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Results for “Ischemic Preconditioning”

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PubMed2003

Effects of ischemic preconditioning on myocardial protective on cardiac surgery: possibility of ischemic preconditioning and adenosine administration.

SUBJECT: We evaluated the efficacy for concomitant use of ischemic preconditioning (IPC) and cardioplegic arrest with adenosine premedication on myocardial protection. METHODS: Twenty-one pigs were divided into three groups: 1) control group, 2) IPC group which had IPC, 3) IPC+adenosine triphosphate (ATP) group which had an administration of 140 gamma of ATP (Adetphos, Kowa, Tokyo, Japan) during IPC. IPC was employed by 3 minutes of aortic cross clamping and 5 minutes of reperfusion. After cardioplegic arrest, the hemodynamical state was observed during 60 minutes of reperfusion. Serum adenosine, troponin-T, E-max, and Tau (the time constant of early diastolic left ventricular pressure decay) were compared. RESULTS: Serum adenosine levels and at the end of IPC and 60 minutes reperfusion were significantly higher in the IPC and IPC+ATP groups than the control group. Comparison of the myocardial contractile force indicator E-max showed that the IPC and IPC+ATP groups showed significantly higher recovery rates of myocardial contractile force than the control group. Tau was the lowest in the IPC+ATP group than the other groups. In the histopathological study, the control group showed widely distributed hypercontraction bands and waving degeneration of myofibrils. On the other hand, the structure of myofibrils was well preserved in the IPC and IPC+ATP groups. CONCLUSIONS: The concomitant use of IPC enhanced the effect of a myocardial protective solution. However, the administration of adenosine during IPC did not show any further advantage than IPC along. (Ann Thorac Cardiovasc Surg 2003; 9: 307-13)

Adenosine↗

PubMed1997

Inhibitory effects of glibenclamide and pertussis toxin on the attenuation of ischemia-induced myocardial acidosis following ischemic preconditioning in dogs.

Ischemic preconditioning is known to be mediated by several humoral factors, such as adenosine, norepinephrine, and bradykinin. We examined intracellular signal transduction of ischemic preconditioning following receptor stimulation. Alterations in the pH of the ischemic bed were monitored to assess the response of control and ischemic-preconditioned myocardium to glibenclamide and pertussis toxin. Pentobarbital-anesthetized open-chest dogs were subjected to 40 min of ligation of the left anterior descending coronary artery. Ischemic preconditioning was elicited by 25-min periods of coronary ligation followed by 5 min of reperfusion before a 40-min period of ligation. Glibenclamide (0.3 mg/kg)was given i.v. 20 min before the onset of ischemic preconditioning. Pertussis toxin (6-10 micrograms/kg) was given i.v. 3 days before the experiment. Tissue myocardial pH was measured by a glass micro-pH electrode. Ischemia for 5 min decreased myocardial pH and reperfusion returned it to the preischemic levels. Ischemia for 40 min decreased the myocardial pH from 7.43 +/- 0.06 to 6.43 +/- 0.08. Ischemic preconditioning significantly attenuated the decrease in myocardial pH (6.57 +/- 0.06) induced by 40 min of ischemia. Pretreatment with either glibenclamide or pertussis toxin completely abolished the effect of ischemic preconditioning on ischemic myocardial acidosis. Ischemic preconditioning can attenuate ischemia-induced myocardial acidosis in dogs, and this effect is mediated by activation of adenosine triphosphate-sensitive potassium channels and pertussis toxin-sensitive guanosine triphosphate-binding protein.

Acetylcholine↗

PubMed2006

TNFR1 mediates increased neuronal membrane EAAT3 expression after in vivo cerebral ischemic preconditioning.

A short ischemic event (ischemic preconditioning) can result in subsequent resistance to severe ischemic injury (ischemic tolerance). Glutamate is released after ischemia and produces cell death. It has been described that after ischemic preconditioning, the release of glutamate is reduced. We have shown that an in vitro model of ischemic preconditioning produces upregulation of glutamate transporters which mediates brain tolerance. We have now decided to investigate whether ischemic preconditioning-induced glutamate transporter upregulation takes also place in vivo, its cellular localization and the mechanisms by which this upregulation is controlled. A period of 10 min of temporary middle cerebral artery occlusion was used as a model of ischemic preconditioning in rat. EAAT1, EAAT2 and EAAT3 glutamate transporters were found in brain from control animals. Ischemic preconditioning produced an up-regulation of EAAT2 and EAAT3 but not of EAAT1 expression. Ischemic preconditioning-induced increase in EAAT3 expression was reduced by the TNF-alpha converting enzyme inhibitor BB1101. Intracerebral administration of either anti-TNF-alpha antibody or of a TNFR1 antisense oligodeoxynucleotide also inhibited ischemic preconditioning-induced EAAT3 up-regulation. Immunohistochemical studies suggest that, whereas the expression of EAAT3 is located in both neuronal cytoplasm and plasma membrane, ischemic preconditioning-induced up-regulation of EAAT3 is mainly localized at the plasma membrane level. In summary, these results demonstrate that in vivo ischemic preconditioning increases the expression of EAAT2 and EAAT3 glutamate transporters the upregulation of the latter being at least partly mediated by TNF-alpha converting enzyme/TNF-alpha/TNFR1 pathway.

ADAM Proteins↗

PubMed1998

Adenosine-enhanced ischemic preconditioning decreases infarct in the regional ischemic sheep heart.

BACKGROUND: Recently we have reported a myoprotective protocol, adenosine-enhanced ischemic preconditioning, that extends the protection afforded by ischemic preconditioning in the isolated crystalloid-perfused heart. In this report the efficacy of adenosine-enhanced ischemic preconditioning in the in situ blood-perfused heart was investigated. METHODS: Sheep were subjected to 60 minutes of regional ischemia and 120 minutes of reperfusion. Ischemic preconditioned hearts received 5 minutes of zero flow regional ischemia and 5 minutes of reperfusion before regional ischemia. Adenosine-enhanced ischemic preconditioned hearts received a bolus injection of 10 mmol adenosine at the immediate start of ischemic preconditioning. Adenosine-treated hearts received an adenosine bolus, 10 minutes before regional ischemia. The ratio of infarct size to area at risk and mechanical function were determined. RESULTS: The infarct size to area at risk ratio in regional ischemia was 55.4%+/-2.1%. This ratio was significantly decreased with ischemic preconditioning and adenosine (22.2%+/-2.2% and 19.3%+/-1.4%, respectively; p < 0.001 versus regional ischemia) and adenosine-enhanced ischemic preconditioning (8.0%+/-2.0%, p < 0.001 versus regional ischemia and ischemic preconditioning, and p < 0.01 versus adenosine). CONCLUSIONS: Adenosine-enhanced ischemic preconditioning significantly decreases infarct size in the in situ blood-perfused heart and provides superior protection compared with ischemic preconditioning.

Adenosine↗

PubMedDate not supplied

Does ischemic preconditioning occur during rehabilitation of ischemic patients?

Ischemic preconditioning is generally a short duration phenomenon, but during acute myocardial infarction a better inhospital outcome of patients with previous angina suggests that the effect of ischemic preconditioning could be longer than it was considered until now. It was also demonstrated that during successive exercise stress testings (ET) ST depression became lesser as a consequence of ischemic preconditioning. We investigated the possible occurrence of ischemic preconditioning during rehabilitation of ischemic patients. There were studied 43p with old myocardial infarction or stable effort angina, 29 men and 14 women, aged 33-68 years, divided in two groups: group I (19p) was included in a cardiac rehabilitation programme (15-20 sessions) and group II (24p) was not. All the patients were submitted to two ET at a month interval, for group I before and after cardiac rehabilitation programme. The peak-effort level was significantly greater for group I (80.26 +/- 7.2w vs 93.42 +/- 8.3w p < 0.05) but not for group II (65.5 +/- 5.8w vs 72.91 +/- 6.5w p > 0.05) during the two ET. The double product (21.573 +/- 3122 vs 24.168 +/- 3423 for group I and 23.551 +/- 3100 vs 21.000 +/- 2752 for group II) was not significantly different (p > 0.05) during the two ET. The same unsignificant modification was noted for maximal ST depression for group II (1.458 +/- 0.32 vs 1.166 +/- 0.21 mm p > 0.05) but not for group I patients in which maximal ST depression during the second ET was significantly less than during the first ET (1.52 +/- 0.23 vs 0.736 +/- 0.12 mm p < 0.05). Because cardiac rehabilitation does not influence the ischemic threshold and because the lesser maximal ST depression during the second ET was noted at the same, or even greater, double product (MVO2), we consider that it can be attributed to ischemic preconditioning.

Adult↗

PubMed2001

Involvement of nitric oxide in ischemic preconditioning.

In ischemic preconditioning, nitric oxide (NO) limits the extension of a subsequent infarct and protects against ischemia/reperfusion-induced endothelial dysfunction, arrhythmias and myocardial stunning. The protective activity concerns both the first and the second window of protection. The antiarrhythmic effect is attributed to microvessel dilation and to the production of cyclic guanosine monophosphate in the myocardium. The limitation of the infarct size is likely to depend on the opening of the mitochondrial adenosine triphosphate-sensitive potassium channels, to which NO participates via the activation of a protein kinase C (PKC). The endothelial protection involves an NO-mediated reduction in neutrophil adherence to the coronary endothelium and platelet aggregation and is accompanied by an enhanced response to vasodilator stimuli. During preconditioning ischemia, NO is released from the coronary endothelium as a result of bradykinin-induced activation of B2 endothelial receptors. In addition to the early protection, endothelium-derived NO is also responsible for a signaling cascade which leads to the activation of myocardial inducible NO synthase, which in turn is responsible for the release of NO involved in the delayed protection. The signaling cascade includes the activation of PKC-epsilon, tyrosine kinase and some mitogen-activated protein kinases. It has been suggested that the activation of PKC-epsilon is mediated by peroxynitrite produced by the combination of NO and the superoxide anion, the latter being generated during reperfusion which follows preconditioning ischemia.

Animals↗

PubMed2005

Ischemic preconditioning protects post-ischemic renal function in anesthetized dogs: role of adenosine and adenine nucleotides.

AIM: To investigate the effects of renal ischemic preconditioning (IPC) on both renal hemodynamics and the renal interstitial concentrations of adenosine and adenine nucleotides induced by ischemia-reperfusion injury. METHODS: Renal hemodynamics responses to ischemia-reperfusion injury in mongrel dog models were determined with or without multiple brief renal ischemic preconditioning treatments, as well as the adenosine A1 receptor antagonist (KW-3902), respectively. The renal interstitial concentrations of adenosine and adenine nucleotides in response to ischemia-reperfusion injury, either following 1-3 cycles of IPC or not, were measured simultaneously using microdialysis sampling technology. RESULTS: One 10-min IPC, adenosine A1 receptor antagonist (KW-3902) also shortened the recovery time of renal blood flow (RBF) and urine flow (UF), as well as mean blood pressure (BP). Advanced renal IPC attenuated the increment of adenosine and adenine nucleotides, as well as recovery time during the 60-min reperfusion which followed the 60-min renal ischemia. All of these recovery times were dependent on the cycles of 10-min IPC. The renal interstitial concentrations of adenosine and adenine nucleotides increased and decreased during renal ischemia and reperfusion, respectively. CONCLUSION: A significant relativity in dog models exists between the cycles of 10-min renal IPC and the recovery time of BP, UF, and RBF during the 60-min renal reperfusion following 60-min renal ischemia, respectively. Renal IPC can protect against ischemia-reperfusion injury and the predominant effect of endogenous adenosine induced by prolonged renal ischemia; renal adenosine A1 receptor activation during the renal ischemia-reperfusion injury is detrimental to renal function.

Adenine↗

PubMedDate not supplied

On the role of Ca2+ in cerebral ischemic preconditioning.

Cerebral ischemic preconditioning (IPC) represents a potent endogenous method of inducing tolerance to otherwise lethal ischemia, both in in vivo and in vitro models. Investigation into the mechanism of this phenomenon has yet again transformed the way that neuroscientists view Ca2+. Generally viewed as an agent of neuronal death, particularly within an excitotoxic setting of cerebral ischemia, Ca2+ is now regarded as a key mediator of IPC. Classification of the role of Ca2+ in IPC defies simple description, but seems to possess a stimulatory role during the tolerance-inducing ischemia and an inhibitory or modulatory role during or following the second normally lethal ischemia.

Animals↗

PubMedDate not supplied

Threshold level of NF-kB activation in small bowel ischemic preconditioning procedure.

Ischemic preconditioning (IPC), which is obtained by exposure to brief periods of vascular occlusion, improves organ tolerance to prolonged ischemia. The aim of this study was to evaluate the threshold level of NF-kB activation in small intestine during an IPC procedure. Various intestinal IPC were performed on 20 Wistar rats in seven groups: group I (GI, nonpreconditioned); group II (GII, 1-minute ischemia and 1-minute reperfusion); group III (GIII, two cycles of 1-minute ischemia and 1-minute reperfusion); group IV (GIV, 2-minutes ischemia and 2-minutes reperfusion); group V (GV, two cycles of 2-minute ischemia and 2-minute reperfusion); group VI (GVI, 5-minute ischemia and 10-minute reperfusion); group VII (GVII, two cycles of 5-minute ischemia and 10-minute reperfusion). Bowel biopsies were collected after laparotomy (control) as well as at 30, 60, and 120 minutes following IPC. We determined the cytoplasmic and nuclear NF-kB by a chemiluminescence-based ELISA method. Our results showed low, constant NF-kB levels in GI. In the preconditioned groups (GII-GVII), NF-kB was significantly elevated at 30 minutes following IPC (P < .05 vs control). After 1 hour, NF-kB activity decreased to the control level. However, 2 hours after IPC both forms of NF-kB were elevated significantly again, which was independent of the number of IPC cycles (P < .05 vs control). Our experiments revealed that one cycle of 1-minute ischemia and 1-minute reperfusion is a critical threshold level for NF-kB activation during small bowel IPC. Longer and more IPC cycles did not result in further elevation of NF-kB activation.

Animals↗

PubMed2004

Myocardial protection with postconditioning is not enhanced by ischemic preconditioning.

BACKGROUND: Ischemic preconditioning (IPC) has been used in off-pump coronary artery bypass surgery (OPCAB) to reduce potential injury secondary to ligation of the target vessel. Previous studies have shown that a brief period of repetitive coronary occlusion applied at the onset of reperfusion, postconditioning (postcon), attenuates myocardial injury. This study tested the hypothesis that coincident application of IPC and postcon would provide more cardioprotection than either intervention alone by inhibiting oxidant-mediated injury after ischemia and reperfusion. METHODS: Four groups of open-chest canines endured 60 minutes coronary occlusion followed by 3 hours reperfusion: control (n = 10), no intervention; IPC (n = 9), 5 minutes left anterior descending coronary artery occlusion preceded 10 minutes of reperfusion before prolonged occlusion; postcon (n = 10), 3 cycles of 30 seconds reperfusion-30 seconds reocclusion were imposed immediately upon reperfusion; IPC+postcon (n = 8), IPC and postcon algorithms were combined. RESULTS: Collateral blood flow during ischemia was similar in all groups. Compared to control (24% +/- 2%), infarct size was comparably reduced in IPC (13% +/- 2%* [* denotes p less than 0.05 compared with control]), and postcon (10% +/- 1%*), consistent with a reduction in plasma creative kinase activity in these groups; infarct size was not further reduced by IPC+postcon (12% +/- 3%*). Tissue water content in ischemic myocardium was comparably reduced in IPC, postcon, and IPC+postcon compared to control. Superoxide anion generation detected by dihydroethidium staining in area at risk myocardium was comparably reduced in all intervention groups relative to control. Plasma malondialdehyde (microM), a lipid peroxidation byproduct of oxidant injury, was less at 1 hour of reperfusion in IPC (2.2 +/- 0.2*), postcon (2.1 +/- 0.2*), and IPC+postcon (2.5 +/- 0.2*) relative to control (3.3 +/- 0.2). Ventricular fibrillation occurred less often in all intervention groups. CONCLUSIONS: No additive cardioprotective effects by IPC and postcon were observed in a canine model of regional ischemia and reperfusion. The potent attenuation of myocardial injury by postcon may suggest a clinically applicable strategy during some surgical revascularization procedures (ie, OPCAB).

Animals↗

PubMed2002

Mitochondrial function during ischemic preconditioning.

Background. Ischemic preconditioning (IPC) protects the myocardium from ischemia reperfusion injury. The effect of IPC on the mitochondria is not well known. However, one of the mechanisms postulated in IPC (the opening of the mitochondrial K(ATP) channels) is likely to result in changes in mitochondrial function. Therefore, the purpose of this study was to determine the effect of IPC on mitochondrial function during ischemia reperfusion. Methods. Isolated rat hearts (n = 6/group) were subjected to (1) 30 minutes of equilibration, 25 minutes of ischemia, and 30 minutes of reperfusion (RP) (control group) or (2) 10 minutes of equilibration, two-5 minute episodes of IPC (each followed by 5 minutes of re-equilibration), 25 minutes of ischemia, and 30 minutes of RP (IPC group). Left ventricular rate pressure product (RPP) was measured. At end-equilibration (end-EQ) and at end-reperfusion (end-RP) mitochondria were isolated. Mitochondrial respiratory function (state 2, 3, and 4), respiratory control index (RCI), rate of oxidative phosphorylation (ADP/Delta t), and ADP:O ratio were measured by polarography with the use of NADH- or FADH-dependent substrates. Results. IPC improved recovery of RPP at end-RP (72% +/- 5% in IPC vs 30% +/- 4% in control, P <.05). Ischemia reperfusion (IR) decreased state 3, ADP/Delta t, and RCI in both groups compared with end-EQ. IPC improved state 3 (47 +/- 3 in IPC vs 37 +/- 2 ng-atoms O/min/mg protein in control), ADP/Delta t (17 +/- 1 in IPC vs 13 +/- 1 nmol/s/mg protein in control), and RCI (3.7 +/- 0.1 in IPC vs 2.1 +/- 0.2 in control) at end-RP compared with control with the use of NADH-dependent substrate (P <.05 vs control). IPC also improved state 3 (85 +/- 6 in IPC vs 71 +/- 4 ng-atoms O/min/mg protein in control), ADP/Delta t (18 +/- 2 in IPC vs 12 +/- 1 nmol/s/mg protein in control), RCI (2 +/- 0.1 in IPC vs 1.5 +/- 0.1 in control), and ADP:O ratios (1.4 +/- 0.04 in IPC vs 1.7 +/- 0.09 in control) at end-RP compared with control with the use of FADH-dependent substrate (P <.05 vs control). Conclusions. The cardioprotective effects of IPC can be attributed at least in part to the preservation of mitochondrial function during reperfusion.

Adenosine Triphosphate↗

PubMed2006

Remote organ ischemic preconditioning protect brain from ischemic damage following asphyxial cardiac arrest.

Ischemic preconditioning (IPC) is a phenomenon whereby an organ's adaptive transient resistance to a lethal ischemic insult occurs by preconditioning this organ with a sub-lethal/mild ischemic insult of short duration. Besides IPC, recent studies reported that a short sub-lethal ischemia and reperfusion in various organs can induce ischemic tolerance in another organ as well. This phenomenon is known as remote ischemic preconditioning (RPC). In the present study we tested the hypothesis that tolerance for ischemia can be induced in brain by RPC and IPC in a rat model of asphyxial cardiac arrest (ACA). RPC was induced by tightening the upper two-thirds of both hind limbs using a tourniquet for 15 or 30 min and IPC was induced by tightening bilateral carotid artery ligatures for 2 min. Eight minutes of ACA was induced 48 h after RPC or IPC. After 7 day of resuscitation, brains were extracted and examined for histopathological changes. In CA1 hippocampus, the number of normal neurons was 63% lower in cardiac-arrested rats as compared to the control group. The number of normal neurons in the 15 min RPC, 30 min RPC, and IPC groups was higher than the ACA group by 54, 70, and 67%, respectively. This study demonstrates that RPC and IPC are able to provide neuroprotection in a rat model of ACA. Besides direct application of RPC or IPC paradigms, the exploration of the mechanisms of observed neuroprotection by RPC and IPC may also lead to a possible therapy for CA patients.

Animals↗

PubMed2005

Cardioprotective-mimetics reduce myocardial infarct size in animals resistant to ischemic preconditioning.

BACKGROUND: Ischemic preconditioning (IPC) elicits two distinct windows of cardioprotection, an early phase that lasts for 1-2 h and a delayed phase that lasts for 24-72 h. However, there is conflicting data as to how long the heart is resistant to IPC-induced cardioprotection after the initial protection wanes, leading to the demonstration of IPC-resistance. This resistance to IPC appears to be dependent on the timing of the next IPC stimulus, the species of animals used and the model studied. Furthermore, the mechanisms responsible IPC-resistance are unknown. It is also important to demonstrate therapeutic interventions that will produce cardioprotection during this period of IPC-resistance. METHODS AND RESULTS: To examine potential mechanisms responsible for acute IPC-induced resistance, the NHE-1 inhibitor EMD 85131 (2-methyl-5-methylsulfonyl-1-(1-pyrrollyl)-benzoylguanidine), which exerts its effects via mechanisms distinct from IPC, and the K(ATP) channel opener bimakalim, which bypasses the signaling mechanisms of IPC to directly open K(ATP) channels, were examined in a canine model of IPC-resistance. One 10 min. IPC stimulus followed by 10 min. of reperfusion produced a significant reduction in IS/AAR compared to Control (7.1 +/- 2.6% versus 26.0 +/- 6.2%; P < 0.05). However, IPC did not significantly protect the myocardium if a 2 h reperfusion period occurred between the initial IPC stimulus and the subsequent prolonged (60 min) ischemic challenge (IS/AAR: 22.5 +/- 4.8%: P > 0.05). Furthermore, hearts treated with IPC followed by 2 h of reperfusion were resistant to an additional IPC stimulus administered just prior to the subsequent 60 min. occlusion period (IS/AAR: 22.9 +/- 3.2%: P > 0.05). In contrast, administration of the NHE-1 inhibitor EMD 85131 (IS/AAR: 7.4 +/- 2.5%: P < 0.05) or the K(ATP) channel opener bimakalim (IS/AAR: 11.8 +/- 2.4%: P < 0.05) both afforded significant cardioprotection when administered at 2 h of reperfusion in previously preconditioned canine hearts resistant to IPC. CONCLUSIONS: IPC resistance occurs in this canine model of ischemia-reperfusion injury. However, in spite of IPC resistance, hearts can still be pharmacologically protected by direct application of the K(ATP) channel opener bimakalim or the NHE inhibitor EMD 85131.

Animals↗

PubMed1998

Acute hyperglycemia abolishes ischemic preconditioning in vivo.

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.

Animals↗

PubMed2001

[The role of ischemic preconditioning in off-pump CABG: is it really necessary to accomplish scrupulous ischemic preconditioning?].

In an attempt to avoid the deleterious effect of cardiopulmonary bypass, off-pump coronary artery bypass grafting has been rediscovered and spread. We often accomplish the ischemic preconditioning (IP) in off-pump CABG. IP is the phenomenon in which sublethal episode of myocardial ischemia result in increased tolerance to a later, potentially lethal, episode of ischemia. To evaluate the cardioprotective effect of IP and an ATP-sensitive potassium channel (KATP) opener, oxidative radical scavenger, 43 clinical cases were examined. The myocardial tissue oxygen saturation was measured by near-infra red spectroscopy during IP. Twelve cases were subjected to accomplish simple IP (5 min x twice), and 29 cases received pharmacological IP (administrated allopurinol preoperatively and nicorandil intraoperatively; 3 min x once). The result showed that the tissue oxygen of pharmacological IP group is superior to that of simple IP group. The concomitant use of IP and KATP opener, oxidative radical scavenger both ameliorated cardiac dysfunction during the ischemia in anastomotic occlusion of the coronary artery, and improved the postischemic functional recovery. These results suggest that we would be able to decrease both duration and the number of times of IP by using KATP opener and oxidative radical scavenger.

Allopurinol↗

PubMed1999

Reactive oxygen species function as second messenger during ischemic preconditioning of heart.

Ischemic preconditioning has been shown to trigger a signaling pathway by potentiating tyrosine kinase phosphorylation leading to the activation of p38 MAP kinase and MAPKAP kinase 2. Recently, the nuclear transcription factor, NFkappaB, was found to play a role in the signaling process. Since NFkappaB is a target of oxygen free radicals, we hypothesized that reactive oxygen species might play a role in the signaling process. To test this hypothesis, isolated rat hearts were perfused in the absence or presence of either dimethyl thiourea (DMTU), a OH* radical scavenger, or SN 50 peptide, a NFkappaB blocker. Hearts were then subjected to ischemic preconditioning by four repeated episodes of 5 min ischemia each followed by 10 min reperfusion. All hearts were then made globally ischemic for 30 min followed by 2 h of reperfusion. The results of our study demonstrated enhanced tyrosine kinase phosphorylation during ischemic preconditioning which was blocked by DMTU. DMTU also inhibited preconditioning mediated increased phosphorylation of p38 MAP kinase and MAPKAP kinase 2 activity. However, DMTU had no effect on the translocation and activation of protein kinase C (PKC) resulting from preconditioning. Preconditioning reduced myocardial infarct size as expected. This cardioprotective effect of preconditioning was abolished by both DMTU and SN 50. Preconditioning resulted in the nuclear translocation and activation of NFkappaB. Increased NFkappaB binding was blocked by both DMTU and SN 50. The results of this study demonstrate that reactive oxygen species play a crucial role in signal transduction mediated by preconditioning. This signaling process appears to be potentiated by tyrosine kinase phosphorylation resulting in the activation of p38 MAP kinase and MAPKAP kinase 2 leading to the activation of NFkappaB suggesting a role of oxygen free radicals as second messenger. Free radical signaling seems to be independent of PKC although PKC is activated during preconditioning process suggesting the role of two separate signaling pathways in ischemic preconditioning.

Adaptation, Physiological↗

PubMed1995

Transient inhibition of glucose uptake mimics ischemic preconditioning by salvaging ischemic myocardium in the rabbit heart.

The aim of this study was to test whether transient inhibition of glucose uptake could precondition the rabbit heart. Rabbit hearts experienced 30 min regional ischemia followed by either 120 min (isolated heart protocol) or 180 min (in situ protocol) reperfusion. Infarct size was determined by tetrazolium staining. In isolated heart experiments, 15 min perfusion with glucose-free Krebs buffer starting 30 min prior to ischemia significantly limited infarct size to 9.9 +/- 2.6% of the risk zone as compared with 29.4 +/- 1.7% infarction in controls. This protection could be blocked (30.8 +/- 3.4%) by polymyxin B (50 microM), a protein kinase C inhibitor, but not by 8-(p-sulfophenyl)theophylline, an adenosine receptor inhibitor, suggesting the mechanism was similar to that of ischemic preconditioning but without involvement of adenosine receptors. Pyruvate and acetate inhibit glucose uptake without incurring a metabolic deficit. When 20 mM pyruvate or 1 mM acetate was added to the glucose-containing buffer for 15 min prior to ischemia, protection was evident (12.0 +/- 3.0% and 10.0 +/- 3.7% infarction, respectively). However, when acetate (1 mM) was present in the perfusate throughout the experiment, neither omission of glucose nor addition of pyruvate caused protection (26.1 +/- 2.2% and 28.9 +/- 4.7% infarction, respectively). Furthermore, when in situ hearts which preferably utilize lipid substrates were treated with pyruvate (2 g/kg i.v. 20 min before ischemia), infarct size was 40.3 +/- 3.0%, which did not differ from that in untreated hearts (38.6 +/- 3.2%). Hence transient inhibition of glucose uptake can precondition the heart, but only if other substrates which are utilized in preference to glucose are absent.

Acetates↗

PubMed2005

TNFR1 upregulation mediates tolerance after brain ischemic preconditioning.

A short ischemic event (ischemic preconditioning (IPC)) can result in subsequent resistance to severe ischemic injury (ischemic tolerance (IT)). The expression and neuroprotective role of tumor necrosis factor (TNF-alpha) have been described in models of IPC and we have showed the participation of its processing enzyme, the TNF-alpha convertase enzyme (TACE) in this process. We have now decided to explore the expression and localization of TNF receptors (TNFR) as well as other signalling mechanisms involved in IT. A period of 10 mins of temporary middle cerebral artery occlusion (tMCAO) was used for focal IPC. To evaluate the ability of IPC to produce IT, permanent MCAO was performed 48 hours after IPC. Ischemic preconditioning produced a reduction in infarct volume, as we showed previously. Ischemic preconditioning caused upregulation of neuronal TNFR1 that was reduced by the selective TACE inhibitor BB1101. Intracerebral administration of TNFR1 antisense oligodeoxynucleotide, which caused a reduction in TNFR1 expression, inhibited the IPC-induced protective effect, showing that TNFR1 upregulation is implicated in IT. Moreover, treatment with BB1101, TNFR1 antisense and lactacystin-a specific proteasome inhibitor-blocked IPC-induced NF-kappaB. Immunohistochemical studies showed the expression of TACE and TNFR1 in neurons. In summary, these data show that IPC produces neuronal upregulation of TACE and TNFR1, and that the pathway TACE/TNF-alpha/TNFR1/NF-kappaB is involved in IT.

ADAM Proteins↗