRYAB and HSPB2, have been implicated in cardioprotection ex vivo. However, the biological roles of CRYAB/HSPB2 coexpression for either ischemic preconditioning and/or protection in situ remain poorly defined. Wild-type (WT) and age-matched (∼5–9 mo) CRYAB/HSPB2 double knockout (DKO) mice were subjected either to 30 min of coronary occlusion and 24 h of reperfusion in situ or preconditioned with a 4-min coronary occlusion/4-min reperfusion × 6, before similar ischemic challenge (ischemic preconditioning). Additionally, WT and DKO mice were subjected to 30 min of global ischemia in isolated hearts ex vivo. All experimental groups were assessed for area at risk and infarct size. Mitochondrial respiration was analyzed in isolated permeabilized cardiac skinned fibers. As a result, DKO mice modestly altered heat shock protein expression. Surprisingly, infarct size in situ was reduced by 35% in hearts of DKO compared with WT mice (38.8 ± 17.9 vs. 59.8 ± 10.6% area at risk, P < 0.05). In DKO mice, ischemic preconditioning was additive to its infarct-sparing phenotype. Similarly, infarct size after ischemia and reperfusion ex vivo was decreased and the production of superoxide and creatine kinase release was decreased in DKO compared with WT mice ( P < 0.05). In permeabilized fibers, ADP-stimulated respiration rates were modestly reduced and calcium-dependent ATP synthesis was abrogated in DKO compared with WT mice. In conclusion, contrary to expectation, our findings demonstrate that CRYAB and HSPB2 deficiency induces profound adaptations that are related to 1) a reduction in calcium-dependent metabolism/respiration, including ATP production, and 2) decreased superoxide production during reperfusion. We discuss the implications of these disparate results in the context of phenotypic responses reported for CRYAB/HSPB2-deficient mice to different ischemic challenges.

Role of the β1-Adrenergic Pathway in Anesthetic and Ischemic Preconditioning against Myocardial Infarction in the Rabbit Heart In Vivo 

2006 ◽  
Vol 105 (3) ◽  
pp. 503-510 ◽  
Author(s):  
Markus Lange ◽  
Thorsten M. Smul ◽  
Christoph A. Blomeyer ◽  
Andreas Redel ◽  
Karl-Norbert Klotz ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Coronary Artery ◽  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Myocardial Infarct ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Myocardial Infarct Size ◽  
Area At Risk

Background Anesthetic and ischemic preconditioning share similar signal transduction pathways. The authors tested the hypothesis that the beta1-adrenergic signal transduction pathway mediates anesthetic and ischemic preconditioning in vivo. Methods Pentobarbital-anesthetized (30 mg/kg) rabbits (n = 96) were instrumented for measurement of systemic hemodynamics and subjected to 30 min of coronary artery occlusion and 3 h of reperfusion. Sixty minutes before occlusion, vehicle (control), 1.0 minimum alveolar concentration desflurane, or sevoflurane, and esmolol (30.0 mg x kg(-1) x h(-1)) were administered for 30 min, respectively. Administration of a single 5-min cycle of ischemic preconditioning was instituted 35 min before coronary artery occlusion. In separate groups, the selective blocker esmolol or the protein kinase A inhibitor H-89 (250 microg/kg) was given alone and in combination with desflurane, sevoflurane, and ischemic preconditioning. Results Baseline hemodynamics and area at risk were not significantly different between groups. Myocardial infarct size (triphenyltetrazolium staining) as a percentage of area at risk was 61 +/- 4% in control. Desflurane, sevoflurane, and ischemic preconditioning reduced infarct size to 34 +/- 2, 36 +/- 5, and 23 +/- 3%, respectively. Esmolol did not alter myocardial infarct size (65 +/- 5%) but abolished the protective effects of desflurane and sevoflurane (57 +/- 4 and 52 +/- 4%, respectively) and attenuated ischemic preconditioning (40 +/- 4%). H-89 did not alter infarct size (60 +/- 4%) but abolished preconditioning by desflurane (57 +/- 5%) and sevoflurane (61 +/- 1%). Ischemic preconditioning (24 +/- 7%) was not affected by H-89. Conclusions The results demonstrate that anesthetic preconditioning is mediated by the beta1-adrenergic pathway, whereas this pathway is not essential for ischemic preconditioning. These results indicate important differences in the mechanisms of anesthetic and ischemic preconditioning.

Favorable effects of hyperosmotic reperfusion on myocardial edema and infarct size

1992 ◽  
Vol 262 (1) ◽  
pp. H17-H22 ◽  
Author(s):  
D. Garcia-Dorado ◽  
P. Theroux ◽  
R. Munoz ◽  
J. Alonso ◽  
J. Elizaga ◽  
...  
Keyword(s):  
At Risk ◽  
Infarct Size ◽  
Water Content ◽  
Myocardial Edema ◽  
Area At Risk ◽  
Triphenyltetrazolium Chloride ◽  
Group A ◽  
And Control

Myocardial water content and infarct size were studied in 39 pigs randomly assigned to a nonintervention group, a group with an intracoronary infusion of a control solution, and a group with a hyperosmotic infusion to 450 mosM by the addition of D-mannitol. The intracoronary solutions were selectively infused into the left anterior descending coronary artery just distal to the occlusion site starting 48 min after occlusion. Reperfusion was performed 3 min later and the infusion rate progressively tapered off over the following 33 min. Multiple myocardial fragments were then obtained in nine pigs, from endocardial, mesocardial, and epicardial regions of the ischemic and control myocardium. Water content measured after 48 h of dessication was significantly greater in the reperfused [530 +/- 7 ml/100 (mean +/- SE) g dry wt] compared with control myocardium (374 +/- 3; P less than 0.0001) and similar in reperfused control and isotonic infusion groups (556 +/- 7 and 543 +/- 8 ml/100 g dry wt); it was 491 +/- 11 with intracoronary D-mannitol infusion, representing 35% less increase (P less than 0.001). In the 30 remaining pigs, area at risk and infarct size were measured 24 h later by in vivo fluorescein and in vitro triphenyltetrazolium chloride. Infarct size was similar in control and in the isotonic reperfused hearts, 6.80 +/- 1.05 and 6.22 +/- 0.76% of ventricular weight, and smaller with D-mannitol, 4.46 +/- 0.46 (P less than 0.05). The ratio of infarct size to area at risk was also smaller [0.415 +/- 0.029 vs. 0.543 +/- 0.052 and 0.547 +/- 0.045 (P less than 0.02)].(ABSTRACT TRUNCATED AT 250 WORDS)

Acute hyperglycemia abolishes ischemic preconditioning in vivo

1998 ◽  
Vol 275 (2) ◽  
pp. H721-H725 ◽  
Author(s):  
Judy R. Kersten ◽  
Todd J. Schmeling ◽  
Karl G. Orth ◽  
Paul S. Pagel ◽  
David C. Warltier
Keyword(s):  
Myocardial Infarction ◽  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Plasma Glucose ◽  
Myocardial Infarct ◽  
Coronary Artery Occlusion ◽  
Myocardial Infarct Size ◽  
Area At Risk ◽  
Acute Hyperglycemia

Ischemic preconditioning provides a powerful means to reduce myocardial infarct size in vivo and has been proposed to limit the extent of myocardial infarction in patients. In contrast, hyperglycemia correlates with increases in mortality after acute myocardial infarction. Thus we hypothesized that acute hyperglycemia alters the protection afforded by ischemic preconditioning, and this hypothesis was tested in acutely instrumented dogs subjected to a prolonged (60 min) coronary artery occlusion and 3 h of reperfusion. Ischemic preconditioning was elicited by four 5-min occlusion-reperfusion periods in the presence or absence of an intravenous infusion of 15% dextrose in water to produce acute hyperglycemia (plasma glucose concentration of 300 mg/dl). The dose-dependent effects of hyperglycemia on myocardial infarct size independent of preconditioning stimuli were further evaluated in dogs subjected to increases in plasma glucose concentrations to either 300 or 600 mg/dl. Infarct size (triphenyltetrazolium staining) was 24 ± 2% of the area at risk in control dogs and was significantly ( P < 0.05) decreased by ischemic preconditioning (8 ± 1%). Modest degrees of hyperglycemia (300 mg/dl) had no effect on infarct size (34 ± 4%) but abolished the protective effect of ischemic preconditioning (30 ± 5%). In contrast, profound hyperglycemia (600 mg/dl) increased infarct size (44 ± 6%). Hemodynamics and coronary collateral blood flow (radioactive microspheres) were similar between groups. Thus acute hyperglycemia adversely modulates myocardial injury in response to ischemia in vivo.

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