Adenosine-enhanced ischemic preconditioning provides enhanced postischemic recovery and limitation of infarct size in the rabbit heart

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.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.276.4.h1323 ◽

1999 ◽

Vol 276 (4) ◽

pp. H1323-H1330 ◽

Cited By ~ 18

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.

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Stretch-induced protection shares a common mechanism with ischemic preconditioning in rabbit heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1998.274.3.h955 ◽

1998 ◽

Vol 274 (3) ◽

pp. H955-H964 ◽

Cited By ~ 10

Author(s):

A. Gysembergh ◽

H. Margonari ◽

J. Loufoua ◽

A. Ovize ◽

X. André-Fouët ◽

...

Keyword(s):

Infarct Size ◽

Ischemic Preconditioning ◽

Adenosine Receptors ◽

Volume Overload ◽

Coronary Artery Occlusion ◽

Polymyxin B ◽

Rabbit Heart ◽

Artery Occlusion ◽

Common Mechanism ◽

Kinase C

We sought to determine whether stretch-induced preconditioning may be related to activation of adenosine receptors, ATP-sensitive K+([Formula: see text]) channels, and/or protein kinase C (PKC) in the rabbit heart. Anesthetized rabbits underwent 30 min of coronary artery occlusion followed by 3 h of reperfusion. Ischemic preconditioning was induced by one episode of 5 min of ischemia followed by 5 min of reperfusion, and stretch preconditioning was induced by a transient volume overload. The abilities of gadolinium (Gd3+), a blocker of stretch-activated channels, glibenclamide (Glib), a blocker of [Formula: see text] channels, 8-( p-sulfophenyl)-theophylline (8-SPT), a blocker of adenosine receptors, and polymyxin B (PMXB), an antagonist of PKC, to prevent the infarct size-limiting effect of stretch-induced preconditioning were evaluated. Because the infarct size-reducing effect of stretch occurred in the absence of ischemia and was prevented by previous administration of Gd3+, Glib, 8-SPT, and PMXB, we propose that activation of mechanosensitive ion channels protects the rabbit heart from subsequent sustained ischemic insult, likely through a mechanism that involves downstream activation of PKC, adenosine receptors, and/or [Formula: see text] channels.

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Ischemic Preconditioning in Isolated Rabbit Heart : Effect on Left Ventricular Function, Infarct Size, and Protein Kinase C

Korean Circulation Journal ◽

10.4070/kcj.1996.26.2.541 ◽

1996 ◽

Vol 26 (2) ◽

pp. 541

Author(s):

Ho-Jun Yoo ◽

Jun-Soo Park ◽

Hyun Kim ◽

Un-Ho Ryoo ◽

Bong-Jin Rah ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Left Ventricular Function ◽

Infarct Size ◽

Ventricular Function ◽

Ischemic Preconditioning ◽

Rabbit Heart ◽

Left Ventricular ◽

Isolated Rabbit Heart ◽

Kinase C

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Equal reduction in infarct size by ethylisopropyl-amiloride pretreatment and ischemic preconditioning in the in situ rabbit heart

Myocardial Ischemia and Reperfusion ◽

10.1007/978-1-4615-4979-6_2 ◽

1998 ◽

pp. 13-18

Author(s):

Jens Munch-Ellingsen ◽

Jan Eirik Løkebø ◽

Einar Bugge ◽

Kirsti Ytrehus

Keyword(s):

Infarct Size ◽

Ischemic Preconditioning ◽

Rabbit Heart

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Ecto-5′-Nucleotidase Mediates Infarct Size-Limiting Effect by Ischemic Preconditioning in the Rabbit Heart

Journal of Cardiovascular Pharmacology ◽

10.1097/00005344-199712000-00012 ◽

1997 ◽

Vol 30 (6) ◽

pp. 775-783 ◽

Cited By ~ 4

Author(s):

Kazuo Komamura ◽

Masafumi Kitakaze ◽

Hiroharu Funaya ◽

Yasunori Ueda ◽

Koichi Node ◽

...

Keyword(s):

Infarct Size ◽

Ischemic Preconditioning ◽

Rabbit Heart

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Preconditioning protects ischemic rabbit heart by protein kinase C activation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1994.266.3.h1145 ◽

1994 ◽

Vol 266 (3) ◽

pp. H1145-H1152 ◽

Cited By ~ 68

Author(s):

K. Ytrehus ◽

Y. Liu ◽

J. M. Downey

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Infarct Size ◽

Ischemic Preconditioning ◽

Isolated Heart ◽

Polymyxin B ◽

Rabbit Heart ◽

Risk Zone ◽

Kinase C ◽

Regional Myocardial Ischemia

Myocardial protection in the rabbit induced by ischemic preconditioning is thought to be adenosine receptor linked, but the signaling pathway responsible for the protection has yet to be identified. This study tests whether protein kinase C could be involved. Either of two inhibitors of protein kinase C, staurosporine (50 micrograms/kg) or polymyxin B (24 mg/kg), were administered to rabbits subjected to 30 min regional myocardial ischemia followed by 180 min reperfusion. Half of the rabbits were preconditioned while the other half served as nonpreconditioned controls. Nonpreconditioned hearts without drug or treated with staurosporine or polymyxin B resulted in 37.8 +/- 3.1, 40.5 +/- 2.8, and 42.0 +/- 7.0% infarction of the risk zone, respectively. Preconditioning limited infarct size to 7.3 +/- 2.7%. Both inhibitors blocked protection in preconditioned hearts with 36.2 +/- 2.7 and 40.9 +/- 2.5% of the risk zone infarcted, respectively. Activation of protein kinase C with 4 beta-phorbol 12-myristate 13-acetate (PMA) or with 1-oleyl-2-acetyl glycerol (OAG) mimicked preconditioning in buffer-perfused hearts. PMA (0.01 nmol/min) or OAG (10 nmol/min) for 5 min was followed by 10 min of washout. Infarct size after 30 min regional ischemia was limited in the PMA and OAG groups (6.4 +/- 1.4 and 11.7 +/- 3.3 vs. 28.0 +/- 4.5% in untreated controls) and was equipotent with ischemic preconditioning (11.8 +/- 2.2%). Polymyxin B also blocked protection from ischemic preconditioning in the isolated heart (33.0 +/- 5.0%).(ABSTRACT TRUNCATED AT 250 WORDS)

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Preservation of ischemia and isoflurane-induced preconditioning after brain death in rabbit hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00361.2002 ◽

2002 ◽

Vol 283 (5) ◽

pp. H1769-H1774 ◽

Cited By ~ 10

Author(s):

Pascal Chiari ◽

Vincent Piriou ◽

Guylaine Hadour ◽

Claire Rodriguez ◽

Joseph Loufouat ◽

...

Keyword(s):

Brain Death ◽

Infarct Size ◽

Ischemic Preconditioning ◽

Coronary Occlusion ◽

Rabbit Heart ◽

Catecholamine Release ◽

Plasma Catecholamine ◽

Balloon Inflation ◽

Time Points ◽

Catecholamine Levels

We sought to determine whether brain death-induced catecholamine release preconditions the heart, and if not, whether it precludes further protection by repetitive ischemia or isoflurane. Anesthetized rabbits underwent 30 min of coronary occlusion and 4 h of reperfusion. The effect on infarct size of either no intervention (controls), ischemic preconditioning (IPC), or isoflurane inhalation (Iso) was evaluated with or without previous brain death (BD) induced by subdural balloon inflation. Plasma catecholamine levels were measured at several time points. Although it dramatically increase plasma catecholamine levels, BD failed to reduce infarct size that averaged 0.49 ± 0.34 without BD versus 0.45 ± 0.27 g with BD. IPC and Iso, alone as well as after BD, significantly reduced infarct size that averaged 0.11 ± 0.04, 0.21 ± 0.15, 0.10 ± 0.09, and 0.22 ± 0.10 g in IPC, Iso, BD + IPC, and BD + Iso groups, respectively (means ± SD, P < 0.05 vs. controls). BD-induced catecholamines “storm” does not precondition the rabbit heart that however retains the ability to be protected by repetition of brief ischemia or isoflurane inhalation.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1998.275.4.h1329 ◽

1998 ◽

Vol 275 (4) ◽

pp. H1329-H1337 ◽

Cited By ~ 1

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.

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