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PubMed2006

Attenuation of lung reperfusion injury by modified ventilation and reperfusion techniques.

BACKGROUND: High ventilation and perfusion pressures after lung transplantation may have deleterious effects. We hypothesized that using combined protective approaches for ventilation and perfusion would be optimal for reducing injury and improving function after ischemia-reperfusion. METHODS: Using an isolated, blood-perfused, rabbit lung model, lungs underwent 120 minutes of reperfusion either immediately (Sham) or after 18 hours of cold ischemia (IR). Groups Sham-P and IR-P underwent protective ventilation and reperfusion, and Groups Sham-C and IR-C underwent conventional ventilation and reperfusion. Protective ventilation involved gradually increasing the flow rate during 5 minutes to 1.8 liters/min, and conventional ventilation entailed immediate initiation of flow at 1.8 liters/min. Protective reperfusion involved gradually increasing perfusion during 5 minutes to 60 ml/min, and conventional reperfusion entailed immediate perfusion at 60 ml/min. Two other groups underwent either protective ventilation with conventional perfusion or vice versa. Airway pressure, pulmonary artery pressure, and arterial blood gases were measured throughout reperfusion. Wet/dry weight, highest oxygenation index, and bronchoalveolar lavage (BAL) protein were also measured. RESULTS: Protective ventilation and perfusion after ischemia (IR-P) resulted in significant improvements in lung function as measured by increased Po(2) and decreased Pco(2), airway pressure, and highest oxygenation index compared with conventional reperfusion (IR-C). Injury was significantly reduced in IR-P lungs as measured by reduced edema (wet/dry weight) and vascular leakage (BAL protein). In most cases, IR-P lungs performed better, with less injury than protective ventilation or perfusion alone. CONCLUSIONS: This protective approach of ventilation and perfusion after ischemia may improve lung function after transplantation, a simple method that could easily be applied clinically.

Administration, Inhalation↗

PubMedDate not supplied

The effect of atrial dilatation on reperfusion arrhythmias: development of supraventricular tachycardias on reperfusion with atrial stretching.

UNLABELLED: The study was aimed at investigating the effect of atrial dilatation on the genesis of supraventricular tachyarrhythmias following myocardial reperfusion. Experiments were carried out in 26 mongrel dogs under pentobarbital narcosis with artificial ventilation. Electrophysiological study was performed for studying the arrhythmic condition of the heart. Investigations were carried out: (i) in normal condition, (ii) during atrial stretching (balloon dilatation of the left atrium), (iii) in reperfusion following myocardial ischemia, (iv) in reperfusion combined with atrial stretching. On reperfusion the irritability of the atrium increased moderately (on atrial extrastimuli in 3 dogs non-sustained atrial tachycardia, in 7 dogs repeated atrial responses could be induced). Reperfusion with atrial stretching, however, very markedly enhanced the atrial vulnerability, and in 19 dogs atrial tachycardia appeared spontaneously. Comparison of the effect of atrial stretching to that of atrial stretching + reperfusion showed that the reperfusion significantly augmented the arrhythmia-inducing effect of atrial stretching. CLINICAL INVESTIGATIONS: Aortocoronary bypass operations were followed by development of supraventricular tachycardia in 41 out of 428 operated cases. Atrial dilatation was detected in 37 cases, mostly before the appearance of atrial tachycardia. The data seem to prove that atrial dilatation has an important part in the pathogenesis of supraventricular tachyarrhythmias following reperfusion of myocardial ischemia.

Animals↗

PubMed2002

Adenovirus mediated gene transfer of antiapoptotic protein in hepatic ischemia-reperfusion injury: the paradoxical effect of Bcl-2 expression in the reperfused liver.

BACKGROUND: Although Bcl-2 is well known to have antiapoptotic activities in vitro and in vivo, the role of Bcl-2 remains controversial. In the present study, we evaluated whether the adenovirus mediated gene transfer of hBcl-2 could exert an antiapoptotic effect in a rat model of hepatic ischemia-reperfusion (I/R) injury. MATERIALS AND METHODS: Each 6 x 10(9) plaque forming unit adenovirus vector encoding LacZ (AxCAilacZ) or hBcl-2 (AxCAhbcl2) was intravenously administered 48 h before I/R injury, in groups 1 and 2, respectively. In group 3, 1 ml of normal saline was injected instead of the virus vectors. Hepatic I/R injury was induced by the temporal occlusion of all hepatic influent vessels for 30 min under a portosystemic shunt. The animals were sacrificed at 6 h, 1, 3, and 14 days after reperfusion (each n = 12 in groups 1 and 2, and n = 8 in group 3). The expressions of hBcl-2 and Bax were evaluated at both the mRNA level by reverse transcription polymerase chain reaction and the protein level by immunohistochemistry. To assess the hepatocyte and sinusoidal endothelial cell damage after I/R injury, the serum asparate aminotransferase (AST), alanine aminotransferase, and hyaluronic acid were all evaluated. The number of apoptotic cells was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end-labeling (TUNEL). RESULTS: To evaluate the antiapoptotic activities of the hBcl-2 sequence encoded into AxCAhbcl2, rat hepatocarcinoma cells were transfected with AxCAhbcl2 (10(3) moi) or AxCAilacZ (10(3) moi) and then challenged with TGF-beta1 protein (5 ng/ml) to induce apoptosis. Apoptotic cells were counted by TUNEL staining in about 2500 cells, and it was found that adenovirus mediated gene transfer of hBcl-2 significantly protected rat hepatocarcinoma cells from TGF-beta1 induced apoptosis (14.2 +/- 1.2%) in comparison to those of LacZ (21.9 +/- 1.4%). In the reperfused liver in vivo, the mRNA expression of hBcl-2 was detected only in the hBcl-2 transfected group 2. In group 2, a strong degree of Bcl-2 immunoreactivity was recognized as early as 6 h after reperfusion, while it was not recognized in groups 1 and 3 at 6 h after reperfusion. The AST levels were significantly higher in group 2 (AST: 356 +/- 100.1 IU/L) than those in group 1 (AST: 102.7 +/- 15 IU/L) at 1 day after reperfusion (P < 0.05). The number of TUNEL positive cells was significantly higher in group 2 than in groups 1 and 3 at 1 day after reperfusion. CONCLUSIONS: These results indicated that an overexpression of antiapoptotic protein Bcl-2 paradoxically exerted a proapoptotic effect in the reperfused liver. The in vivo role of Bcl-2 should thus be carefully evaluated, depending on the levels of expression and the target organ.

Adenoviridae↗

PubMed1990

Role of eicosanoids and white blood cells in the beneficial effects of limited reperfusion after ischemia-reperfusion injury in skeletal muscle.

Limiting the rate of reperfusion blood flow has been shown to be beneficial locally in models of ischemia-reperfusion injury. We investigated the effects of this on eicosanoids (thromboxane B2, 6-keto-PGF1 alpha, and leukotriene B4), white blood cell activation, and skeletal muscle injury as quantitated by triphenyltetrazolium chloride and technetium-99m pyrophosphate after ischemia-reperfusion injury in an isolated gracilis muscle model in 16 anesthetized dogs. One gracilis muscle in each dog was subjected to 6 hours of ischemia followed by 1 hour of limited reperfusion and then by a second hour of normal reperfusion. The other muscle was subjected to 6 hours of ischemia followed by 2 hours of normal reperfusion. Six dogs each were used as normal reperfusion controls (NR) and limited reperfusion controls (LR), with 5 dogs being treated with a thromboxane synthetase inhibitor (LR/TSI) and another five with a leukotriene inhibitor (LR/LI). LR in all three groups (LR, LR/TSI, and LR/LI) showed a benefit in skeletal muscle injury as measured by triphenyltetrazolim chloride and technetium-99m pyrophosphate when compared with NR. However, there was no significant difference between the groups with LR regarding eicosanoid levels and white blood cell activation when compared with NR. These results demonstrate that LR produces benefits by mechanisms other than those dependent upon thromboxane A2, prostacyclin, or white blood cell activation.

Animals↗

PubMed2003

Intra-myocyte ion homeostasis during ischemia-reperfusion injury: effects of pharmacologic preconditioning and controlled reperfusion.

BACKGROUND: This study determines whether controlled reperfusion or diazoxide improves intramyocyte Na(+) homeostasis using a porcine model of severe ischemia-reperfusion injury. METHODS: Three groups (n = 10 pigs per group) had 75 minutes of left anterior descending artery occlusion during bypass. Group 1 had no treatment (control group), group 2 had controlled reperfusion (500 mL warm cardioplegia) (controlled reperfusion group), and group 3 had diazoxide (50 micromol/L before left anterior descending artery occlusion) (diazoxide group). Biopsies were taken from the left anterior descending artery region before ischemia and at 3, 5, and 10 minutes postreperfusion. Intra-myocyte Na(+) and water contents were determined using atomic absorption spectroscopy, and Na(+) concentrations were calculated. RESULTS: Intra-myocyte Na(+) increased for the diazoxide group pigs at 3-minutes postreperfusion (21.9 +/- 2.9 vs 34.0 +/- 3.4 micromol/mL; p = 0.02), but decreased to 19.9 +/- 3.2 micromol/mL at 10 minutes postreperfusion (p = 1.0 vs baseline). At 10 minutes postreperfusion, intra-myocyte Na(+) in the controlled reperfusion group was lower than baseline (22.3 +/- 2.7 vs 17.2 +/- 3.1 micromol/mL; p < 0.001). Intra-myocyte Na(+) at 10 minutes postreperfusion for the diazoxide and controlled reperfusion groups was lower than for the control group (p < 0.05). CONCLUSIONS: Diazoxide and controlled reperfusion improved intra-myocyte Na(+) homeostasis after severe ischemia-reperfusion injury.

Animals↗

PubMed1991

Hypoxic reperfusion to remove ischaemic catabolites prior to arterial reperfusion does not limit the size of myocardial infarcts in dogs.

STUDY OBJECTIVE: Although timely reperfusion limits myocardial infarct size, it has been postulated that reperfusion itself may kill some myocytes which were alive at the end of an episode of ischaemia (lethal reperfusion injury). The aim of this study was to test the hypothesis that ischaemic catabolites may "prime" myocardium for such injury and that preliminary hypoxic washout of such catabolites, prior to arterial reperfusion, would limit myocardial infarct size. DESIGN: Dogs underwent a 40 min occlusion of the left circumflex coronary artery, followed by 4 d reperfusion. In a treated group, a 5 min episode of coronary artery perfusion with hypoxic buffer was instituted at the end of this ischaemic episode, before blood reperfusion was restored. Control dogs received a similar volume of hypoxic buffer intravenously. Systemic fluid overload was attenuated by haemofiltration. The effect of this preliminary hypoxic washout on myocardial infarct size was assessed. EXPERIMENTAL MATERIAL: 18 anaesthetised, open chest dogs were used. After the acute study they recovered from surgery for 4 d and were then killed for further study. MEASUREMENTS AND MAIN RESULTS: Infarct size, determined by microscopic evaluation, was not significantly different in the two groups, at (control) 31.3 (SEM 6.2)% v (hypoxic reperfusion) 25.8(3.9)% of the vascular area at risk. In control dogs, infarct size was inversely related to the amount of collateral blood flow (measured using microspheres); hypoxic reperfusion did not shift this relation (analysis of covariance, F = 0.236, NS). CONCLUSIONS: The washout of ischaemic catabolites by hypoxic perfusate prior to reoxygenation did not limit infarct size.

Animals↗

PubMed1995

Intracoronary magnesium is not protective against acute reperfusion injury in the regional ischaemic-reperfused dog heart.

Intravenous magnesium lowers mortality in patients with suspected myocardial infarction. We tested the hypothesis that the protective effect may be due to a direct, local influence of magnesium on myocardial reperfusion injury in a dog model of ischaemia/reperfusion. Ten anaesthetized open chest dogs underwent 1 h of left anterior descending artery (LAD) occlusion and 6 h of reperfusion. The animals received intracoronary (i.c.) magnesium aspartate (Mg, n = 5) or vehicle infusion (n = 5) for the first hour of reperfusion. Mg infusion was adapted to actual LAD flow (ultrasonic flow probe) to increase regional plasma concentration by 4 mmol L-1. Regional myocardial function was measured as percent systolic wall thickening (sWTh, sonomicrometry). Intracoronary Mg increased LAD flow during application (at 15 min reperfusion; Mg, 194 +/- 44 (mean +/- SD); control, 116 +/- 41 mL min-1 100 g-1, P < 0.01). sWTh decreased during coronary occlusion from 14.3 +/- 7.1% to -4.7 +/- 2.7% in the control group and from 14.8 +/- 2.5% to -4.1 +/- 3.1% in the Mg group. Throughout the reperfusion period wall function remained depressed in both groups to a similar degree (control, -3.5 +/- 1.8%; Mg, -3.0 +/- 1.9% at 6 h reperfusion). Global haemodynamics were not different. Infarct size after 6 h reperfusion (TTC staining) was similar in both groups (Mg, 20.6 +/- 5.0; control, 24.4 +/- 8.7% of area at risk). Regional magnesium application (i.c.) to post-ischaemic reperfused myocardium had no influence on infarct size or post-ischaemic regional wall function in this model.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Effect of preconditioning ischemia on reperfusion arrhythmias after coronary artery occlusion and reperfusion in the rat.

Severe arrhythmias occur predictably on reperfusion after 5 minutes of coronary occlusion in the rat. There is little data available on whether ischemic preconditioning (PC) of hearts can reduce the incidence of such arrhythmias. The effect of PC (three cycles of 2 minutes of coronary occlusion and 5 minutes of reperfusion) on development of arrhythmias after a subsequent 5-minute coronary artery occlusion and reperfusion was studied. Rats (n = 16 each group) underwent 5-minute occlusion and reperfusion alone or preceded by PC; arrhythmias were monitored during ischemia and for 10 minutes of reperfusion, and biopsies were taken for creatine phosphate and adenosine triphosphate in ischemic and nonischemic zones of the left ventricle. PC reduced the incidence of ventricular tachycardia (VT) during occlusion (81% control versus 13% PC, p less than 0.001). On subsequent reperfusion, ventricular fibrillation (VF) developed in zero PC animals versus 13 (81%) of controls (p less than 0.001), and irreversible VF in zero of PC versus seven (44%) of controls (p = 0.007). VT occurred in four (25%) of PC versus all (100%) of controls (p less than 0.001). PC reduced mean duration of VT plus VF from 320 +/- 54 to 5 +/- 1 seconds (p less than 0.001) and delayed arrhythmia onset from 8 +/- 2 to 85 +/- 35 seconds after reperfusion. There was no difference in creatine phosphate levels in the ischemic zone at the end of reperfusion in PC animals compared with controls without irreversible VF (16.2 +/- 4.1 versus 15.5 +/- 3.9 nmol/mg protein, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMedDate not supplied

Early reperfusion, late reperfusion, and the open artery hypothesis: an overview.

Randomized clinical trials have clearly shown the beneficial effects of early reperfusion within 12 hours, and possibly up to 24 hours, after acute myocardial infarction (AMI). The data on late reperfusion beyond 24 hours are less convincing. Many studies show that an open infarct-related artery after MI, irrespective of the initial reperfusion strategy, is independently associated with improved long-term clinical outcome. However, similar analysis of the large Global Utilization of Streptokinase and tPA for Occluded Arteries (GUSTO) 1 study did not confirm this finding. It is unclear whether mechanical reperfusion of an occluded infarct-related artery late after MI (>24 hours) in asymptomatic patients will confer long-term benefits. The late open artery hypothesis, which proposes several mechanisms by which late reperfusion may offer benefit, remains to be tested in a large clinical trial. This overview focuses on the definitions of early reperfusion, late reperfusion, the relationship between timing of reperfusion and prognosis after AMI, and the late open artery hypothesis.

Clinical Trials as Topic↗

PubMed1991

Myocardial reperfusion injury. Platelet-activating factor stimulates polymorphonuclear leukocyte hydrogen peroxide production during myocardial reperfusion.

To study the roles of platelet-activating factor, polymorphonuclear leukocytes, and oxygen free radicals in myocardial reperfusion injury, we subjected 10 sheep to 90 minutes of mid-left anterior descending coronary artery followed by 6 hours of reperfusion. Stainings with gentian violet and tetratriphenyl ammonium chloride demonstrated 20% +/- 3% of the left ventricular mass at risk for ischemia, of which 75% +/- 10% underwent infarction. Coronary sinus blood was assayed for platelet-activating factor and neutrophil hydrogen peroxide production before and during coronary occlusion and during reperfusion. Platelet-activating factor was isolated by column chromatography and lipid extraction and quantified by radioimmunoassay. Neutrophil hydrogen peroxide production was measured by a 2',7'-dichlorofluorescein flow-cytometric assay. Platelet-activating factor was elevated to 899 +/- 210 pg/ml at 15 minutes of reperfusion, compared with the preocclusion level of 271 +/- 55 pg/ml and coronary occlusion level of 359 +/- 64 pg/ml (p less than 0.05; analysis of variance). Neutrophil hydrogen peroxide production, measured on a relative fluorescence scale, was also elevated to a level of 141 +/- 27 at 1 hour of reperfusion, compared with the preocclusion level of 103 +/- 6 and the coronary occlusion level of 114 +/- 13 (p less than 0.01; analysis of variance). Both of these parameters returned toward baselines at the end of 6 hours of reperfusion. Histologic examination revealed infiltration of polymorphonuclear leukocytes into the interstitium of the reperfused myocardium. Neutrophils isolated from unoperated and healthy sheep demonstrated a graded dose response in hydrogen peroxide production when stimulated by purified platelet-activating factor in vitro. These findings suggest that platelet-activating factor is released in the coronary circulation and is a mediator of oxygen free radical production in polymorphonuclear leukocytes during myocardial reperfusion.

Animals↗

PubMed1991

Studies of controlled reperfusion after ischemia. XX. Reperfusate composition: detrimental effects of initial asanguineous cardioplegic washout after acute coronary occlusion.

UNLABELLED: This study tests whether initial asanguineous washout of potentially toxic substances that accumulate during ischemia improves recovery produced by blood cardioplegic reperfusion and evaluates the role of plasma versus whole blood cardioplegia. METHODS: Twenty-four dogs underwent 2 hours of occlusion of the left anterior descending coronary artery and 20 minutes of blood cardioplegic reperfusion on total vented bypass. In 13 dogs, a 5-minute infusion of either a crystalloid (n = 7) or plasma (n = 6) cardioplegic solution (containing the same pH, calcium potassium, and osmolarity as blood cardioplegia) was given immediately before reoxygenation with blood cardioplegia. Regional oxygen uptake and coronary vascular resistance were measured during controlled reperfusion, and segmental shortening (ultrasonic crystals), tissue water content, and histochemical damage (triphenyltetrazolium chloride stain) were assessed 1 hour after bypass was discontinued. RESULTS: Asanguineous cardioplegic washout before reoxygenation with blood cardioplegic solution resulted in a progressive (+42%) increase in coronary vascular resistances (from 123 to 176 units, p less than 0.05) and low oxygen utilization during 20 minutes of blood cardioplegic reperfusion (29 ml/100 gm, p less than 0.05); coronary vascular resistance remained low throughout blood cardioplegic reperfusion without washout (from 109 to 98 units), and oxygen utilization was 54 ml/100 gm (p less than 0.05). Neither plasma nor crystalloid washout restored substantial regional systolic shortening (3% systolic shortening versus 73% systolic shortening with blood cardioplegia), and asanguineous washout caused more myocardial edema (81.1% +/- 80.9% versus 79.5% water content, p less than 0.05) and produced extensive transmural triphenyltetrazolium chloride damage (48% +/- 41% versus 8% nonstaining in area at risk, p less than 0.05) than initial blood cardioplegic reperfusion. CONCLUSION: Asanguineous cardioplegic washout before blood cardioplegic reperfusion limits oxygen utilization during subsequent controlled reperfusion, restricts early recovery of systolic shortening, allows more myocardial edema, and produces extensive histochemical damage, which may be avoided by initial reoxygenation with blood cardioplegia. The red blood cells appear more important than the plasma components of blood cardioplegia.

Adenosine Triphosphate↗

PubMed1986

Reperfusion conditions: importance of ensuring gentle versus sudden reperfusion during relief of coronary occlusion.

This study tests the hypothesis that more muscle salvage after acute ischemia is possible by "gentle," temporary reperfusion than with sudden, complete revascularization. Ten dogs underwent 4 hours of left anterior descending coronary artery ligation with reperfusion during total vented bypass for 1 hour of the 2-hour reperfusion period. In five dogs, reperfusion was accomplished by release of the occlusion suddenly and completely. The five others received selective low-pressure (40 to 50 mm Hg) coronary reperfusion with normal blood for 20 minutes at 30 ml/min before the occlusion was relieved completely. Systolic shortening with ultrasonic crystals, triphenyltetrazolium chloride staining, and myocardial wet and dry weights were measured. Sudden relief of occlusion failed to restore contractility spontaneously (-7 +/- 1% systolic shortening, p less than 0.05) or with inotropic infusion (-2 +/- 4% systolic shortening, p less than 0.05) and caused the greatest amount of edema (82.2%, systolic shortening, p less than 0.05) and triphenyltetrazolium chloride nonstaining (76% area at risk, p less than 0.05). In contrast, temporary, gentle reperfusion allowed slight spontaneous recovery in four of five hearts (4 +/- 2% systolic shortening), increasing to 26 +/- 12% systolic shortening (p less than 0.05) with inotropic stimulation, limited edema (80.7%, p less than 0.05), and reduced triphenyltetrazolium chloride nonstaining to 55% (p less than 0.05). Early temporary, gentle reperfusion limits the postischemic damage that occurs with sudden, complete revascularization (aortic unclamping without control of reperfusion pressure or flow). These findings may have implications during revascularization for acute myocardial infarction when perfusion pressure and flow can be controlled.

Animals↗

PubMed1997

Relation of absence of ST reelevation immediately after reperfusion and success of reperfusion with myocardial salvage.

To examine whether resolution in ST elevation without ST reelevation immediately after reperfusion indicates successful reperfusion with myocardial salvage, we studied 40 patients who had an extensive acute myocardial infarction with early reperfusion: 24 patients had ST reelevation and 16 patients had no ST reelevation. Results indicate that (1) in the group with ST reelevation, rapid progression of myocardial damage occurs by reperfusion itself (i.e., reperfusion injury) and (2) in the group without ST reelevation, myocardial damage had already been extensive and irreversible at the time of reperfusion; thus, the absence of ST reelevation is not always a sign of reperfusion with myocardial salvage.

Adult↗

PubMed1998

Controlled reperfusion and pentoxifylline modulate reperfusion injury after single lung transplantation.

OBJECTIVE: Rodent models have suggested that initial low-pressure reperfusion of transplanted lungs reduces injury after ischemia. We investigated this phenomenon and the use of pentoxifylline in a porcine model of left single lung transplantation. METHODS: Donor lungs were preserved with Euro-Collins solution for a mean ischemic time of 18.4 hours. Neutrophil trapping in the graft, pulmonary artery pressure, and gas exchange were assessed over a 12-hour period. Partial occlusion of the contralateral pulmonary artery allowed manipulation of the pulmonary artery pressure in the transplanted lung. Group A (n = 5) was perfused at a mean pulmonary artery pressure of 20 mm Hg, group B was reperfused at a mean pulmonary artery pressure of 45 mm Hg for 10 minutes before reducing the pressure to the same as group A, and group C was reperfused at a mean pressure of 20 mm Hg for 10 minutes, then increased to a mean of 45 mm Hg for the remainder of the experiment. Group D was reperfused as in group A with the addition of intravenous pentoxifylline. RESULTS: Leukocyte sequestration was observed in the first 10 minutes after reperfusion in groups A, B, and C, with maximal sequestration at 2 minutes. Significantly more sequestration was observed in the first 6 minutes in group B than in groups A and C, which were similar. Pentoxifylline significantly reduced leukocyte sequestration. Pulmonary venous oxygen tension in the allograft lung was worst in group B. Groups A and C were similar, but group D was superior to all other groups (p < 0.001). CONCLUSIONS: Low-pressure reperfusion, even when limited to the first 10 minutes, modulates reperfusion injury possibly through a leukocyte-dependent mechanism. The addition of pentoxifylline in the recipient confers significant additional benefit.

Animals↗

PubMed1992

Cardiac microdialysis measurement of extracellular adenine nucleotide breakdown products during regional ischemia and reperfusion in canine heart: protective effect of propranolol against reperfusion injury.

Using cardiac microdialysis, we studied release of the adenine nucleotide breakdown products (ANBP) adenosine (ADS), inosine (INS), and hypoxanthine (HYP) into the interstitium of canine myocardium during 20- and 40-min occlusion of the anterior descending coronary artery and reperfusion. Dialysate ANBP concentrations reached maximum values not at the end of ischemia but in the first 10 min of reperfusion. The effect was more pronounced after 20-min ischemia. Further reperfusion led to an ANBP decrease that was more prolonged after 40-min ischemia. Pretreatment with DL-propranolol (0.5 mg/kg, intravenously, i.v.) given 40 min before coronary occlusion had no effect on adenine nucleotide catabolism rate during 20- and 40-min ischemia, but it facilitated washout of ANBP from ischemic zone immediately after the start of reperfusion. A similar effect was elicited by a D-stereoisomer of propranolol with no beta-adrenoceptor blocking activity. Results suggest that the reperfusion injury and probably the no-reflow phenomenon were the cause of enhanced adenine nucleotide catabolism at the beginning of reperfusion and prolonged ANBP washout from the ischemic zone. Reduction of reperfusion injury by propranolol could be related to the membrane stabilizing and antioxidant activity of this agent. Examination of DL-propranolol kinetics in arterial and coronary venous blood plasma showed that drug accumulation in the myocardium was almost maximum at the start of ischemia; therefore, the efficiency of cardio-protection with DL-propranolol was not limited by pharmacokinetic causes. Insertion of an additional microdialysis probe in the myocardium allowed monitoring of extracellular propranolol concentrations.

Adenine Nucleotides↗

PubMed2002

Microvascular reperfusion injury: rapid expansion of anatomic no reflow during reperfusion in the rabbit.

The aim was to define the degree and time course of reperfusion-related expansion of no reflow. In five groups of anesthetized, open-chest rabbits (30-min coronary occlusion and different durations of reperfusion), anatomic no reflow was determined by injection of thioflavin S at the end of reperfusion and compared with regional myocardial blood flow (RMBF; radioactive microspheres) and infarct size (triphenyltetrazolium). The area of no reflow progressively increased from 12.2 +/- 4.2% of the risk area after 2 min of reperfusion to 30.8 +/- 3.1% after 2 h and 34.9 +/- 3.3% after 8 h and significantly correlated with infarct size after 1 h of reperfusion (r = 0.88-0.97). This rapid expansion of no reflow predominantly occurred during the first 2 h, finally encompassing approximately 80% of the infarct size, and was accompanied by a decrease of RMBF within the risk area, being hyperemic after 2 min of reperfusion (3.78 +/- 0.75 ml x min(-1) x g(-1)) and plateauing at a level of approximately 0.9 ml x min(-1) x g(-1) by 2 and 8 h of reperfusion (preischemic RMBF: 2.06 +/- 0.01 ml x min(-1) x g(-1)). The development of macroscopic hemorrhage lagged behind no reflow, was closely correlated with it, and may be the consequence of microvascular damage.

Animals↗

PubMed1989

Neutrophil depletion limited to reperfusion reduces myocardial infarct size after 90 minutes of ischemia. Evidence for neutrophil-mediated reperfusion injury.

Reperfusion of ischemic myocardium may accelerate necrosis of injured myocytes. To determine the role of neutrophil leukocytes in this process, we examined whether neutrophil depletion during reperfusion could modify infarct size in anesthetized dogs. The proximal circumflex coronary artery was occluded for 90 minutes and then reperfused for 2 hours via an extracorporeal circuit with either whole blood (n = 11) or with blood depleted of neutrophils by leukocyte filters (n = 11). The leukocyte filters caused near-total neutropenia in blood reperfusing the ischemic myocardium (7 +/- 7 neutrophils/microliters compared with 2,551 +/- 317/microliters in controls, mean +/- SEM; p less than 0.001. Infarct size was measured by planimetry of myocardial slices stained with triphenyltetrazolium chloride (TTC), and the accuracy of TTC for identifying necrotic myocardium was verified by electron microscopy. The size of the ischemic risk region was the same in the control (41.6 +/- 1.0%) and neutropenic (41.8 +/- 2.1%) groups. Collateral blood flow to the risk region was the same in control (0.15 +/- 0.03 ml/min/g) and neutropenic (0.13 +/- 0.03 ml/min/g) groups. Among dogs with collateral flow less than 0.2 ml/min/g, infarct size was reduced in the neutropenic group (27.7 +/- 6.7% of risk region, n = 8), compared with control dogs (52.5 +/- 5.7%; n = 7; p = 0.02). Multiple linear regression described the relation between infarct size, risk region size, and collateral flow in the control group, and the same regression relation was used to predict infarct size for the neutropenic group. Mean predicted infarct size in the neutropenic group (n = 11) was 16.8 +/- 3.4% of left ventricle, whereas mean observed infarct size was 9.6 +/- 3.1% (p less than 0.01). The extent of the no-reflow zone (absence of thioflavin-S-fluorescence) was also less in the neutropenic than the control group (2.2 +/- 0.8% vs. 8.1 +/- 2.7% of the risk region, p less than 0.05). Neutropenia limited to the reperfusion period is associated with significant reductions in the extent of the infarct and no-reflow zones after 90 minutes of ischemia. These findings support the hypothesis that reperfusion necrosis occurs after prolonged myocardial ischemia and indicate that neutrophil leukocytes are important mediators of such reperfusion injury.

Animals↗

PubMed1991

Reduction of myocardial reperfusion injury by intravenous adenosine administered during the early reperfusion period.

Adenosine influences the function of several cell types thought to be involved in the pathogenesis of myocardial reperfusion injury. We have previously demonstrated that intracoronary administration of adenosine enhances myocardial salvage 24 hours after reperfusion. To determine if these beneficial effects could be obtained during a prolonged period of reperfusion using an intravenous route of administration, 22 closed-chest dogs were subjected to 90 minutes of proximal left anterior descending coronary artery occlusion and 72 hours of reperfusion. Animals randomly received either intravenous adenosine (0.15 mg/kg/min) or an equal volume of Ringer's lactate during the first 150 minutes of reperfusion. The area at risk was defined in vivo with Monastral blue, and infarct size was measured histologically with Mallory's trichrome stain. Serial global and regional ventricular function were determined with contrast ventriculography and analyzed using a computerized radial shortening method. Biopsies were obtained from the central ischemic zone to assess endothelial ultrastructure and capillary obstruction. No significant effects in heart rate or blood pressure were noted during adenosine infusion. Transmural collateral blood flow during ischemia was similar in the groups. Infarct size expressed as a percentage of the anatomical area at risk was significantly less in the adenosine-treated group (35.3 +/- 4.3% in controls versus 17.1 +/- 4.3% in treated animals, p less than 0.01). A progressive decrease in transmural blood flow was noted in control animals during reperfusion, resulting in a significant reduction at 3 hours compared with the preocclusion value (0.69 +/- 0.11 ml/min/g [at baseline versus 0.45 +/- 0.10 ml/min/g at 3 hours, p less than 0.05]). In contrast, flow in adenosine animals at 3 hours was similar to baseline values (0.91 +/- 0.15 ml/min/g at baseline versus 0.98 +/- 0.14 ml/min/g at 3 hours, p = NS) and was significantly higher (p less than 0.05) than the control group. Radial shortening in the ischemic zone was significantly improved at 3 (-2.6 +/- 2.8% in controls versus 11.6 +/- 3.3% in treated animals, p less than 0.01) and 72 hours (5.5 +/- 2.0% in controls versus 17.3 +/- 3.5% in treated animals, p less than 0.01) after reperfusion in treated animals. Electron microscopy showed reduced neutrophil and erythrocyte plugging of capillaries with relative preservation of endothelial cell structure in the adenosine group.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine↗