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PubMedDate not supplied

Hypothermia and controlled reperfusion: two non-pharmacologic methods which diminish ischemia-reperfusion injury in skeletal muscle.

The mechanisms of ischemia-reperfusion (I-R) injury in skeletal muscle remain controversial. We have previously reported two non-pharmacologic methods to salvage skeletal muscle from I-R injury, post-ischemic hypothermia and controlled reperfusion. In all experiments, both canine gracilis muscles were subjected to six hours of ischemia followed by one hour of reperfusion. Controlled reperfusion was achieved by partially occluding one gracilis artery to limit the rate of reperfusion blood flow to its pre-ischemic rate, while the contralateral artery was allowed to perfuse freely at a normal rate. Post-ischemic hypothermia was achieved by cooling one gracilis muscle to 21 degrees centigrade (hypothermic reperfusion) after 5 hours of warm ischemia, while the opposite gracilis muscle was maintained at ambient temperature (normothermic reperfusion). Both methods resulted in a significant diminution in muscle infarct and edema. The mechanisms by which this is accomplished are currently unknown, but may be related to a diminished inflammatory response to ischemia. This review of these methods suggests that the hyperemic rate of reperfusion blood flow is a significant factor in the pathophysiology of post-reperfusion edema, and that significant control of skeletal muscle reperfusion injury may be achieved by limiting the rate of reperfusion blood flow or by applying post-ischemic hypothermia.

Animals↗

PubMedDate not supplied

Increased inflammatory response and neovascularization in reperfused vs. non-reperfused murine myocardial infarction.

INTRODUCTION: Fundamental knowledge of the inflammatory response after myocardial infarction (MI) is indispensable for intervention toward cardiac regeneration. Although reperfusion is preferred as clinical therapy, for basic research, also permanent ligation MI models are widely used. METHODS: In this report, we pathohistologically compared the kinetics of the inflammatory and angiogenic response after MI induced by permanent ligation or ligation followed by reperfusion of the left anterior descending coronary artery in mice. RESULTS: Permanent ligation resulted in a higher mortality rate accompanied by increased left ventricular dilatation and more progressive wall thinning. However, reperfused infarcts showed higher inflammatory cell influx. Neutrophil numbers were higher after reperfusion post-MI, although their presence was prolonged after ligation. Also, the number of macrophages after reperfusion was continuously higher, but the course of macrophage influx was comparable in both models. The number of lymphocytes was low in both models. Only the peak in myofibroblast numbers at 7 days was higher after ligation than after reperfusion. Moreover, cardiomyocyte remnants were cleared faster, and collagen deposition started earlier after reperfusion. In addition, reperfusion resulted in an increased angiogenic response, as was reflected in increased numbers of medium-sized and large vessels at 7 and 14 days post-MI. CONCLUSION: We show less adverse remodeling together with a higher presence of inflammatory cells and enhanced neovascularization in reperfused MI. These differences between non-reperfused and reperfused MI should be taken into consideration for experimental use of MI models.

Animals↗

PubMed2002

Initial reperfusion with magnesium after cardioplegic arrest attenuates myocardial reperfusion injury.

BACKGROUND: Magnesium's effect on calcium ion concentrations may attenuate myocardial reperfusion injury. The aim of this study was therefore to investigate the effects on the recovery of myocardial function of initial reperfusion with varying Mg(2+) concentrations following cardioplegic arrest. METHODS: Isolated guinea pig hearts underwent 3.5 hours of cardioplegic arrest in St. Thomas Hospital II solution (STH) or Bretschneider HTK solution (HTK) at 24 degrees C. Control hearts were reperfused with normal Krebs-Henseleit solution (KHS). In the therapy groups, hearts were initially reperfused with 5, 10, or 20 mM Mg(2+) for 15 minutes, followed by 30 minutes of perfusion with KHS. RESULTS: During initial reperfusion, elevated Mg(2+) concentrations markedly reduced rate-pressure product, dP/dt and O 2 demand. Release of LDH and CK was reduced in the therapy groups pretreated with Bretschneider HTK. After Mg(2+) washout, left ventricular function recovery and compliance was improved after HTK but not after STH cardioplegia. Following both STH and HTK cardioplegia, Mg(2+) reperfusion reduced reperfusion arrhythmias. CONCLUSIONS: The combination of HTK cardioplegia with 15 min initial Mg(2+) (5 and 10 mM, but not 20 mM) reperfusion was clearly superior to HTK followed by immediate Krebs-Henseleit reperfusion as well as STH cardioplegia with or without initial Mg(2+) reperfusion. The high Mg(2+) concentrations in the STH solution might mask beneficial effects of Mg(2+) reperfusion.

Animals↗

PubMed2002

Effects of anti-intercellular adhesion molecule-1 antibody on reperfusion injury induced by late reperfusion in the rat middle cerebral artery occlusion model.

OBJECTIVE: Inflammatory processes have been implicated in the mechanisms of reperfusion injury. The migration of leukocytes into ischemic tissue on reperfusion, which involves binding to the intercellular adhesion molecule (ICAM) of the endothelial cell, is thought to exacerbate tissue injury. The aim of the present study was to assess the effects of an anti-ICAM-1 antibody on reperfusion-induced injury after late reperfusion in a rat middle cerebral artery occlusion (MCAO) suture model. METHODS: The animals were divided into four groups: 1) Group 1 (n = 7), 6 hours of permanent MCAO; 2) Group 2 (n = 7), 3 hours of MCAO followed by 3 hours of reperfusion; 3) Group 3 (n = 6), 6 hours of permanent MCAO and treatment with anti-ICAM-1 antibody (designated 1A29, 1 mg/kg) at 2 hours after onset of MCAO; and 4) Group 4 (n = 6), 3 hours of MCAO followed by 3 hours of reperfusion and 1A29 treatment. During the experiment, regional cerebral blood flow was measured by a laser Doppler flowmetric scanning technique. At the 6-hour time point, all rats were killed, and the results of leukocyte infiltration by myeloperoxidase activity and histological analysis using 2,3,5-triphenyltetrazolium chloride staining were examined. RESULTS: Regional cerebral blood flow values before and after MCAO were not significantly different among the four groups. Regional cerebral blood flow values after reperfusion were not significantly different in the two reperfused groups. The percentage brain injury volumes in both the total and cortical areas and the myeloperoxidase activity in the latter were significantly larger in Group 2 (the reperfused group) than in the other groups (P < 0.05) but were decreased by anti-ICAM-1 antibody treatment (Group 2 versus Group 4, P < 0.05). However, there were no differences between Groups 1 and 3 without reperfusion. Myeloperoxidase activities correlated positively with infarct volumes (P < 0.01). CONCLUSION: The findings of this study demonstrate that the anti-ICAM antibody treatment is effective at inhibiting early inflammatory processes and reperfusion-induced injury caused by late arterial recanalization, which would contribute to widening the therapeutic window of thrombolytic therapy.

Animals↗

PubMed1990

Early afterdepolarizations induced in vivo by reperfusion of ischemic myocardium. A possible mechanism for reperfusion arrhythmias.

Recent studies in vitro have shown that afterdepolarizations may develop during reperfusion after hypoxia, thus suggesting that these afterdepolarizations may contribute to the genesis of reperfusion arrhythmias. We recorded monophasic action potentials (MAPs) during myocardial ischemia and reperfusion to investigate whether afterdepolarizations develop in vivo when reperfusion arrhythmias occur. In 15 anesthetized cats, 24 trials of 10 minutes of occlusion of the left anterior descending coronary artery were followed by reperfusion. In 13 of 24 (54%) trials, afterdepolarizations developed at the moment of reperfusion, with a mean amplitude of 2.4 +/- 1.1 mV (13 +/- 8% of MAP amplitude). When cycle length was either increased by vagal stimulation or decreased by atrial pacing, early afterdepolarization (EAD) amplitude was modified, according to what has been described for EAD in vitro, with a positive linear correlation between cycle length and EAD amplitude (r = 0.91, p less than 0.0001). The occurrence of EAD was not related to rapid changes in left ventricular pressure. In the eight of 13 (62%) cases in which EAD development was associated with reperfusion arrhythmias, the coupling interval of the EAD and of premature ventricular contractions showed a significant correlation (r = 0.86, p less than 0.0001). However, in five of 13 (38%) cases, occurrence of reperfusion arrhythmias was not accompanied by the presence of EAD on the MAP recording. In two animals, a 2:1 block of EAD conduction was observed, and this was reflected on the intracavitary electrocardiogram as T wave alternans. Thus, EADs occur frequently after reperfusion in vivo, with a time course that parallels the onset of reperfusion arrhythmias. This finding further supports the role of triggered activity in the genesis of reperfusion arrhythmias in vivo.

Action Potentials↗

PubMed1995

Deleterious effects of a systemic lytic state on reperfused myocardium. Minimization of reperfusion injury and enhanced recovery of myocardial function by direct angioplasty.

BACKGROUND: The beneficial effects of flow restoration and the deleterious impact of reperfusion injury on ischemic myocardium are well known. However, most experimental studies have induced reperfusion by mechanical release of nonthrombotic occlusions, only occasionally in the presence of a systemic lytic state. Conditions differ markedly in patients undergoing pharmacological or mechanical recanalization of thrombotically occluded coronary arteries. Accordingly, this study was designed to determine whether the method of coronary occlusion and mode of recanalization influence the response of the heart to reperfusion. METHODS AND RESULTS: The acute effects of reperfusion on right ventricular (RV) function and histology were studied in open-chest dogs subjected to right coronary artery (RCA) balloon occlusion and deflation alone (group 1), pharmacological lysis of thrombotic occlusions (group 2), balloon occlusion with reperfusion induced by balloon deflation in the presence of a systemic lytic state (group 3), and recanalization of thrombotically occluded vessels by direct angioplasty (group 4). In all groups, 1 hour of RCA occlusion led to RV free wall (FW) dyskinesis. In group 1, reperfusion promptly improved RVFW function, with normal RVFW thickness and only minimal edema by microscopy. In contrast, in group 2, clot lysis led to acute RVFW swelling and impaired recovery of RVFW contraction associated with striking interstitial edema, contraction band necrosis, and hemorrhage by microscopy. In group 3, balloon deflation in the presence of a lytic state led to a similar but less severe pattern of abrupt RVFW swelling and impaired recovery of RVFW function but lesser histological alterations than in group 2. However, mechanical recanalization of thrombotically occluded vessels (group 4) led to prompt recovery of RVFW function without significant RVFW swelling or histological abnormalities. CONCLUSIONS: Our observations indicate that the responses of ischemic myocardium to reperfusion are influenced by factors beyond those effects attributable to ischemia and reperfusion per se. Pharmacological lysis of coronary thrombi results in alterations characteristic of reperfusion injury and associated with impaired functional recovery. Such changes are also evident, although to a lesser extent, when reperfusion of northrombotic occlusions is induced by mechanical recanalization in the presence of a systemic lytic state but not in its absence. However, such effects were not seen with direct mechanical recanalization of thrombotically occluded vessels. In aggregate, these findings indicate that induction of a systemic lytic state, together with products released by lysis of intracoronary thrombi, generates an inurious milieu that exerts adverse effects on reperfused myocardium.

Angioplasty, Balloon, Coronary↗

PubMed2003

Proteins released from liver after ischaemia induced an elevation of heart resistance against ischaemia-reperfusion injury: 1. Beneficial effect of protein fraction isolated from perfusate after ischaemia and reperfusion of liver.

OBJECTIVES: Numerous mechanisms have been proposed to participate in adaptation of heart to ischaemia by ischaemic preconditioning. We have described previously a release of cardio-protective protein fraction during ischaemic preconditioning of dog heart. In the current study the effect of high soluble protein fraction (HS fraction) released from isolated perfused rat liver after ischaemia and reperfusion was examined on isolated perfused rat heart during ischaemia-reperfusion injury. METHODS: Livers were subjected to 30 or 60 min ischaemia followed with 120 min reperfusion. HS fraction was isolated using ammonium sulphate precipitation and dissolved in perfusion solution before Langendorf perfusion of isolated rat hearts. The protein pattern of HS fraction was detected with SDS-PAGE and western blot with ConA and anti ConA antibody. Hearts were then subjected to 20 min ischaemia followed by 20 min reperfusion. During reperfusion, the haemodynamic parameters of hearts were measured. Heart levels of adenine nucleotide were measured in HClO4 extracts using HPLC on C18 column. RESULTS: Liver ischaemia induced changes in protein pattern of HS fraction released from the liver during reperfusion period. Particularly, we registered an increase in amount of several low-molecular weight proteins and decreased amount of high-molecular weight proteins. Proteins in this fraction isolated from perfusate after liver ischaemia interact with ConA with lower intensity as proteins isolated from perfusate after control non-ischaemic condition. HS fraction isolated from perfusate after ischaemia and reperfusion of liver had beneficial effect on heart function during 20 min ischaemia and subsequent 20 min reperfusion, documented by: i) decrease of arrhythmia score from 2 to 1 in 5 min of reperfusion and from 2 to 0 in 10 min of reperfusion; ii) improved heart contractility monitored as stabilised [dP/dt]max and increased Q parameter; iii) increased coronary flow. Proteins isolated from liver perfused under control non-ischaemic condition did not induce similar effects. The stabilisation of heart haemodynamics, observed after administration of HS proteins isolated from perfusate after ischaemia and reperfusion was associated with slight increase in ATP and ADP levels as well as decrease in AMP level.

Animals↗

PubMed2002

Adenosine A2A receptor activation decreases reperfusion injury associated with high-flow reperfusion.

INTRODUCTION: High pulmonary artery flow rates can result in severe reperfusion injury after lung transplantation. Our hypothesis was that selective activation of the adenosine A(2A) receptor with a highly specific analog (ATL-146e) would inhibit leukocyte activation and decrease reperfusion injury after high-flow reperfusion. METHODS: Using our isolated, ventilated, blood-perfused rabbit lung model, all groups (n = 8 per group) underwent lung harvest, 4 hours of cold storage, and blood reperfusion for 30 minutes. Measurements of pulmonary artery pressure (in millimeters of mercury), arterial oxygenation (in millimeters of mercury), myeloperoxidase, peak inspiratory pressure, and wet/dry weight ratio were obtained. Groups 1 (high flow) and 2 (high flow ATL-146e) underwent reperfusion at 120 mL/min for 30 minutes. Groups 3 (controlled high flow) and 4 (controlled high flow ATL-146e) underwent controlled reperfusion with an initial reperfusion of 60 mL/min for the first 5 minutes, followed by a rate of 120 mL/min for 25 minutes. During reperfusion, groups 2 and 4 received ATL-146e at 4 microg. kg(-1). min(-1). RESULTS: ATL-146e significantly improved lung physiologic measurements under both high-flow (group 1 vs group 2) and controlled high-flow (group 3 vs group 4) conditions after 30 minutes. CONCLUSIONS: The adenosine A(2A) receptor analogue ATL-146e significantly decreases the severity of reperfusion injury in the setting of both high-flow and controlled high-flow reperfusion.

Animals↗

PubMed1988

Reperfusion induced enzyme release: washout effect or manifestation of reperfusion damage?

Isolated isovolumically contracting rat hearts were subjected to ischaemia and subsequent reperfusion to determine whether reperfusion induced release of lactate dehydrogenase from the heart was due to washout of previously unperfused areas by reflow or a manifestation of myocardial damage occurring during reperfusion. Hearts were exposed to 2 h of ischaemia alone or to 2 h of ischaemia followed by reperfusion for at least 2 h. Below an ischaemic coronary flow rate of 40% of the preischaemic value drainage of enzymes liberated from irreversibly damaged myocytes was impaired owing to the presence of unperfused myocardium. The lactate dehydrogenase activity released during 2 h of ischaemia was maximally 60 U per heart and during 2 h of reperfusion maximally 251 U per heart (comprising together 89% of cardiac lactate dehydrogenase content). Lactate dehydrogenase activity released during reperfusion correlated with ischaemic coronary flow rate (r = -0.93). Reperfusion induced reflow of previously unperfused regions resulted in washout of liberated but trapped lactate dehydrogenase, predominantly responsible for lactate dehydrogenase release if ischaemia was severe (ischaemic flow rate below 40%). After the onset of reperfusion there was partial initial recovery of left ventricular developed pressure, with a gradual decline thereafter. In experiments in which ischaemia induced unperfused areas could be excluded--that is, at ischaemic flow rates of 40% or higher--reperfusion gave rise to lactate dehydrogenase release closely associated in time with the decline of left ventricular developed pressure. It is concluded that in this rat heart preparation reperfusion --takes place in previously underperfused (low flow) myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Staged reperfusion attenuates myocardial stunning in dogs. Role of transient acidosis during early reperfusion.

BACKGROUND: Acidosis during early reperfusion is reported to be beneficial for myocardial stunning. We tested in 31 dogs the hypothesis that staged reperfusion is beneficial to myocardial stunning. METHODS AND RESULTS: Contractile dysfunction was observed 3 hours after the onset of reperfusion after 15 minutes of occlusion of the coronary artery. In the staged reperfusion, pH of the coronary venous blood was lower for 20 minutes and fractional shortening was significantly improved compared with the control reperfusion group. When we increased pH of the reperfused myocardium by an intracoronary infusion of sodium bicarbonate, beneficial effects of the staged reperfusion were abolished. Furthermore, an intracoronary infusion of hydrogen chloride, which mimicked the changes in pH in coronary venous blood of the staged reperfusion, attenuated myocardial stunning. CONCLUSIONS: These results indicate that acidosis during staged reperfusion primarily attenuates myocardial stunning. This procedure is clinically applicable for attenuation of reperfusion injury.

Acidosis↗

PubMed1990

Reperfusion injury in ischemic myocardium: protective effect of controlled reperfusion.

Restoration of coronary artery flow following a period of ischemia often results in further ultrastructural damage to cardiac fibers, a phenomenon known as reperfusion injury. We have compared the ultrastructural effects of uncontrolled reperfusion in vivo of ischemic pig myocardium with the ultrastructural effects of reperfusion controlled at flow rates comparable to preischemia levels. Myocardial ischemia was produced for 60 minutes in 9 pigs by means of a reversible coronary artery occlusion, after which coronary artery flow was restored for 120 minutes. This restoration of flow was complete in four pigs (resulting in uncontrolled reperfusion) and partial in five pigs, with constant monitoring and adjustment of flow to maintain rates near preischemia values (controlled reperfusion). Myocardial samples from the ischemic, reperfused region were examined by electron microscopy. Ischemic damage to nuclei, mitochondria, and myofibrils and ischemic depletion of glycogen were graded independently and blindly by two investigators using a simple, nonparametric three-point scale. Ischemic damage was greater in pigs receiving uncontrolled reperfusion than in animals receiving controlled reperfusion, and these differences were significant for ischemic effects on nuclei (p less than 0.01), glycogen (p less than 0.02), and myofibrils (p less than 0.05) but not for ischemic effects on mitochondria (p = 0.095). We conclude that uncontrolled, hyperemic flow during reperfusion of ischemic myocardium is responsible, in part, for the phenomenon of reperfusion injury.

Animals↗

PubMed1988

Myocardial reperfusion injury. Role of myocardial hypoxanthine and xanthine in free radical-mediated reperfusion injury.

The aim of this study was to differentiate myocardial reperfusion injury from that of ischemia. We assessed the role of the myocardial adenosine 5'-triphosphate (ATP) catabolites, hypoxanthine and xanthine, generated during ischemia and the early phase of reperfusion, in reperfusion injury by modulating adenosine transport and metabolism with specific metabolic inhibitors. This was followed by intracoronary infusion of exogenous hypoxanthine and xanthine. Twenty-four dogs instrumented with minor-axis piezoelectric crystals and intraventricular pressure transducers were subjected to 30 minutes of normothermic global myocardial ischemia and 60 minutes of reperfusion. In Group 1 (n = 7), normal saline was infused into the cardiopulmonary bypass reservior before ischemia and before reperfusion. Saline solution containing 25 microM p-nitrobenzylthioinosine (NBMPR) and 100 microM erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) was infused in Group 2 (n = 10) dogs. Group 3 (n = 7) dogs were treated exactly like those in Group 2 except, at the end of the ischemic period and immediately before releasing the cross-clamp, a solution of EHNA-NBMPR containing 100 microM hypoxanthine and 100 microM xanthine was infused into the aortic root. Left ventricular performance and myocardial adenine nucleotide pool intermediates were determined before and after ischemia. ATP was depleted by about 50% (p less than 0.05 vs. preischemia) in all groups after 30 minutes of ischemia. Inosine was the major ATP catabolite (9.29 +/- 1.2 nmol/mg protein) in Group 1, while adenosine (9.91 +/- 0.7 nmol/mg protein) was the major metabolite in EHNA-NBMPR-treated dogs (Groups 2 and 3). Hypoxanthine levels were fivefold more in Group 1 compared with Groups 2 and 3 (p less than 0.05). Left ventricular performance in Group 1 decreased from 76.8 +/- 7.6 to 42.9 +/- 9.8 and 52.3 +/- 8.4 dynes/cm2 x 10(3) (p less than 0.05), while myocardial ATP decreased from 30.9 +/- 2.2 to 17.2 +/- 1.0 and 16.5 +/- 1.0 nmol/mg protein during 30 and 60 minutes of reperfusion, respectively (p less than 0.05 vs. preischemia). Ventricular function in Group 2 dogs completely recovered within 30 minutes of reperfusion, and myocardial ATP recovered to the preischemic level at 60 minutes of reperfusion. In Group 3, left ventricular performance was depressed by 39% and 30% during 30 and 60 minutes of reperfusion (p less than 0.05), respectively, and myocardial ATP did not recover during reperfusion despite a significant intramyocardial adenosine accumulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenine↗

PubMed1991

Differentiation of reperfused-viable (stunned) from reperfused-infarcted myocardium at 1 to 3 days postreperfusion by in vivo phosphorus-31 nuclear magnetic resonance spectroscopy.

Thrombolytic therapy has increased the need for a technique to assess the viability of recently reperfused myocardium. This study examined the ability of in vivo phosphorus-31 (P-31) nuclear magnetic resonance (NMR) spectroscopy to distinguish reperfused-viable (stunned) from reperfused-infarcted myocardium at 6, 30, and 54 hours following coronary artery occlusion in a canine model. A 15-minute occlusion produced reperfused-viable myocardium in five animals and a 360-minute occlusion produced reperfused-infarcted myocardium in six animals. Postreperfusion risk zone myocardial phosphocreatine (PCr) concentration measured by P-31 NMR spectroscopy was significantly depressed throughout the 3-day study period in infarcted but not in viable myocardium (p less than 0.01 between groups, all time points). The postreperfusion ratio of inorganic phosphate (Pi) to PCr concentration, as determined by NMR spectroscopy, was elevated throughout the study period in infarcted but not in viable reperfused myocardium (p less than 0.01 between groups, all time points). Postreperfusion Pi concentration was elevated at 6 hours but not subsequently in reperfused-infarcted myocardium, and was not elevated in reperfused-viable myocardium. Logistic regression models selected PCr concentration and the Pi/PCr ratio as providing the best discrimination between reperfused-viable and reperfused-infarcted myocardium. The accuracy of P-31 NMR variables selected by logistic regression analysis for determining myocardial viability ranged from 97% to 100%.

Animals↗

PubMed2000

Reducing postischemic reperfusion damage in neonates using a terminal warm substrate-enriched blood cardioplegic reperfusate.

BACKGROUND: In adult cardiac operations, a warm cardioplegic reperfusate ("hot shot") before removing the aortic cross-clamp improves postbypass myocardial function and metabolic recovery. This modality, however, is rarely used in infants, despite the fact that postbypass cardiac dysfunction remains problematic, especially in cyanotic ("stressed") patients. METHODS: To produce stress, 15 neonatal piglets underwent 60 minutes of ventilator hypoxia (fraction of inspired oxygen, 8% to 10%). All piglets then received similar protection with multidose cold blood cardioplegic solution during 70 minutes of arrest and were separated into three groups to examine the role of a warm reperfusate as well as possible augmentation by aspartate and glutamate enrichment. In 5 piglets (group 1), the cross-clamp was simply removed; in 5 (group 2), an unsupplemented warm blood cardioplegic reperfusate was given; and in 5 (group 3), the warm reperfusate was enriched with aspartate and glutamate. Myocardial function was assessed using pressure-volume loops and expressed as a percentage of control. RESULTS: Compared with hearts receiving reperfusion with unmodified blood (group 1), a warm unsupplemented cardioplegic reperfusate (group 2) slightly improved systolic contractility (end-systolic elastance, 41% versus 50%; p < 0.05 versus group 1) and preload recruitable stroke work (41% versus 52%; p < 0.05 versus group 1), reduced diastolic stiffness (263% versus 245%; p < 0.05 versus group 1), and increased adenosine triphosphate (10.7 versus 11.9 microg/g tissue, p < 0.05 versus group 1). However, if aspartate and glutamate was included in the warm reperfusate (group 3), there was complete recovery of systolic function (end-systolic elastance, 105%+/-3%; p < 0.001 versus all groups) and preload recruitable stroke work (103%+/-2%; p < 0.001 versus all groups), a minimal rise in diastolic stiffness (154%+/-7%; p < 0.001 versus all groups), and preservation of adenosine triphosphate (15.5+/-0.5 microg/g; p < 0.001 versus all groups). CONCLUSIONS: A warm cardioplegic reperfusate helps reduce the reperfusion injury, resulting in improved myocardial function and metabolic recovery in hypoxic (stressed) neonatal hearts, and this effect is maximized if the reperfusate is enriched with aspartate and glutamate, which completely preserves myocardial function.

Adenosine Triphosphate↗

PubMed1992

[Reperfusion injury after heart-lung transplantation--OP41483-alpha-CD (prostaglandin I2 analogue) as a preventive for the reperfusion injury, especially the oxygen derived free radicals].

In clinical heart-lung transplantation, reperfusion injury is a serious problem. This study was undertaken to evaluate the preventive effect of OP 41483-alpha-CD (OP) as a stable prostaglandin I2 analogue on the reperfusion injury, especially oxygen derived free radicals after the heart-lung transplantation. The heart-lung transplantation was performed according to the Schäefers' method. Explanted heart-lung block was immersed and preserved in the UW solution for just 4 hours at 4 degrees C. In the OP group, OP was administered to the grafts through the pulmonary artery for 25 minutes before and after the reperfusion. No spin adducts were detected in the plasma before harvest of the graft by ESR spectroscopy. But after the onset of reperfusion, free radical in the plasma could be detected. Those signals were 2.007 of the g factor and 15.5 G of the hyperfine splitting constancy (aN). These findings suggested that the free radical detected in the blood of this model was hydroxyl radical. Max dp/dt, left ventricular pressure and cardiac index were higher in the OP group than in the control group after reperfusion, but there was no difference in the left ventricular end-diastolic pressure between two groups. And adenosine triphosphate contents of the myocardial cell was higher in the OP group than in the control group at 60 min after the onset of reperfusion. Oxygenation by the graft's lung was better in the OP group than in the control group after reperfusion. Radical intensities of the plasma by ESR after reperfusion were significantly higher in the pulmonary vein than in the coronary sinus. When OP was administered, radical intensities in the lung and the plasma of the pulmonary vein were significantly lower in the OP group than in the control group. Thiobarbituric acid-reactive substances increased gradually, in two groups with less increase in the OP group. These show that the free radicals, especially.OH generated from the transplanted heart and lung contribute to the reperfusion injury. The platelet counts in the systemic blood, furthermore, did not change appreciably in the OP group, but decreased rapidly in the control group. Probably the microemboli formation was partially inhibited by the administration of OP. Following the onset reperfusion, the free radicals attack the cell membranes and cause the cell damage. When OP was administered through the pulmonary artery, less free radicals were generated in the lung, and the microemboli were possibly inhibited by platelets anti-agglutination. OP administration is useful in the heart-lung transplantation.

Animals↗

PubMed1990

Is adenosine 5'-triphosphate derangement or free-radical-mediated injury the major cause of ventricular dysfunction during reperfusion? Role of adenine nucleoside transport in myocardial reperfusion injury.

The aim of this study was to determine the dual role of ATP as an energy substrate and as a major source of oxygen-derived free-radical-mediated reperfusion injury by using adenine nucleoside blocker, p-nitrobenzylthioinosine (NBMPR), and adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA). In a randomized study, 16 dogs were instrumented with minor-axis LTZ-piezoelectric crystals and intraventricular pressure transducers to monitor, off bypass, left ventricular performance by using a sensitive and load-independent index of contractility (slope of the stroke work-end-diastolic length relation). Hearts were subjected to 60 minutes of normothermic global ischemia and 120 minutes of reperfusion. Normal saline without (Group 1, n = 8) or with (Group 2, n = 8) NBMPR and EHNA was infused in three boluses into the cardiopulmonary bypass reservoir before ischemia and reperfusion. Transmural serial biopsies were obtained before and during ischemia and reperfusion and analyzed for myocardial adenine nucleotide pool intermediates by using high-performance liquid chromatography. In the control group, three hearts developed ischemic contracture and another three hearts exhibited cardiogenic shock during reperfusion. In the EHNA/NBMPR-treated group, left ventricular performance recovered within 30 minutes of reperfusion (p less than 0.05 vs. control). Myocardial ATP was depleted to 20% of normal in both groups by the end of ischemia (p less than 0.05). Intramyocardial adenosine in the EHNA/NBMPR-treated group was 12-fold greater (15.09 +/- 1.6 nmol/mg protein) than the control group at the end of the ischemic period (p less than 0.05). Inosine was about fourfold higher in the control group (19.07 +/- 1.50 nmol/mg protein) compared with the drug-treated group (p less than 0.05). During reperfusion, myocardial ATP levels increased to approximately 50% of normal in the EHNA/NBMPR group while remaining depressed (20% of normal) in the control group. Thus, despite the dramatic loss of myocardial ATP during ischemia, complete recovery of ventricular performance and significant repletion of ATP during reperfusion were observed when adenosine transport and deamination were modulated during ischemia and reperfusion. These results suggest that 1) the myocardium may have more ATP than is needed for basic cardiac functions and 2) washout of ATP diffusible catabolites is detrimental to ventricular performance during reperfusion. Specific blockade of nucleoside transport resulted in complete functional recovery despite low but critical ATP levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenine↗

PubMed1998

Prevention of rapid reperfusion-induced lung injury with prostaglandin E1 during the initial period of reperfusion.

We have found that the instantaneous restoration of blood flow causes acute dysfunction and massive edema in rat lungs after 4 hours of room temperature ischemia. This is associated with an early increase in pulmonary artery pressure (Ppa) and can be prevented by a stepwise increase in flow rate during the first 10 minutes of reperfusion. The objectives of this study were to determine whether rapid reperfusion causes lung injury after hypothermic preservation, and whether this injury can be attenuated by a short-course of prostaglandin E1 (PGE1). Rat lungs were flushed preserved with low-potassium dextran solution for 12 hours at 4 degrees C and randomly divided into three groups: (1) control (no PGE1); (2) PGE1 only in the flush solution; and (3) PGE1 in both flush solution and blood perfusate during the first 10 minutes of reperfusion. Postpreservation pulmonary function was assessed in an isolated rat lung reperfusion model developed previously. We found that rapid initiation of reperfusion led to significant pulmonary dysfunction, which was attenuated by a short-course of PGE1 in the blood perfusate. The addition of PGE1 to the flush solution alone did not have such an effect. Administration of PGE1 to the blood perfusate during the first 10 minutes resulted in significant lower Ppa and airway pressure and better gas exchange. There was a positive correlation between the peak Ppa during the first 10 minutes of reperfusion and the final shunt fraction. The physical forces generated by the rapid initiation of blood reperfusion appear to induce severe injury. The first 10 minutes of reperfusion seem to be a transition phase in which mechanical factors play an important role relating to ultimate post reperfusion lung function. A short course of PGE1 may be a useful maneuver to prevent rapid reperfusion-induced lung injury.

Airway Resistance↗

PubMed1987

Calcium-accentuated ischemic damage during reperfusion: the time course of the reperfusion injury in the isolated working rat heart model.

The purpose of this study was to determine the time course of calcium-induced postischemic reperfusion injury to the myocardium, using an initial short-term calcium-enriched reperfusion solution. The isolated rat heart model was subjected to 30 min of normothermic potassium cardioplegia-induced ischemic arrest. Control hearts received normal calcium Krebs-Henseliet buffer (KHB) reperfusion. Experimental hearts were challenged with 10 min of calcium-enriched (KHB) reperfusion starting at 0, 1, 2, 5, 15, and 30 min after the beginning of reperfusion. Aortic flow recovery 60 min after reperfusion was used to determine functional recovery. Control hearts recovered 82 +/- 3% of preischemic aortic flow. Hearts which received calcium challenge at 0 and 1 min after the start of reperfusion recovered 43 +/- 4 and 69 +/- 3% of preischemic aortic flow, respectively (P less than 0.01 and P less than 0.05, respectively). Hearts which received calcium challenge 2, 5, 15, and 30 min after reperfusion recovered 75 +/- 2, 80 +/- 2, 85 +/- 2, and 83 +/- 2% of preischemic aortic flow, respectively. Our results indicate that the postischemic myocardium is very susceptible to calcium-accentuated ischemic damage during the initial period of reperfusion. The postischemic heart, however, quickly recovers its ability to withstand a calcium challenge. Five minutes after the start of reperfusion the heart is not influenced by calcium challenge.

Animals↗