6-ketoprostaglandin-f1-alpha and Reperfusion-Injury

To explore the protective effect and mechanism of ligustrazine (LGT) and propofol (PRO) on peri-operational liver ischemia-reperfusion injury (HIRI).. Thirty-six patients scheduled for hepatic surgery were randomly divided into the control group, the LGT group, the PRO group and the LGT + PRO group, 9 patients in each group. Changes of superoxide dismutase (SOD), lipid peroxide (LPO), ratio of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha), alanine aminotransferase (ALT) activity, and the ultrastructure of liver tissue were dynamically observed.. Compared with the control group, SOD activity was significantly higher, LPO concentration, TXB2/6-keto-PGF1alpha ratio and ALT value were significantly lower (P < 0.05 and P < 0.01) in the LGT group, the PRO group and the LGT + PRO group during HIRI, with the abnormal changes of hepatic ultrastructure 25 min after reperfusion significantly alleviated in the three treated group.. Combination of ligustrazine and propofol shows protective effect on liver by decreasing oxygen free radical level, reducing lipid peroxidation and adjusting TXA2/PGI2 imbalance after hepatic ischemia-reperfusion in patients undergoing hepatic cancer surgery.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Drug Therapy, Combination; Female; Humans; Lipid Peroxides; Liver; Liver Neoplasms; Male; Middle Aged; Propofol; Pyrazines; Reperfusion Injury; Superoxide Dismutase

We previously showed that the selective neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI) increases cerebral microcirculation in a juvenile ischemic rat model. We address the roles of cyclooxygenase (COX)-elaborated prostaglandins in collateral recruitment and blood supply.. Six-keto-prostaglandin F. These results show that the juvenile rat brains mostly respond to ischemia by a COX-2-dependent prostaglandins production and suggest that the transcriptional responses observed under 7-NI facilitate and reorient COX-2-dependent prostaglandins production.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cerebrovascular Circulation; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Microcirculation; Prostaglandin-E Synthases; Rats; Reperfusion Injury

This study is to investigate the effects of paeoniflorin on cerebral blood flow and the balance of PGI2/TXA2 of rats with focal cerebral ischemia-reperfusion injury. A total of 72 SD rats (3) were randomly divided into 6 groups: sham operation group, cerebral ischemia-reperfusion model group (I/R gourp), low (10 mg.kg-1), middle (20 mg.kg-1) and high (40 mg.kg-1) doses of paeoniflorin groups and nimrnodipine group. Focal cerebral ischemia in rats was made by inserting a monofilament suture into internal carotid artery for 90 min and then reperfused for 24 h. The effects of paeoniflorin on neurological deficit scores and the infarction volume of brain were detected. Relative regional cerebral blood flow (rCBF) was continuously monitored over ischemic hemispheres by laser-Doppler flowmetry (LDF). The expression of COX-2 in hippocampal CAl region was estimated by immunohistochemistry and the contents of prostacyclin I2 (PGI2), thromboxane A2 (TXA2), and ratio of PGIJ2/TXA2 in serum were measured by ELISA kits. Paeoniflorin significantly ameliorated neurological scores, reduced the infarction volume, and increased regional cerebral blood flow relative to the I/R group. In addition, paeoniflorin could inhibit COX-2 expression and the release of TXA2 and prevent the downregulation of PGI2 induced by I/R injury. The neuroprotective effects of paeoniflorin against focal cerebral ischemia-reperfusion rats might be attributed to improve the supply of injured hemisphere blood flow and adjust the balance between PGI2/TXA2.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Brain; CA1 Region, Hippocampal; Cyclooxygenase 2; Glucosides; Infarction, Middle Cerebral Artery; Male; Monoterpenes; Neuroprotective Agents; Paeonia; Plants, Medicinal; Random Allocation; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Reperfusion Injury; Thromboxane B2

The present study aimed to investigate the protective effects of injectable caltrop fruit saponin preparation (ICFSP) on ischemia-reperfusion injury in rat brain. Rats were injected with ICFSP and then subjected to cerebral ischemia-reperfusion injury induced by middle cerebral artery occlusion. Then the neurological deficit score was evaluated by Bederson's method. The infarct size was assessed by TTC staining. The content of malondialdehyde (MDA) and nitric oxide (NO), and the activity of superoxide dismutase (SOD) in rat cerebrum were measured with kits, and the content of 6 K prostaglandin F1α (6-K-PGF 1α), thromboxane B2 (TXB2) and endothelin (ET) in blood plasma was measured by radioimmunoassay. The results demonstrated that ICFSP led to a decrease in infarct size (p < 0.01), neurological deficit score (p < 0.05) and plasma content of TXB2 and ET (p < 0.05), and an increase of the plasma level of 6-K-PGF 1α (p < 0.05) and SOD activity in cerebrum, where the MDA and NO content were decreased. The treatment improved forelimb function. ICFSP showed a similar potency compared to that of Ligustrazine hydrochloride parenteral solution (LHPS) and nimodipine (Nim). We concluded that ICFSP protects the brain damage caused by ischemia-reperfusion injury in rats, and this may be closely related to the regulation of reactive oxygen species (MDA and SOD activity) and NO levels in the rat cerebrum, as well as vasoactive factors in the plasma (6-K-PGF 1α, TXB2 and ET).

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents; Calcium Channel Blockers; Cerebral Infarction; Cerebrum; Endothelins; Forelimb; Fruit; Infarction, Middle Cerebral Artery; Injections; Male; Malondialdehyde; Neuroprotective Agents; Nitric Oxide; Phytotherapy; Plant Extracts; Rats; Rats, Wistar; Reperfusion Injury; Saponins; Superoxide Dismutase; Thromboxane B2; Tribulus

Chemical composition of hepatic lipids is an evolving player in steatotic liver ischemia/reperfusion (I/R) injury. Thromboxane A(2) (TXA(2)) is a vasoactive pro-inflammatory lipid mediator derived from arachidonic acid (AA), an omega-6 fatty acid (Ω-6 FA). Reduced tolerance of the macrosteatotic liver to I/R may be related to increased TXA(2) synthesis due to the predominance of Ω-6 FAs.. TXA(2) levels elicited by I/R in ob/ob and wild type mice were assessed by ELISA. Ob/ob mice were fed Ω-3 FAs enriched diet to reduce hepatic synthesis of AA and TXA(2) or treated with selective TXA(2) receptor blocker before I/R.. I/R triggered significantly higher hepatic TXA(2) production in ob/ob than wild type animals. Compared with ob/ob mice on regular diet, Ω-3 FAs supplementation markedly reduced hepatic AA levels before ischemia and consistently blunted hepatic TXA(2) synthesis after reperfusion. Sinusoidal perfusion and hepatocellular damage were significantly ameliorated despite downregulation of heme oxygenase-1. Hepatic transcript and protein levels of IL-1β and neutrophil recruitment were significantly diminished after reperfusion. Moreover, TXA(2) receptor blockage conferred similar protection without modification of the histological pattern of steatosis. A stronger protection was achieved in the steatotic compared with lean animals.. Enhanced I/R injury in the macrosteatotic liver is explained, at least partially, by TXA(2) mediated microcirculatory failure rather than size-related mechanical compression of the sinusoids by lipid droplets. TXA(2) blockage may be a simple strategy to include steatotic organs and overcome the shortage of donor organs for liver transplantation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Fatty Acids, Omega-3; Fatty Liver; Lipid Metabolism; Lipids; Liver; Macrophage Activation; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Microcirculation; Neutrophil Activation; Oxidative Stress; Receptors, Thromboxane A2, Prostaglandin H2; Reperfusion Injury; Thromboxane A2

Prostaglandin I2 (PGI2) produced by endothelial cells improves ischemia/reperfusion-induced acute renal injury by inhibiting leukocyte activation in rats. However, the underlying mechanism(s) of increased PGI2 production is not fully understood. Activation of sensory neurons increases endothelial PGI2 production by releasing calcitonin gene-related peptide (CGRP) in rats with hepatic ischemia or reperfusion. We examined here whether activation of sensory neurons increases PGI2 endothelial production, thereby reducing ischemia/reperfusion-induced acute renal injury.. Anesthetized rats were subjected to 45 min of renal ischemia/reperfusion. Rats were pretreated with CGRP, capsazepine (a vanilloid receptor-1 antagonist), CGRP(8-37) (a CGRP receptor antagonist), or indomethacin (a cyclooxygenase inhibitor), or subjected to denervation of primary sensory nerves before ischemia/reperfusion.. Renal tissue levels of CGRP and 6-keto-prostaglandin F1alpha, a stable metabolite of PGI2, increased after renal ischemia/reperfusion, peaking at 1 h after reperfusion. Overexpression of CGRP was also noted at 1 h after reperfusion. Increases in renal tissue levels of 6-keto-prostaglandin F1alpha at 1 h after reperfusion were significantly inhibited by pretreatment with capsazepine, CGRP(8-37), and indomethacin. Pretreatment with capsazepine, CGRP(8-37), indomethacin, and denervation of primary sensory nerves significantly increased blood urea nitrogen and serum creatinine levels, renal vascular permeability, renal tissue levels of myeloperoxidase activity, cytokine-induced neutrophil chemoattractant, and tumor necrosis factor-alpha, and decreased renal tissue blood flow. However, pretreatment with CGRP significantly improved these changes.. Our results suggest activation of sensory neurons in the pathologic process of ischemia/reperfusion-induced acute renal injury. Such activation reduces acute renal injury by attenuating inflammatory responses through enhanced endothelial PGI2 production.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Capillary Permeability; Capsaicin; Chemokine CCL2; Denervation; Immunohistochemistry; Indomethacin; Kidney; Kidney Diseases; Male; Peptide Fragments; Peroxidase; Rats; Rats, Wistar; Renal Circulation; Reperfusion Injury; Sensory Receptor Cells; TRPV Cation Channels; Tumor Necrosis Factor-alpha

We recently demonstrated that calcitonin gene-related peptide (CGRP) released from sensory neurons reduces spinal cord injury (SCI) by inhibiting neutrophil activation through an increase in the endothelial production of prostacyclin (PGI(2)). Carperitide, a synthetic alpha-human atrial natriuretic peptide (ANP), reduces ischemia/reperfusion (I/R)-induced tissue injury. However, its precise therapeutic mechanism(s) remains to be elucidated. In the present study, we examined whether ANP reduces I/R-induced spinal cord injury by enhancing sensory neuron activation using rats. ANP increased CGRP release and cellular cAMP levels in dorsal root ganglion neurons isolated from rats in vitro. The increase in CGRP release induced by ANP was reversed by pretreatment with capsazepine, an inhibitor of vanilloid receptor-1 activation, or with (9S, 10S, 12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]-benzodiazocine-10-carboxylic acid hexyl ester (KT5720), an inhibitor of protein kinase A (PKA), suggesting that ANP might increase CGRP release from sensory neurons by activating PKA through an increase in the cellular cAMP level. Spinal cord ischemia was induced in rats using a balloon catheter placed in the aorta. ANP reduced mortality and motor disturbances by inhibiting reduction of the number of motor neurons in animals subjected to SCI. ANP significantly enhanced I/R-induced increases in spinal cord tissue levels of CGRP and 6-keto-prostaglandin F(1alpha). a stable metabolite of PGI(2). ANP inhibited I/R-induced increases in spinal cord tissue levels of tumor necrosis factor and myeloperoxidase. Pretreatment with 4'-chloro-3-methoxycinnamanilide (SB366791), a specific vanilloid receptor-1 antagonist, and indomethacin reversed the effects of ANP. These results strongly suggest that ANP might reduce I/R-induced SCI in rats by inhibiting neutrophil activation through enhancement of sensory neuron activation.

Topics: 6-Ketoprostaglandin F1 alpha; Anilides; Animals; Atrial Natriuretic Factor; Calcitonin Gene-Related Peptide; Capsaicin; Carbazoles; Cells, Cultured; Cinnamates; Cyclic AMP; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Indoles; Indomethacin; Male; Neurons, Afferent; Peroxidase; Psychomotor Performance; Pyrroles; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Spinal Cord; Spinal Cord Diseases; TRPV Cation Channels; Tumor Necrosis Factor-alpha

To examine whether dalteparin, a low molecular weight heparin, prevents hepatic damage by inhibiting leukocyte activation, we analyzed its effect on ischemia/reperfusion (I/R) injury of rat liver in which activated leukocytes play a critical role.. Prospective, randomized, controlled study.. Research laboratory at a university medical center.. Male Wistar rats weighing 220-280 g.. Hepatic damage was evaluated by changes in serum transaminase concentrations after I/R. Coagulation abnormalities were evaluated by changes in serum concentrations of fragment E of fibrin and fibrinogen degradation products after I/R. Hepatic tissue blood flow was measured by laser-Doppler flow meter. Hepatic edema was evaluated by determination of the change in the wet/dry tissue weight ratio. Rats were intravenously injected with dalteparin or unfractionated heparin (300 units/kg) and subcutaneously injected with DX9056a, a selective inhibitor of activated factor X (3 mg/kg). To determine whether dalteparin inhibits leukocyte activation, we examined the effect of dalteparin on hepatic concentrations of interleukin-12, tumor necrosis factor-alpha, and hepatic myeloperoxidase activity after I/R in vivo. In addition, we examined increases in tumor necrosis factor-alpha production in rat monocytes and in intracellular calcium concentrations in neutrophils in vitro. We also examined the effect of dalteparin on endothelial production of prostacyclin using isolated rat hepatic sinusoidal cells in vitro.. Intravenous administration of dalteparin inhibited increases in serum levels of both transaminases and serum concentrations of fragment E of fibrin and fibrinogen degradation products in animals subjected to hepatic I/R. Hepatic tissue blood flow after reperfusion was increased by dalteparin. Dalteparin inhibited hepatic edema, increases in hepatic tissue levels of interleukin-12 and tumor necrosis factor-alpha, and accumulation of neutrophils in animals subjected to hepatic I/R. Neither DX9065a nor unfractionated heparin showed any therapeutic effects, despite potent inhibition of increases in serum levels of fragment E of fibrin and fibrinogen degradation products. Neither monocytic tumor necrosis factor-alpha production nor neutrophil activation was inhibited by dalteparin in vitro. Dalteparin enhanced the hepatic I/R-induced increases in hepatic tissue levels of 6-keto-prostaglandin (PG) F1alpha, a stable metabolite of prostacyclin, which is capable of inhibiting monocytic tumor necrosis factor-alpha production. Pretreatment with indomethacin completely reversed both of the therapeutic effects of dalteparin, whereas pretreatment with NS-398, a selective inhibitor of cyclooxygenase-2, did not. Dalteparin did not directly increase the endothelial production of prostacyclin in vitro.. Dalteparin might reduce I/R-induced liver injury in rats by attenuating inflammatory responses. These therapeutic effects might be independent of its anticoagulant activity but dependent on its capacity to enhance endothelial production of prostacyclin via cyclooxygenase-1 activation. Furthermore, the mechanism or mechanisms by which dalteparin promotes the endothelial production of prostacyclin in vivo might involve unknown factors other than endothelial cells.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anticoagulants; Calcium; Cyclooxygenase 2 Inhibitors; Dalteparin; Edema; Endothelium; Epoprostenol; Fibrin Fibrinogen Degradation Products; Heparin; In Vitro Techniques; Indomethacin; Inflammation; Interleukin-12; Leukocytes; Liver; Liver Diseases; Male; Monocytes; Naphthalenes; Nitrobenzenes; Peroxidase; Propionates; Prospective Studies; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury; Sulfonamides; Transaminases; Tumor Necrosis Factor-alpha

We previously reported that antithrombin (AT) reduced ischemia/reperfusion (I/R)-induced liver injury in rats by increasing endothelial production of prostacyclin (PGI2). However, the mechanism(s) underlying this phenomenon remains to be fully elucidated. We also demonstrated that activation of capsaicin-sensitive sensory neurons increased endothelial production of PGI2 by releasing calcitonin gene-related peptide (CGRP) in rats subjected to hepatic I/R. In the present study, we investigated whether AT increases endothelial production of PGI2 through activation of the sensory neurons in rats subjected to hepatic I/R. AT significantly enhanced the I/R-induced increases in hepatic tissue levels of CGRP in rats. Increases in hepatic tissue levels of 6-keto-PGF1alpha, a stable metabolite of PGI2, the increase in hepatic-tissue blood flow, and attenuation of both hepatic local inflammatory responses and liver injury in rats administered AT were completely reversed by administration of capsazepine, an inhibitor of sensory neuron activation and CGRP(8-37), a CGRP antagonist. AT did not show any protective effect on liver injury in animals undergoing functional denervation by administration of a large amount of capsaicin. AT significantly increased CGRP release from cultured dorsal root ganglion neurons isolated from rats in the presence of capsaicin. Taken together, these observations strongly suggested that AT might increase hepatic tissue levels of PGI2 via enhancement of hepatic I/R-induced activation of capsaicin-sensitive sensory neurons, thereby reducing liver injury in rats. In this process, CGRP-induced activation of both endothelial nitric oxide synthase and cyclooxygenase-1 might be critically involved.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antithrombin III; Calcitonin Gene-Related Peptide; Capsaicin; Cells, Cultured; Disease Models, Animal; Epoprostenol; Humans; Liver Diseases; Male; Neurons, Afferent; Rats; Rats, Wistar; Reperfusion Injury

Bradykinin mediates acute inflammation by increasing microvascular permeability, vasodilation, leukocyte migration and accumulation, and the production of arachidonic acid via phospholipase A2 activation. Arachidonic acid metabolites, or eicosanoids, are potent modulators of biological functions, particularly inflammation. Bradykinin exerts its inflammatory effects via the bradykinin B2 receptor. The aim of this study was to evaluate the effect of a bradykinin B2 receptor antagonist, FR173657 (FR), on intestinal ischemia-reperfusion (I/R) injury. Twenty-eight mongrel dogs were divided into four groups (n = 7 per group). Group I underwent I/R alone, Group II underwent I/R and received FR treatment, Group III was sham operated, and Group IV was sham operated and received FR treatment. The FR treatment consisted of FR continuously from 30 min prior to ischemia to 2 hr after reperfusion. In the I/R procedure, the superior mesenteric artery (SMA) and vein were clamped for 2 hr and then released to permit reperfusion for 12 hr. The intramucosal pH (pHi), SMA blood flow, and mucosal tissue blood flow were measured during the reperfusion period. The serum thromboxane B2 and 6-keto-prostaglandin F1alpha levels were determined, and tissue samples were examined histologically. Results showed that tissue blood flow, pHi, and SMA blood flow after reperfusion were maintained in Group II in comparison with Group I. Histopathological examination showed less severe mucosal damage after reperfusion in Group II than in Group I. The serum thromboxane B2 and 6-keto-prostagland in F1alpha levels were significantly lower in Group II than in Group I (P < 0.05). We conclude that FR treatment appears to have clear protective effects on small bowel I/R injury by inhibiting the release of eicosanoids.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bradykinin B2 Receptor Antagonists; Dogs; Female; Hemodynamics; Hydrogen-Ion Concentration; Intestinal Mucosa; Intestine, Small; Male; Mesenteric Artery, Superior; Quinolines; Regional Blood Flow; Reperfusion Injury; Thromboxane B2

Anti-inflammatory action of Antithrombin III (AT III) is still not well understood in ischemia/reperfusion (I/R) injury. In the present study, we aimed to investigate the anti-inflammatory action of AT III on remote lung and local skeletal muscle tissue injury in a rat model of bilateral lower limb I/R model.. Bilateral lower limb ischemia and reperfusion were produced by means of tourniquets occlusions and releases, respectively. Three groups of rats were used in this controlled study: sham group (sham, n=3) underwent 5 h of anesthesia only; control group (I/R, n=7) underwent 3 h of bilateral lower limb ischemia followed by 2 h of reperfusion; and AT III pretreated group (I/R-AT III, n=6) underwent the same procedure as the control group, but also received i.v. 250 U kg-1 AT III 30 min before ischemia induction under midazolam and fentanyl anesthesia.. Lung and muscle tissue accumulation of polymorphonuclear leukocytes (PMN) were assessed by measuring tissue myeloperoxidase (MPO) activity. Histopathological changes in tissues were assessed by PMN counts in the lung, and muscle tissues and by histological lung injury score. Plasma 6-keto prostaglandin F(1alpha) and tumor necrosis factor alpha levels were measured by an enzyme immunoassay technique. Myeloperoxidase activity could not be detected in the muscle tissues of all groups. The lung and muscle tissue PMN counts in the I/R group were significantly higher compared with the I/R-AT III group (P<0.05).. Data from the present study provides some evidence that AT III pretreatment attenuates remote lung and local skeletal muscle tissue injury caused by lower limb I/R.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anticoagulants; Antithrombin III; Disease Models, Animal; Ischemia; Ischemic Preconditioning; Lower Extremity; Lung; Muscle, Skeletal; Neutrophil Infiltration; Neutrophils; Peroxidase; Pilot Projects; Rats; Rats, Wistar; Reperfusion; Reperfusion Injury; Tumor Necrosis Factor-alpha

Antithrombin (AT) reveals its antiinflammatory activity by promoting endothelial release of prostacyclin (PGI(2)) in vivo. Since neuroinflammation is critically involved in the development of ischemia/reperfusion (I/R)-induced spinal cord injury (SCI), it is possible that AT reduces the I/R-induced SCI by attenuating the inflammatory responses. We examined this possibility using rat model of I/R-induced SCI in the present study. AT significantly reduced the mortality and motor disturbances by inhibiting reduction of the number of motor neurons in animals subjected to SCI. Microinfarctions of the spinal cord seen after reperfusion were markedly reduced by AT. AT significantly enhanced the I/R-induced increases in spinal cord tissue levels of 6-keto-PGFIalpha, a stable metabolite of PGI2. AT significantly inhibited the I/R-induced increases in spinal cord tissue levels of TNF-alpha, rat interleukin-8 and myeloperoxidase. In contrast,Trp(49) -modified AT did not show any protective effects. Pretreatment with indomethacin significantly reversed the protective effects of AT. An inactive derivative of factor Xa, which selectively inhibits thrombin generation, has been shown to fail to reduce SCI. Taken together, these observations strongly suggested that AT might reduce I/R-induced SCI mainly by the antiinflammatory effect through promotion of endothelial production of PGI(2). These findings also suggested that AT might be a potential neuroprotective agent.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antithrombins; Coloring Agents; Disease Models, Animal; Epoprostenol; Factor Xa; Humans; Inflammation; Interleukin-8; Ischemia; Male; Peroxidase; Rats; Rats, Wistar; Reperfusion Injury; Spinal Cord; Spinal Cord Injuries; Tetrazolium Salts; Time Factors; Tryptophan; Tumor Necrosis Factor-alpha

We previously reported that nitric oxide (NO) derived from endothelial NO synthase (NOS) increased endothelial prostacyclin (PGI(2)) production in rats subjected to hepatic ischemia-reperfusion (I/R). The present study was undertaken to determine whether neutrophil elastase (NE) decreases endothelial production of PGI(2), thereby contributing to the development of I/R-induced liver injury by decreasing hepatic tissue blood flow in rats. Hepatic tissue levels of 6-keto-PGF(1alpha), a stable metabolite of PGI(2), were transiently increased and peaked at 1 h after reperfusion, followed by a gradual decrease until 3 h after reperfusion. Sivelestat sodium hydrochloride and L-658,758, two NE inhibitors, reduced I/R-induced liver injury. These substances inhibited the decreases in hepatic tissue levels of 6-keto-PGF(1alpha) at 2 and 3 h after reperfusion but did not affect the levels at 1 h after reperfusion. These NE inhibitors significantly increased hepatic tissue blood flow from 1 to 3 h after reperfusion. Both hepatic I/R-induced increases in the accumulation of neutrophils and the microvascular permeability were inhibited by these two NE inhibitors. Protective effects induced by the two NE inhibitors were completely reversed by pretreatment with nitro-l-arginine methyl ester, an inhibitor of NOS, or indomethacin. Administration of iloprost, a stable derivative of PGI(2), produced effects similar to those induced by NE inhibitors. These observations strongly suggest that NE might play a critical role in the development of I/R-induced liver injury by decreasing endothelial production of NO and PGI(2), leading to a decrease in hepatic tissue blood flow resulting from inhibition of vasodilation and induction of activated neutrophil-induced microvascular injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Capillary Permeability; Cephalosporins; Chemokines, CXC; Cyclooxygenase Inhibitors; Endothelium; Enzyme Inhibitors; Epoprostenol; Glycine; Iloprost; Indomethacin; Intercellular Signaling Peptides and Proteins; Leukocyte Elastase; Liver; Liver Circulation; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Peroxidase; Rats; Rats, Wistar; Reperfusion Injury; Sulfonamides; Transaminases; Vasodilator Agents

This study was conducted to determine which isoform of cyclooxygenase (COX) is more significantly involved in the anti-thrombin (AT)-induced increase in prostaglandin production in the liver of rats, subjected to hepatic ischemia/reperfusion (I/R). Hepatic tissue levels of 6-keto-PGF(1alpha), a stable metabolite of prostacyclin (PGI(2)), and PGE(2) were transiently increased 1 hour after reperfusion. Thereafter, hepatic PGE2 levels were gradually increased until 6 hours after reperfusion, while hepatic 6-keto-PGF(1alpha) levels were decreased to the pre-ischemia levels at 6 hours after reperfusion. AT significantly enhanced increases in hepatic tissue levels of 6-keto-PGF(1alpha) and PGE(2) seen 1 hour after reperfusion, while it inhibited increases in hepatic PGE(2) levels seen 6 h after reperfusion. Neither dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, nor Trp(49)-modified AT which lacks affinity for heparin, showed any effects on these changes. Pretreatment with indomethacin (IM), a non-selective inhibitor of COX, inhibited AT-induced increases in hepatic tissue levels of 6-keto-PGF(1alpha) and PGE(2) seen 1 hour after reperfusion, whereas pretreatment with NS-398, a selective inhibitor of COX-2, did not. The increase in hepatic tissue blood flow and inhibition of hepatic inflammatory responses seen in animals given AT were reversed by pretreatment with IM, but were not affected by pretreatment with NS-398. Administration of ilo-prost, a stable analog of PGI(2), and PGE(2) produced effects similar to those induced by AT. Increases in hepatic tissue levels of PGE(2) 6 hours after reperfusion were inhibited by pretreatment with NS-398. Although AT did not affect COX-1 mRNA levels 1 hour after reperfusion, it inhibited the I/R-induced increases in hepatic tissue levels of both PGE(2) and COX-2 mRNA 6 hours after reperfusion. These observations strongly suggested that AT might reduce the I/R-induced liver injury by increasing the production of PGI2 and PGE2 through activation of COX-1. Furthermore, since TNF-alpha is capable of inducing COX-2, inhibition of TNF-alpha production by AT might inhibit COX-2-mediated PGE(2) production. These effects induced by AT might contribute to its anti-inflammatory activity.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antithrombin III; Cyclooxygenase 1; Enzyme Activation; Isoenzymes; Kinetics; Liver; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Prostaglandins E; Rats; Rats, Wistar; Reperfusion Injury; RNA, Messenger

Antithrombin (AT) supplementation in patients with severe sepsis has been shown to improve organ failures in which activated leukocytes are critically involved. However, the precise mechanism(s) for the therapeutic effects of AT is not well understood. We examined in rats whether AT reduces ischemia/reperfusion (I/R)-induced renal injury by inhibiting leukocyte activation. AT markedly reduced the I/R-induced renal dysfunction and histologic changes, whereas neither dansyl glutamylglycylarginyl chloromethyl ketone-treated factor Xa (DEGR-F.Xa), a selective inhibitor of thrombin generation, nor Trp49-modified AT, which lacks affinity for heparin, had any effect. Renal tissue levels of 6-keto-PGF(1 alpha), a stable metabolite of prostacyclin (PGI(2)), increased after renal I/R. AT enhanced the I/R-induced increases in renal tissue levels of 6-keto-PGF(1 alpha), whereas neither DEGR-F.Xa nor Trp49-modified AT had any effect. AT significantly inhibited I/R-induced decrease in renal tissue blood flow and the increase in the vascular permeability. Ischemia/reperfusion-induced increases in renal tissue levels of tumor necrosis factor-alpha, cytokine-induced neutrophil chemoattractant, and myeloperoxidase were significantly inhibited in animals given AT. Pretreatment of animals with indomethacin reversed the effects induced by AT. Iloprost, an analog of PGI(2), produced effects similar to those induced by AT. These observations strongly suggest that AT reduces the I/R-induced renal injury by inhibiting leukocyte activation. The therapeutic effects of AT might be mainly mediated by PGI(2) released from endothelial cells through interaction of AT with cell surface glycosaminoglycans.

Topics: 6-Ketoprostaglandin F1 alpha; Amino Acid Chloromethyl Ketones; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antithrombin III; Capillary Permeability; Drug Evaluation, Preclinical; Endothelium, Vascular; Epoprostenol; Factor Xa; Iloprost; Indomethacin; Ischemia; Kidney; Lymphocyte Activation; Male; Peroxidase; Rats; Rats, Wistar; Reperfusion Injury; Specific Pathogen-Free Organisms; Tumor Necrosis Factor-alpha

Capsaicin-sensitive sensory neurons are nociceptive neurons that release calcitonin gene-related peptide (CGRP) on activation by various noxious stimuli. CGRP has been shown to increase the endothelial production of prostacyclin, which reduces ischemia/reperfusion (I/R)-induced liver injury. Therefore, if the sensory neurons can be activated by the pathologic process of hepatic I/R, they might help ameliorate I/R-induced liver injury by promoting the endothelial production of prostacyclin, also known as prostaglandin I(2). In this study, we examined these possibilities using a rat model of I/R-induced liver injury. Male Wistar rats were subjected to 60-minute hepatic ischemia and subsequent reperfusion. Hepatic levels of 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)), a stable metabolite of prostacyclin, were significantly increased after hepatic I/R, peaking 1 hour after reperfusion. Administration of capsaicin and CGRP significantly enhanced I/R-induced increases in hepatic levels of 6-keto-PGF(1alpha), increased hepatic-tissue blood flow after reperfusion, and inhibited the I/R-induced increase in tissue levels of both tumor necrosis factor-alpha (TNF-alpha) and myeloperoxidase. Capsazepine, a vanilloid receptor antagonist; CGRP(8-37), a CGRP-receptor antagonist; l-nitro-arginine-methyl-ester (L-NAME), a nonselective inhibitor of nitric oxide (NO) synthase (NOS); and indomethacin, a nonselective inhibitor of cyclooxygenase, inhibited the I/R-induced increases in hepatic tissue levels of 6-keto-PGF(1alpha) and decreased hepatic-tissue blood flow after reperfusion. These compounds significantly enhanced the I/R-induced increases in hepatic tissue levels of both TNF-alpha and myeloperoxidase. Although I/R-induced liver injury was significantly reduced by capsaicin and CGRP, it was exacerbated by capsazepine, CGRP(8-37), L-NAME, and indomethacin. Administration of aminoguanidine, a selective inhibitor of the inducible form of NOS, and NS-398, a selective inhibitor of cyclooxygenase-2, demonstrated no effects on the liver injury or the hepatic levels of 6-keto-PGF(1alpha). These findings strongly suggest that the activation of the sensory neurons helps ameliorate I/R-induced liver injury both by increasing hepatic-tissue blood flow and by limiting inflammatory response through the enhancement of endothelial production of prostacyclin. In the sensory neuron-mediated enhancement of endothelial production of prostacyclin, CGRP-induced activation of both e

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Calcitonin Gene-Related Peptide; Capsaicin; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Epoprostenol; Guanidines; Indomethacin; Isoenzymes; Liver; Liver Circulation; Male; Membrane Proteins; Miotics; Neurons, Afferent; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitrobenzenes; Peptide Fragments; Peroxidase; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Reperfusion Injury; Specific Pathogen-Free Organisms; Sulfonamides; Transaminases; Tumor Necrosis Factor-alpha

This study investigated the effects of a selective COX-2 inhibitor, FK3311, on warm ischemia-reperfusion (I/R) injury in the canine lung.. Sixteen adult mongrel dogs were used in this study. In the FK group (n = 8), FK (1 mg/kg) was administered intravenously 15 min before ischemia and 15 min before reperfusion. In the control group (n = 8), a vehicle was injected in the same manner. Warm ischemia was induced for 3 h by clamping the left pulmonary artery, veins, and bronchus. Five-minute clamping tests of the right pulmonary artery were performed before ischemia and 30 min after reperfusion. During the test, left pulmonary vascular resistance (L-PVR), cardiac output (CO), and arterial oxygen pressure (PaO(2)) were measured. The lung specimens were simultaneously harvested for wet-to-dry weight ratio (WDR) measurements, histopathological studies, and polymorphonuclear neutrophil (PMN) counts. Serum thromboxane (Tx) B(2) and 6-keto-prostaglandin (PG) F(1alpha) (stable metabolites of TxA(2) and PGI(2), respectively) were also measured 30 min after reperfusion.. L-PVR, CO, PaO(2), and WDR were significantly (P < 0.05) better in the FK group than in the control group. Histological tissue edema was mild, and PMN infiltration was significantly (P < 0.05) reduced in the FK group compared to the control group. The serum TxB(2) levels were significantly (P < 0.05) lower in the FK group than in the control group, while 6-keto-PGF(1alpha) levels were not significantly (P < 0.05) reduced. Two-day survival rate was significantly (P < 0.05) better in the FK group than in the control group.. FK has protective effects on pulmonary I/R injury stemming from marked inhibition of TxA(2).

Topics: 6-Ketoprostaglandin F1 alpha; Anilides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiac Output; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dogs; Epoprostenol; Hemodynamics; Ischemia; Isoenzymes; Lung; Neutrophils; Oxygen; Partial Pressure; Prostaglandin-Endoperoxide Synthases; Pulmonary Artery; Pulmonary Circulation; Pulmonary Veins; Reperfusion Injury; Thromboxane B2; Time Factors; Vascular Resistance

The rat tail ischaemia--reperfusion model of acute hyperalgesia described by Gelgor et al. (Pain 24 (1986) 251) has been investigated pharmacologically and electrophysiologically. Despite the advantages of this reusable animal model, biochemical changes associated with the behavioural response have not been determined. After injury+/-subcutaneous diclofenac pretreatment, we investigated the behavioural response (changes to thermally-induced tail flick latency) and measured diclofenac, prostaglandin E(2), 6-keto-prostaglandin F(1 alpha) and thromboxane B(2) concentrations in the tail, spinal cord and brain. Subcutaneous injection of 40 mg kg(-1) diclofenac sodium abolished the hyperalgesic response, suppressed the increased eicosanoid production in the tail, inhibited eicosanoid synthesis in the brain, but gave equivocal effects on eicosanoid concentrations in the spinal cord. Injection of 10 and 20 mg kg(-1) diclofenac reduced the duration of hyperalgesia but did not abolish the behavioural response. Diclofenac concentrations in all three tissues were similar, being approximately 5--10% of the corresponding plasma concentrations. We propose that both central and peripheral mechanisms are associated with the hyperalgesia and that the findings lend indirect support to a central action for non-steroidal anti-inflammatory drugs.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Brain Chemistry; Diclofenac; Dinoprostone; Dose-Response Relationship, Drug; Eicosanoids; Hyperalgesia; Injections, Subcutaneous; Male; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Reperfusion Injury; Tail; Thromboxane B2

Liver grafts from non-heart-beating donors inevitably suffer from warm ischemic injury. In these grafts, large quantities of inflammatory cytokines and arachidonic acid metabolites are induced, further aggravating injury. Cyclooxygenase (COX) is an intracellular enzyme that converts arachidonic acid into prostaglandin (PG)G2 and PGH2. COX has two isoforms: constitutive COX-1 and inducible COX-2. The aim of this study was to evaluate the effects of COX-2 inhibition by FK3311 (FK) on warm ischemic injury in a canine total hepatic vascular exclusion (THVE) model.. Sixteen mongrel adult dogs were studied. The portal triad of the hilum and the inferior vena cava above and below the liver was clamped for 1 hour. Splanchnic decompression was achieved by active splenofemorojugular bypass. The animals were divided into two groups. FK (1 mg/kg) was administered in the FK group (n = 8), and saline was administered in the control group (n = 8). Hepatic venous blood was collected to measure serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase (LDH), and hyaluronic acid levels. Serum thromboxane (Tx)B2 and 6-keto-PGF1alpha levels were also measured. Hepatic tissue blood flow was estimated simultaneously. Liver specimens were harvested for histologic study and polymorphonuclear neutrophils were counted.. Alanine aminotransferase, aspartate aminotransferase, and hyaluronic acid 2 and 6 hours after reperfusion and LDH 30 minutes and 2 and 6 hours after reperfusion were significantly (p < 0.05) lower in the FK group than in the control group. Hepatic tissue blood flow remained significantly (p < 0.05) higher in the FK group than in the control group 1, 2, and 6 hours after reperfusion. Histologic tissue damage was mild and polymorphonuclear neutrophil infiltration was significantly lower (p < 0.05) in the FK group than in the control group 1 and 6 hours after reperfusion. Thirty minutes after reperfusion, TxB2 was significantly reduced (p < 0.05) in the FK group, and 6-keto-PGF1alpha was not significantly lower.. FK protected against hepatic warm ischemia-reperfusion injury by marked inhibition of TxA2.

Topics: 6-Ketoprostaglandin F1 alpha; Alanine Transaminase; Analysis of Variance; Anilides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2; Disease Models, Animal; Dogs; Enzyme Inhibitors; Hyaluronic Acid; Isoenzymes; L-Lactate Dehydrogenase; Leukocyte Count; Liver; Liver Circulation; Neutrophils; Prostaglandin-Endoperoxide Synthases; Random Allocation; Reperfusion Injury; Thromboxane B2

Pringle's procedure is commonly used during liver surgery, and it sometimes causes liver failure. Metabolites of arachidonic acid, which are converted by cyclooxygenase (Cox), are involved in ischemia-reperfusion injury. This study evaluated the effects of FK 3311, which selectively inhibits Cox-2, on ischemia-reperfusion injury during liver resection in dogs.. The animals were divided into four groups and subjected to 60 min of warm ischemia by partial inflow occlusion. The FK-treated groups (FK0.2: 0.2 mg/kg, FK1: 1 mg/kg, FK3: 3mg/kg) received FK3311, and the control group received vehicle. Following reperfusion, the nonischemic lobes were resected and remnant liver function was evaluated.. Tissue blood flow and serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and lactate dehydrogenase were significantly better in the FK1 and FK3 groups, especially FK1, than in the control group. Thromboxane B(2) was significantly lower in the FK1 and FK3 groups than in the control group. The level of 6-keto-prostaglandin F(1alpha) was significantly lower in the FK3 group and relatively unchanged in the FK1 group. Histological damage was milder in the FK1 group. There were significantly fewer polymorphonuclear neutrophils in the FK1 group than in the control group.. FK3311 ameliorates the ischemia-reperfusion injury caused by Pringle's procedure during extensive liver resection. This agent may be clinically useful in extended liver surgery involving vascular isolation.

Topics: 6-Ketoprostaglandin F1 alpha; Alanine Transaminase; Anilides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspartate Aminotransferases; Cyclooxygenase 2; Dogs; Female; Injections, Intravenous; Isoenzymes; L-Lactate Dehydrogenase; Liver; Liver Circulation; Liver Failure; Male; Postoperative Complications; Prostaglandin-Endoperoxide Synthases; Reperfusion Injury; Thromboxane B2

Ischemia-reperfusion injury with the resulting inflammatory response is a devastating complication of lung transplantation; much of the tissue damage could be diminished by control of the inflammatory response. Recent studies have show that antithrombin III (AT III) has an anti-inflammatory effect in addition to its established role in the regulation of blood coagulation. Thus, we hypothesized that the administration of AT III might help to prevent ischemia-reperfusion injury after lung transplantation.. The study was performed in a dog model of orthotopic lung transplantation. Dogs were randomly assigned to receive either vehicle (controls) or AT III. We observed that in control dogs, during the 180-minute period after lung transplantation, the arterial O(2) partial pressure decreased and both the alveolar-arterial O(2) difference and the pulmonary vascular resistance increased. By contrast, these parameters remained unchanged in the group of dogs receiving AT III. Dogs with transplants receiving AT III did not show an increase in cell adhesion molecules, and histological examination revealed almost an absence of inflammatory response. The administration of AT III produced a marked increase in serum prostacyclin (PGI(2)) levels, whereas in control dogs, the PGI(2) levels did not change. The beneficial effect of AT III was not observed when dogs received indomethacin to prevent the stimulation of PGI(2) release by AT III.. Our results demonstrate that AT III prevents ischemia-reperfusion injury in a dog model of lung transplantation and that this effect is conditioned by an increase in PGI(2) production.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antithrombin III; Cell Adhesion Molecules; Dogs; Epoprostenol; Hemodynamics; Indomethacin; Leukocytes, Mononuclear; Lung; Lung Transplantation; Pulmonary Alveoli; Pulmonary Gas Exchange; Reperfusion Injury; Time Factors

We investigated whether antithrombin (AT) can reduce ischemia/reperfusion (I/R)-induced injury of rat liver by promoting prostacyclin release from endothelial cells. Although intravenous administration of AT (250 U/kg) markedly reduced hepatic injury, neither dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, nor Trp49-modified AT, which lacks affinity for heparin, had any effect. Hepatic levels of 6-keto-PGF1, a stable prostacyclin (PGI2) metabolite, were increased significantly after I/R of the rat liver. AT significantly increased the hepatic level of 6-keto-PGF1, whereas neither DEGR-Xa nor Trp49-modified AT increased it. Hepatic tissue blood flow was markedly reduced after I/R. Although AT significantly increased the hepatic tissue blood flow after I/R, neither DEGR-Xa nor Trp49-modified AT increased the blood flow. Hepatic levels of cytokine-induced neutrophil chemoattractant (CINC) and myeloperoxidase (MPO) were significantly increased after hepatic I/R. The levels of these two indicators were reduced by AT but were unaffected by either DEGR-Xa or Trp49-modified AT. Pretreatment of animals with indomethacin (IM) completely inhibited the protective effects of AT on the I/R-induced hepatic damage and the leukocyte activation as well as the AT-induced increase in hepatic 6-keto-PGF1 levels after I/R. Iloprost, a stable analog of PGI2, exhibited effects similar to those of AT and also significantly inhibited the exacerbation of liver injury, the decrease in hepatic tissue blood flow, and the increases in hepatic CINC and MPO levels seen in rats subjected to I/R but pretreated with IM. These findings suggest that AT may prevent I/R-induced hepatic injury by increasing the hepatic levels of PGI2 through the interaction of AT with cell-surface glycosaminoglycans, thus increasing hepatic tissue blood flow and inhibiting leukocyte activation in animals subjected to I/R.

Topics: 6-Ketoprostaglandin F1 alpha; Amino Acid Chloromethyl Ketones; Animals; Antithrombin III; Disease Models, Animal; Epoprostenol; Factor Xa; Iloprost; Indomethacin; Injections, Intravenous; Liver; Male; Rats; Rats, Wistar; Reperfusion Injury; Sulfonium Compounds; Tryptophan

Platelet-related events being associated with the increment of infarct size at reperfusion in the presence of a residual stenosis, we tested in dogs whether intravenous aspirin (ASA) could limit infarct size. The left anterior descending coronary artery was occluded for 90 min and reperfused for 6 h in the presence of a residual critical stenosis. Controls received saline, and treated groups were given 2, 6, or 12 mg/kg ASA, i.v., 5 min before reperfusion. Infarct size did not differ significantly between groups (control, 43.80+/-6.28%; ASA, 2 mg/kg: 41.07+/-7.78%; ASA, 6 mg/kg: 37.55+/-3.44%; ASA, 12 mg/kg: 29.40+/-5.41%), as well as transmural collateral blood flow and [111In]-platelet accumulation in the infarcted myocardium (2.5-3.6 x 10(5) platelets/g). However, myocardial neutrophil accumulation was significantly reduced (p < 0.05) in groups given 6 (15.0+/-2.6 x 10(6)/g tissue) and 12 mg/kg (18.4 +/-3.8) ASA, but not in the 2-mg/kg group (21.0+/-5.2), as compared with control group (32.0+/-7.2). Ex vivo platelet aggregation to collagen was abolished during reperfusion in all treated groups (p < 0.05). Transcardiac arteriovenous differences in 6-keto-PGF1alpha were reduced significantly 1 h after reperfusion in groups given 6 or 12 mg/kg ASA (94.7+/-13.1 and 71.7+/-19.2 pg/ml, respectively) but not in the 2-mg/kg group (178.3+/-78.2 pg/ml), as compared with control (405.4+/-171.6 pg/ml). ASA-insensitive platelet activation at the site of stenosis or inhibition by ASA of prostacyclin production by jeopardized myocardium may explain the observed lack of benefit of ASA.

Topics: 6-Ketoprostaglandin F1 alpha; Anesthesia; Animals; Aspirin; Blood Cell Count; Cell Movement; Coronary Disease; Dogs; Female; Infarction; Infusions, Intravenous; Male; Malondialdehyde; Neutrophils; Platelet Aggregation; Reperfusion Injury

The effect of ozagrel, a selective thromboxane A(2) (TXA(2)) synthetase inhibitor, on the obstruction after cerebral ischemia-reperfusion was studied in experimental animal models. The reduced spontaneously locomotor activity and the obstruction of motor coordination were improved by the administration of ozagrel in the conscious cerebral ischemia-reperfusion mouse model. Ozagrel suppressed the decrease in specific gravity of the brain tissue induced by the occlusion-reperfusion in the conscious cerebral ischemia-reperfusion SHR model, and recovered the postischemic decrease in cortical PO(2) after middle cerebral artery occlusion-reperfusion in cats. The level of TXB(2), a metabolite of TXA(2), in the brain increased after the cerebral ischemia-reperfusion, and ozagrel prevented this increase. Additionally, ozagrel also increased the level of 6-keto-PGF(1alpha), a metabolite of prostaglandin I(2) (PGI(2)), in the brain tissue after cerebral ischemia-reperfusion, and the administration of PGI(2) improved the reduced spontaneous locomotor activity in the conscious cerebral ischemia-reperfusion mouse model. Our data suggest that ozagrel suppressed the obstruction following cerebral ischemia-reperfusion by preserving the cerebral blood flow via preventing the increase in TXA(2) and causing an increase in the PGI(2) level.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Brain Chemistry; Cerebral Cortex; Enzyme Inhibitors; Epoprostenol; Imidazoles; Ischemic Attack, Transient; Male; Methacrylates; Mice; Motor Activity; Neuroprotective Agents; Oxygen Consumption; Psychomotor Performance; Rats; Rats, Inbred SHR; Reperfusion Injury; Specific Gravity; Thromboxane A2; Thromboxane-A Synthase

We investigated the effects of low-dose Beraprost sodium (BPS), a stable prostaglandin I2 (PGI2) analogue, on microvascular permeability and the plasma concentrations of thromboxane and adenosine 3',5'-cyclic monophosphate (cAMP) in blood-perfused rabbit lungs subjected to ischemia-reperfusion (I/R). After an ischemic insult for 2 h, saline as a vehicle, 3 pmol/L of BPS (BPS-1), 150 to 300 pmol/L of BPS (BPS-2), 900 pmol/L of BPS (BPS-3), or 60 micromol/L of indomethacin (IND) was administered into the reservoir, then the lungs were reperfused and reventilated for 1 h. Vascular permeability was assessed by determining the microvascular filtration coefficient (Kf, ml/min/mm Hg/100 g wet lung). I/R resulted in increases in vascular resistance, Kf, and thromboxane. BPS-2, BPS-3, and IND inhibited the increase in vascular resistance, and BPS-3 and IND attenuated the increases in Kf and thromboxane. BPS-3 increased, but IND decreased, the concentrations of cAMP in the perfusate. Perfusate thromboxane released after reperfusion was significantly correlated with Kf. We conclude that cyclooxygenase products play a critical role in I/R-induced lung vascular injury and that 900 pmol/L of BPS inhibits the production of thromboxane and enhances the permeability barrier via a cAMP-elevating effect. However, vasodilatory action of BPS may exacerbate the reperfused lung injury by increasing the flow through injured capillaries via inhibition of thromboxane-induced vasoconstriction.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Capillaries; Capillary Permeability; Cyclic AMP; Epoprostenol; Indomethacin; Lung; Lung Diseases; Male; Microcirculation; Rabbits; Reperfusion Injury; Respiration, Artificial; Thromboxane B2; Tumor Necrosis Factor-alpha; Vascular Resistance; Vasodilation; Vasodilator Agents

These serial clinical and experimental studies were designed to clarify the pathogenesis of postburn MODS. Both animal and clinical studies were performed. In animal experiments, 46 male cross-bred dogs were cannulated with Swan-Ganz catheters and 39 of them were inflicted with 50% TBSA third degree burns (7 were used as controls). The burned dogs were randomly divided into 4 groups: immediate infusion, delayed infusion, delayed fast infusion and delayed fast infusion combined with ginsenosides. All dogs were kept under constant barbiturate sedation during the whole study period. Hemodynamics, visceral MDA, mitochondrial respiratory control rate (RCR) and ADP/O ratio, ATP, succinic dehydrogenase (SDH), organ water content as well as light and electron microscopy of visceral tissues were determined. In the clinical study, 61 patients with extensive deep burns were chosen, of which 16 sustained MODS. Plasma TXB2/6-keto-PGF1alpha ratio, TNF, SOD, MDA, circulatory platelet aggregate ratio (CPAR), PGE2, interleukin-1, total organ water content and pathological observations of visceral tissues from patients who died of MODS were carried out. Results demonstrated that ischemic-reperfusion damage due to severe shock, sepsis and inhalation injury are three main causes of postburn death. All inflammatory mediators increased markedly in both animals and patients who sustained organ damage or MODS. SDH, RCR, ADP/O and ATP decreased significantly. These findings suggested that ischemic damage and systemic inflammatory response syndrome (SIRS) initiated by mediators or cytokines might be important in the pathogenesis of postburn MODS.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Adenosine Triphosphate; Adult; Animals; Body Water; Burns; Central Nervous System Agents; Dinoprostone; Dogs; Female; Fluid Therapy; Ginsenosides; Hemodynamics; Humans; Hypnotics and Sedatives; Interleukin-1; Male; Malondialdehyde; Mitochondria; Multiple Organ Failure; Oxygen Consumption; Panax; Plants, Medicinal; Platelet Aggregation; Random Allocation; Reperfusion Injury; Saponins; Sepsis; Shock; Succinate Dehydrogenase; Superoxide Dismutase; Syndrome; Systemic Inflammatory Response Syndrome; Thromboxane B2; Tumor Necrosis Factor-alpha

The role of nitric oxide, produced during reperfusion as a function of preservation time, in the development of the inflammatory process in pancreas transplantation has been explored. For this purpose, the effect of nitric oxide synthase inhibition, as well as 6-keto-prostaglandin F1alpha, leukotriene B4, and lipoperoxidation levels were evaluated in an experimental model of rat pancreas transplantation after different periods of cold preservation. The results show posttransplantation increases in 6-keto-prostaglandin F1alpha, leukotriene B4, and lipoperoxidation levels in pancreatic tissue and in plasma lipase. When ischemia was induced for 30 min, nitric oxide synthase inhibition prevented these increases, and L-arginine was able to reverse this effect. By contrast, nitric oxide synthase inhibition has no effect when ischemia was prolonged for 12 hr. In summary, this study suggests that, during reperfusion, nitric oxide modulates 6-keto-prostaglandin F1alpha synthesis, lipoperoxidation levels, and the development of pancreatic injury but only when the ischemic period is quite short.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arginine; Cold Temperature; Enzyme Inhibitors; Leukotriene B4; Lipase; Lipid Peroxidation; Male; Malondialdehyde; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Organ Preservation; Pancreas; Pancreas Transplantation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Time Factors

This study investigated metabolic and biochemical consequences of colonic ischemia/reperfusion (I/R) in the rat and evaluated whether antioxidants prevent I/R-induced functional damage in the rat colon. The surgical preparation involved a 10 cm segment of the colon and occlusion of the superior mesenteric artery (SMA) to induce I/R. Arterial blood from the aorta and venous blood from the superior mesenteric vein (SMV) was collected to measure blood gases, lactic acid (LA) and arachidonic acid (AA) metabolites. Tissue xanthine oxidase (XO) and thiobarbituric acid (TBA) derivatives were measured before and after reperfusion. In addition, vascular and mucosal permeability, and the effect of MDL 73404 (a water soluble vitamin E analog) and 5-aminosalicylic acid on LA, AA, XO and TBA was measured. After ischemia, the colon displayed a metabolic shift from aerobic to anaerobic course by increasing lactic acid production in the colon (183% increase in SMV lactate level compared 87% in the SMA; p < 0.03). After 10 minutes of reperfusion, circulating 6-keto-prostaglandin F1 alpha increased by 3.85 fold (p < 0.001) and thromboxane B2 increased by 2 to 3 fold. An Ischemia time longer than 60 minutes was required to cause changes in tissue XO levels. Tissue TBA levels showed a good dose response corresponding with I/R time. I/R (60 minutes) caused a three and 16 fold increase (p < 0.01) in vascular and mucosal permeability, respectively. MDL 73404 and 5-aminosalicylic acid significantly inhibited the vascular permeability and decreased LA, AA, XO and TBA. These observations provide the first direct experimental evidence for I/R-induced damage in the colon and some of its effects can be reversed by conventional and novel antioxidants.

Topics: 6-Ketoprostaglandin F1 alpha; Aerobiosis; Aminosalicylic Acids; Anaerobiosis; Animals; Antioxidants; Arachidonic Acid; Colon; Disease Models, Animal; Glutathione; Lactic Acid; Male; Mesalamine; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Thiobarbituric Acid Reactive Substances; Thromboxane B2; Vitamin E; Xanthine Oxidase

We investigated the effects of thromboxane (TX) A2 in rats with ischemia-reperfusion-induced intrauterine growth retardation. A saline solution or OKY-046, a selective TXA2 synthetase inhibitor, was injected into the caudal vein of pregnant rats on gestation day 17 before the induction of 60-min uteroplacental ischemia. The fetuses and placentas were delivered and examined on gestation day 21. Blood from the uterine vein of the occluded horn shortly after uteroplacental ischemia was collected, and plasma concentrations of TXB2 and 6-keto-prostaglandin (PG) F1 alpha were determined in the other rats on gestation day 17. Treatment with OKY-046 prevented the ischemia-induced reduction in the fetal body and placental weights. The ratio of 6-keto-PGF1 alpha to TXB2 was significantly increased in the OKY-046-treated group. We conclude that the action of TXA2 might play a salient role in our model.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Embryonic and Fetal Development; Enzyme Inhibitors; Female; Fetal Growth Retardation; Injections, Intravenous; Methacrylates; Pregnancy; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Thromboxane B2; Thromboxane-A Synthase

To study the effects of dl-3-n-butylphthalide (NBP) on the changes of thromboxane B2 (TXB2) and 6-keto-PGF1 alpha (6-keto-PGF1 alpha) contents in hippocampus, striatum, and cerebral cortex of rats subjected to focal cerebral ischemia followed by reperfusion.. Focal cerebral ischemia was induced by inserting a nylon suture into intracranial segment of internal carotid artery from external carotid artery and blockade of the origin of middle cerebral artery. For reperfusion, the suture was pulled out to restore the blood flow to the ischemic brain. Determination of TXB2 and 6-keto-PGF1 alpha was performed by RIA method.. Reperfusion following focal cerebral ischemia resulted in increases in TXB2 at 5 min and 6-keto-PGF1 alpha at 30 min and a decrease in the ratio of epoprostenol (PGI2)/thromboxane A2 (TXA2) (6-keto-PGF1 alpha/TXB2) at 5 min in hippocampus, striatum, and cerebral cortex. NBP 10 mg.kg-1 reduced the content of TXB2 without decreasing effect on 6-keto-PGF1 alpha. NBP 20 mg.kg-1 reduced both TXB2 and 6-keto-PGF1 alpha in lesser extent than aspirin (Asp, 20 mg.kg-1). NBP 20 or 10 mg.kg-1 elevated the ratio of PGI2/TXA2 after reperfusion, but Asp 20 mg.kg-1 did not increase the ratio except in striatum at 5 min after reperfusion.. NBP increases the ratio of PGI2/TXA2 which may have beneficial effects on the impaired microcirculation in postischemic brain tissues.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Benzofurans; Brain; Ischemic Attack, Transient; Neuroprotective Agents; Rats; Reperfusion Injury; Thromboxane B2

It has been suggested that thromboxane A2 (TXA) plays important roles in preservation/reperfusion organ injury. In this report, we investigated the prostanoid release from the liver and the effect of a selective TXA synthetase inhibitor (E)-3-[p-(1H-imidazol-yl-methyl)-phenyl]-2-propenoic acid, OKY046) during cold preservation and after reperfusion. Rat livers were preserved in lactated Ringer's solution at 4 degrees C for 2, 4, and 6 hr and perfused with oxygenated Krebs-Henseleit buffer using recirculating perfusion system, and prostanoids were measured during cold preservation and after reperfusion. OKY046 and a novel TXA receptor antagonist [(9,11), (11,12)-Dideoxa-9a, 11a-dimethyl-methano-11,12-methano-13,14-dihydro-13-aza-14-oxo-15-cyclo pentyl-16,17,18,19,20-pentanor-15-epi-TXA, ONO3708] were added into the preservation solution and perfusate. Along with the preservation time, both the production and release of TXA was observed to increase; however, almost all the produced TXA was stored in the liver tissue. Afterwards, the stored TXA was released into perfusate in 15 min after reperfusion. OKY046 significantly decreased both the production and release of TXA. In addition, OKY046 improved the histological damage and trypan blue uptake of liver cells. Our results demonstrate that TXA, stored in the liver during preservation, might therefore be a potential trigger of reperfusion injury, and as a result, OKY046 reduces reperfusion injury by decreasing the production of TXA during preservation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Cold Temperature; Endothelium; Enzyme Inhibitors; Liver; Methacrylates; Organ Preservation; Organ Size; Phospholipases A; Rats; Rats, Inbred Lew; Receptors, Thromboxane; Reperfusion Injury; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

The pathophysiology of ischemia-reperfusion renal injury is mediated, in part, by the generation of the vasoconstricting prostanoid thromboxane A2 (TXA2). This study was undertaken to evaluate the renoprotective effects, as well as the optimal timing and dosage, of a selective thromboxane synthetase inhibitor, OKY-046, in a unilateral nephrectomized, 60 min ischemia, 72 hr reperfusion, rodent model. Forty-one rats were subjected to right nephrectomy only (group A), or right nephrectomy with 60 min of left renal ischemia and treatment with inactive vehicle only (group B), or 2 mg/kg or 4 mg/kg of OKY-046 administered intravenously before (groups C and D) or after (groups E and F) pedicle clamping. Outcome variables included animal survival; change in kidney weight; 0, 24, and 72 hr plasma creatinine (CR); urea nitrogen (BUN); thromboxane B2 (TXB2) and 6-keto prostaglandin F(1alpha) (6 kPGF(2alpha)) levels; creatinine clearance (CRCL); and histologic evidence of renal injury. Animal survival and postperfusion kidney weight were not significantly different among the groups. However, renal functional parameters were significantly improved with the 2 mg/kg dose of OKY-046 administered after renal ischemia. (group B 72 hr Cr= 8.01 +/- 1.1 mg% vs. group E=3.99 +/- 1.5 mg%, and group B 72 hr BUN=241.3 +/- 32.8 mg% vs. group E=52.6 +/- 22.5 mg%). The CRCL was also improved in group E vs. group B, although these results did not reach statistical significance (group B=0.069 ml/min vs. group E=0.194 ml/ min). The 24 hr TXB2 levels were significantly increased in group B (0 hr=754.1 +/- 219.4 pg/ml vs. 24 hr=2055.9 +/- 550.0 pg/ml), and pre- or posttreatment with OKY-046 abrogated this increase (group C 0 hr=517.1 +/- 80.9 pg/ml vs. 24 hr=384.7 +/- 251.5 pg/ml, and group E 0 hr=781.6 +/- 390.4 pg/ml vs. 24 hr=183.0 +/- 81.4 pg/ml). The 24 hr 6 kPGF(1alpha) levels decreased in all groups, whereas 72 hr 6 kPGF(1alpha) levels increased above baseline in groups A, C, and E, but not in group B. These data demonstrate the beneficial effects of thromboxane A2 synthesis inhibition in the setting of ischemia-reperfusion injury and suggest that this renoprotection correlates with late vasodilatory prostanoid synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Enzyme Inhibitors; Hot Temperature; Ischemia; Kidney; Male; Methacrylates; Organ Preservation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Thromboxane B2; Thromboxane-A Synthase

Ischemia-reperfusion injury has been studied in various organs. The effects of leukocyte and platelet depletion on cholestasis and ischemia-reperfusion-induced liver damage were evaluated in the dog liver.. The left hepatic duct was ligated for 4 weeks to create a cholestatic lobe. An ischemic condition was produced for 60 min by stopping the peristaltic pump supplying blood to the liver. The metabolism of substances modulated in the liver during cholestasis and I-R was assessed in non-treated and in leukocyte- and platelet-depleted animals.. The extraction rate of insulin and indocyanine green decreased during cholestasis and ischemia-reperfusion. Cholestasis accelerated the release of thromboxane A2 but not prostaglandin I2 after ischemia-reperfusion. Ischemia-reperfusion accelerated the release of prostaglandin I2 and thromboxane A2 from the liver. Further, ischemia-reperfusion increased the ratio of thromboxane A2 to prostaglandin I2. Cholestasis promoted an increase in the level. Ischemia-reperfusion caused an increase in the lipid peroxide level, and no change in the alpha-tocopherol level. Ischemia-reperfusion caused an increase in the lipid peroxide level, a decrease in the alpha-tocopherol level, and no change in the glutathione level. Depletion of leukocytes and platelets reduced these changes during cholestasis and ischemia-reperfusion.. Depletion of leukocytes and platelets thus appears to protect liver function from cholestasis and ischemia-reperfusion injury by reducing peroxidation of lipids composing the cell membrane and the rate of thromboxane A2 prostaglandin I2, which predicts cellular damage, and by increasing the levels of alpha-tocopherol and glutathione, believed to be free radical scavengers.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cholestasis, Extrahepatic; Dogs; Epoprostenol; Glutathione; Ischemia; Leukocyte Count; Lipid Peroxidation; Liver; Liver Function Tests; Platelet Count; Regional Blood Flow; Reperfusion Injury; Thromboxane A2; Vitamin E

We investigated the effects of pretreatment with a potent platelet-activating factor (PAF) receptor antagonist (E5880) on the changes in hepatic and systemic metabolism induced by transient hepatic ischemia and reperfusion. Sixty-five rabbits were assigned to four groups that either did or did not undergo a period of hepatic ischemia and reperfusion with or without pretreatment. E5880 was administered intraportally 1 minute prior to inflow occlusion. Twenty minutes of warm ischemia was followed by 30 minutes of reperfusion. Blood gas analyses and measurements of levels of arterial pyruvate, lactate, and ketone bodies, arterial and portal ammonia and endotoxin, and intrahepatic adenine nucleotide, pyruvate, and lactate were performed. Results were analyzed by either ANOVA or chi-square analysis. Hepatic tissue ATP and energy charge levels were significantly increased and the AMP level was significantly decreased after 30 minutes of reperfusion in the pretreatment group compared to those without pretreatment. At the same time, parameters reflecting hepatic mitochondrial function, such as the arterial ketone body ratio and arterial ammonia level, improved, although they were not statistically significant. No difference was observed for parameters reflecting systemic changes, such as arterial blood gas values and pyruvate and lactate levels. PAF is thought to mediate metabolic changes after hepatic ischemia and reperfusion. PAF released in the liver may exert local effects, which appear to be attenuated by pretreatment with E5880. Systemic metabolic changes seen after hepatic ischemia and reperfusion may be mediated by factors other than PAF.

Topics: 6-Ketoprostaglandin F1 alpha; Adenine Nucleotides; Ammonia; Analysis of Variance; Animals; Blood Gas Analysis; Blood Glucose; Energy Metabolism; Hydrogen-Ion Concentration; Lactic Acid; Liver; Male; Piperidines; Platelet Activating Factor; Pyridinium Compounds; Pyruvic Acid; Rabbits; Reperfusion Injury; Thromboxane B2

The effect of antithrombin III (AT III) supplementation on energy status, microcirculation, cytoprotection, and prostacyclin (PGI2) production during and after a period of warm ischemia of the rat liver was investigated. AT III supplementation (250 units/kg) stimulate prostaglandin I2 (PGI2) production from 1 hour after administration, with maximal production observed at 3 hours. Ischemia was induced by occluding the hepatoduodenal ligament for 30 minutes, and experiments were continued for 60 minutes after reperfusion. The rats received AT III (250 units/kg IC) 30 minutes before induction of liver ischemia (AT III group). In the AT III group, recovery of the beta-ATP/inorganic phosphate ratio measured by 31P nuclear magnetic resonance showed significant improvement (p < 0.01), and the recovery of tissue blood flow markedly improved (p < 0.01) compared to the saline-treated group (control group). Leakages of aspartame aminotransferase, alanine aminotransferase, and lactate dehydrogenase were mitigated in the AT III group (p < 0. 05). Ultrastructural alterations of sinusoidal endothelial cells were markedly reduced in the AT III group. The PGI2 level at the end of reperfusion was significantly elevated (p < 0.01) in the AT III group compared to the control group. The results of this study indicated that pretreatment with AT III significantly improved the energy status and microcirculation, as well as histologic damage, after liver ischemia and reperfusion. One of the fundamental effects of AT III might be mediated through the production of prostacyclin.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Triphosphate; Alanine Transaminase; Animals; Antithrombin III; Aspartate Aminotransferases; Blood Flow Velocity; Epoprostenol; Injections, Intravenous; L-Lactate Dehydrogenase; Liver; Liver Circulation; Magnetic Resonance Spectroscopy; Male; Microscopy, Electron, Scanning; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Serine Proteinase Inhibitors

Myocardial stunning (MS) is a transient contractile dysfunction occurring subsequent to an episode of ischemia followed by reperfusion. NPC 15669 is a leumedin, which inhibits leukocyte adhesion to the endothelium by blocking Mac-1 upregulation. The effect of NPC 15669 supplementation on the hemostasis during MS is unknown. We linked the potential changes in the hemostasis with NPC 15669 therapy during mild MS. Twelve Yorkshire swine underwent coronary artery occlusion for 8 min followed by 90 min of reperfusion. NP 15669 (10 mg/kg loading dose followed by constant infusion a 6 mg kg-1 h-1) was administered to 6 of the animals; another swine received saline and served as the controls. Concentrations of antithrombin III (AT-III), protein C, total protein S, fibronectin, endothelin 1 (ET-1) and the stable metabolites of thromboxane (TxB2) and prostacyclin (6-keto-PGF1 alpha) were measured in the systemic circulation. NPC 15669 therapy was associated with diminished ET-1 (37.4%) and 6-keto-PGF1 alpha (47.1%) levels and increased fibronectin (77.6%) concentrations during MS. There were no changes in the plasma concentrations of TxB2, total protein S, protein C and AT-III in the NPC 15669 group when compared with controls. Mild MS in associated with substantial changes in the hemostatic profile. NPC 15669 administration in a swine model of MS affects certain hemostatic parameters. These data provide support for the involvement of cellular mechanisms in the pathogenesis of MS. The ability of leumedins to modulate hemostasis may have implications for their use in cardiovascular disease.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antithrombin III; Blood Proteins; Disease Models, Animal; Endothelin-1; Female; Fibronectins; Hemostasis; Leucine; Macrophage-1 Antigen; Myocardial Stunning; Protein C; Protein S; Reperfusion Injury; Swine; Thromboxane B2; Up-Regulation

The effect of acetylsalicylic acid (ASA) on high-energy phosphates (adenosine triphosphate: ATP, creatine phosphate: CrP, inorganic phosphate: Pi) and intracellular pH during myocardial ischemia and reperfusion was studied using phosphorus 31-nuclear magnetic resonance (31P-NMR) in the isolated rabbit hearts. Coronary flow, left ventricular systolic developed pressure (LV Dev.P) and left ventricular end-diastolic pressure (LVEDP) were also measured. Langendorff hearts perfused at 37 degrees C with the perfluorochemical emulsion Fluosol-43 were subjected to 15 min and 30 min of zero-flow ischemia and to 15 min of low-flow ischemia (coronary perfusion pressure = 20 mmHg) followed by 65 min of reperfusion (control, Group I). ASA (0.28 mmol/L) was infused either for the entire experimental period from beginning 45 min prior to ischemia (Group II) and infused immediately after reperfusion (Group III). During ischemia, Group II showed a significant suppression of the decrease in the ATP level and pH with both zero-flow and low-flow ischemia compared to those in the other groups, and moreover the increase in Pi and the decrease in CrP in low-flow ischemia were also suppressed. In Group III, the ATP level during reperfusion was significantly higher than that in Group I, but was not significantly different from that in 30 min zero-flow ischemia. In 30 min zero-flow ischemia, Pi, CrP and coronary flow after reperfusion in Group II tended to recover to preischemic values. There were no differences in LV Dev.P among the 3 groups. In conclusion, ASA has a protective effect on myocardial high-energy phosphates during ischemia and reperfusion in rabbit hearts.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Triphosphate; Animals; Aspirin; C-Reactive Protein; Coronary Vessels; Energy Metabolism; Heart; Hydrogen-Ion Concentration; Muscle Contraction; Muscle Fibers, Skeletal; Myocardial Ischemia; Perfusion; Phosphates; Platelet Aggregation Inhibitors; Rabbits; Reperfusion Injury; Ventricular Function, Left; Ventricular Pressure

The implication of different eicosanoids and oxygen free radicals in the development of pancreatic injury after an ischemia-reperfusion process has been evaluated. For this purpose we have compared the effect of allopurinol and indomethacin administration on the pancreatic levels of eicosanoids in a rat model of pancreatic ischemia-reperfusion. After 60 min of pancreatic ischemia and 2 h of reperfusion, significant increases in 6-keto-PGF1 alpha, PGE2, and LTB4 in pancreas tissue were detected. Allopurinol before the ischemic period reduced 6-keto-PGF1 alpha, PGE2, and LTB4 levels to the range of basal values, while prior indomethacin treatment significantly reduced 6-keto-PGF1 alpha and PGE2 levels, with LTB4 remaining unmodified. Increased postischemic plasma lipases were also significantly reduced by allopurinol to the range of sham-operated animals whereas indomethacin did not modify these levels. The data suggest a role for lipoxygenase metabolites in the development of pancreatic injury and the importance of the enzyme xanthine oxidase as an inductor of eicosanoid biosynthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Allopurinol; Animals; Biomarkers; Cyclooxygenase Inhibitors; Dinoprostone; Free Radicals; Indomethacin; Ischemia; Leukotriene B4; Lipase; Lipoxygenase; Male; Oxidative Stress; Pancreas; Pancreatitis; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Xanthine Oxidase

The cerebral ischemia rabbit model was made by using the occlusion of four vessels. The results showed that TXB2 and cAMP contents in brain tissues and the latter in plasma markedly increased (P < 0.05, P < 0.01), the 6-keto-PGF1 alpha in brain tissues significantly lowered (P < 0.05) in ischemia formed 30 minutes and 45 minutes after reperfusion. After intravenous injection of Astragalus membranaceus (AM) extracts (3.3 g/kg), Huoxuefang (HXFO and Yiqi Houxue Fang (YQHXF) consisted of AM and HXF before ischemia, the marked increase of TXB2 contents after reperfusion was inhibited (P < 0.05) and the 6-keto-PGF1 alpha in brain tissues after reperfusion were increased (P < 0.01) in HXF and YQHXF group, which change the AM extracts didn't have (P < 0.05). HXF could markedly inhibit the increase of cAMP in brain tissues after reperfusion P < 0.05), while the AM extracts and YQHXF couldn't (P > 0.05). All above-mentioned suggested that the above-mentioned suggested that the balance disorder of TXA2/PGI2 in brain tissues might participate in the occurrence of cerebral reperfusion injury and YQHXF might act against this injury by means of improving the balance of TXA2/PGI2 in brain tissues, which was mainly released by HX drugs of it.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Astragalus propinquus; Brain; Brain Ischemia; Cyclic AMP; Drugs, Chinese Herbal; Female; Male; Rabbits; Reperfusion Injury; Thromboxane B2

Ischemia-reperfusion injury has been studied in various organs. Effects of leukocyte and platelet depletion on ischemia-reperfusion injury were evaluated using the isolated, perfused dog pancreas in vivo.. Pancreatic exocrine and endocrine functions were stimulated by an intra-arterial injection of cholecystokinin (10(-12) mol) and intravenous injection of glucose and arginine (1 g/kg body wt), respectively. The functions before and after 60 minutes of ischemia were evaluated in the no treatment and in the leukocyte and platelet depletion groups.. Cholecystokinin increased prostaglandin I2 and thromboxane A2 production and stimulated exocrine pancreatic secretion. Glucose and arginine stimulated insulin and glucagon release from the pancreas. Sixty minutes of ischemia followed by 60 minutes of reperfusion damaged the pancreatic acinar and ductular cells. Ischemia of 60 minutes followed by 90 minutes of reperfusion damaged beta cells. Removal of leukocytes (97.6%) and platelets (99.4%) by using a filter throughout the experiment prevented the ischemia-reperfusion injury, reduced plasma lipid peroxide and thromboxane A2, and increased prostaglandin I2 levels.. Leukocytes and platelets seem to damage the pancreas during ischemia-reperfusion by increasing the peroxidation of structurally important cell membrane lipids and reduced the thromboxane A2 prostaglandin I2 ratio, a predictor of cellular injury.

Topics: 6-Ketoprostaglandin F1 alpha; Amylases; Animals; Blood Platelets; Dogs; Female; In Vitro Techniques; Ischemia; Leukocyte Count; Leukocytes; Lipid Peroxides; Male; Pancreas; Pancreatic Hormones; Platelet Count; Reperfusion Injury; Thromboxane B2; Veins

Prostaglandins are widely known to have cytoprotective effects in a variety of conditions. Thromboxane A2 has the opposite effect of prostaglandins. In this study the effects of the thromboxane A2 receptor antagonist ONO 3708 on ischemia and subsequent reperfusion in the dog liver was evaluated.. Mongrel dogs weighing from 10 to 15 kg were divided into three groups: a control group, a group with induced liver ischemia and subsequent reperfusion, and a group that received ONO 3708 and then underwent induced liver ischemia and subsequent reperfusion. Liver ischemia was induced by the Pringle procedure for 60 minutes. The concentrations of total free amino acids, aromatic amino acids, and branched-chain amino acids in blood taken from the portal and hepatic veins were examined before and after the Pringle procedure in the latter two groups and at the corresponding points in the control group.. Disturbances in amino acid metabolism in the liver occurred 5 minutes after the declamping in the ischemic group, and prostaglandin I2 and thromboxane A2 levels and lipid peroxide production, were increased. In contrast, hepatic amino acid metabolism was unchanged, and prostaglandin I2 and thromboxane A2, and lipid peroxide production, were normalized in the group that was treated with ONO 3708.. ONO 3708 appears to protects hepatic tissue from ischemia-reperfusion injury through free-radical scavenging, by increasing prostaglandin I2 levels, and by decreasing thromboxane A2 production.

Topics: 6-Ketoprostaglandin F1 alpha; Amino Acids; Animals; Dogs; Hepatic Veins; Lipid Peroxides; Liver; Portal Vein; Receptors, Thromboxane; Reperfusion Injury; Thromboxane A2; Thromboxane B2

Effects of prostaglandin (PG) E1 on ischemia-reperfusion (I-R) injury to the pancreas was evaluated using isolated in vivo perfused dog pancreas. Pancreatic endocrine and exocrine functions were stimulated with 10(-12) M cholecystokinin octapeptide (CCK-8). This amount of CCK-8 promoted production of insulin, glucagon, PGI2, and thromboxane (Tx) A2 in the pancreas. Sixty minutes of ischemia and subsequent reperfusion induced damage to pancreatic ductular, acinar, and beta cells. Intra-arterial administration of PGE1 at a dose of 0.5 microgram/kg/min throughout the experiment prevented the I-R injury, reducing plasma lipid peroxides, and elevating PGI2 without changing TxA2 in the pancreas. PGE1 thus appears to protect pancreatic function from I-R injury both by depressing the effect of free-radicals and by decreasing TxA2/PGI2 which predicts cell injury.

Topics: 6-Ketoprostaglandin F1 alpha; Alprostadil; Animals; Dogs; Female; Glucagon; Insulin; Lipid Peroxides; Male; Pancreas; Reperfusion Injury; Thromboxane B2

To evaluate the role of thromboxane A2 (TXA2) in ischemic liver injury, the serum changes in thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-K-PGF1 alpha) following warm ischemia of the total canine liver were examined, and the protective effect of a TXA2 synthetase inhibitor was assessed. Total liver ischemia was performed for 60 min on two groups of dogs: a control group, in which ischemia alone was performed, and an OKY-046 group, which received a TXA2 synthetase inhibitor. A temporary active portacaval shunt was used to eliminate the effects of splanchnic venous stasis during clamping of the hepatic pedicle. Postoperative changes in liver function, assessed by the transaminase enzyme levels, and in prostaglandins were recorded and the histologic liver findings of both groups 1 week after ischemia were compared. The levels of 6-K-PGF1 alpha increased after reperfusion in both groups, while those of TXB2 increased in the control group but maintained low levels in the OKY-046 group. Liver function was better and histologic changes less marked in the OKY-046 group than in the control group, suggesting the important role of TXA2 in ischemic liver injury and the usefulness of a TXA2 synthetase inhibitor for protecting the liver against ischemic injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspartate Aminotransferases; Dogs; Ischemia; L-Lactate Dehydrogenase; Liver; Liver Function Tests; Liver Transplantation; Methacrylates; Organ Preservation; Reperfusion Injury; Thromboxane B2; Thromboxane-A Synthase

Bronchial arterial (BA) perfusion could modify pulmonary arterial (PA) ischemia-reperfusion (IR) injury by promoting clearance of peribronchial edema or limiting edema formation through maintenance of pulmonary vessel integrity via bronchopulmonary anastomotic or pulmonary vasa vasorum flow. The purpose of this study was to determine the effect of BA perfusion on IR injury in isolated sheep lungs. In 12 lungs (BA++) the BA was perfused throughout 30 min of PA ischemia and 180 min of reperfusion. In 12 lungs (BA-+) BA perfusion was begun with PA reperfusion, and in 15 lungs (BA--) the BA was never perfused. After 180 min, extravascular lung water was less (P < 0.05) in BA++ and B-+ lungs [4.70 +/- 0.16 and 4.57 +/- 0.18 g/g blood-free dry lung (bfdl)] than in BA-- lungs (5.23 +/- 0.19 g/g bfdl). The reflection coefficient for albumin was greater (P < 0.05) in BA++ and BA-+ (0.57 +/- 0.06 and 0.75 +/- 0.03) than in BA-- lungs (0.44 +/- 0.04). The filtration coefficient in BA++ and BA-+ lungs (0.016 +/- 0.006 and 0.015 +/- 0.006 g.min-1 x mmHg-1 x kg-1) was not different from that in BA-- lungs (0.025 +/- 0.006 g.min-1 x mmHg-1 x kg-1). These results suggest that BA perfusion decreased reperfusion edema by attenuating the increase in pulmonary vascular permeability caused by IR injury. Moreover the result in BA-+ lungs suggests that the protective effect was mediated by BA perfusion of PA vasa vasorum rather than bronchopulmonary anastomotic flow, which was trivial compared with PA blood flow.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bronchi; Bronchial Arteries; Capillary Permeability; Extravascular Lung Water; Ischemia; Lung; Lymphatic System; Pulmonary Circulation; Pulmonary Edema; Regional Blood Flow; Reperfusion Injury; Respiration, Artificial; Sheep; Thromboxane B2; Water-Electrolyte Balance

Superoxide dismutase (SOD) is a potent scavenger of superoxide radicals produced during normothermic ischemia-reperfusion. Since it has a short half-life, its optimal effect is achieved when it is given prior to reperfusion. The inclusion of SOD in liposomes (lipo-SOD) prolongs its half-life (free SOD: 6 min; lipo-SOD: 4 h). The protective effect of lipo-SOD in a 60-min bilateral renal warm ischemia model was studied. We divided 60 male Wistar rats between two control groups and five study groups according to the drug used (SOD or lipo-SOD) and to the time of SOD administration (prior to ischemia or prior to reperfusion). SOD and lipo-SOD were both given at 20 mg/kg endovenously. Weight, diuresis, creatinine per 100 g (Cr/100 g), and creatinine clearance per 100 g (CrCl/100 g) were studied. Conventional renal histology was performed after reperfusion and on day 7. Renal malondialdehyde, 6 keto PGF 1 alpha, and TxB2 tissue levels were studied after reperfusion. Results showed that the renal protective effect of free SOD on warm ischemic-reperfusion injury depended on the time of administration, being more effective when given before reperfusion. On the other hand, the renal protective effect of liposomed SOD did not depend on the time of administration since efficacy was similar when given before reperfusion or before ischemia. The functional protective effect of liposomed SOD was similar to that of free SOD when they were given prior to reperfusion. Nevertheless, since histological damage observed with liposomed SOD was less than with free SOD, it is suggested that the liposomed galenic form may offer better protection against renal warm ischemia. In addition, liposomed SOD was better at preventing tissue prostanoid generation after renal warm ischemic-reperfusion injury than free SOD. We concluded that liposomed SOD shows a higher renal protective effect against warm ischemia than free SOD.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Creatinine; Drug Carriers; Free Radical Scavengers; Ischemia; Kidney; Liposomes; Male; Malondialdehyde; Rats; Rats, Wistar; Reperfusion; Reperfusion Injury; Superoxide Dismutase; Thromboxane B2

Arachidonate metabolites have been implicated in the development of cerebral injury after ischemia. Particular importance has been placed on the balance of thromboxane A2 and prostaglandin I2 because of its regulative activity on platelet functions and arterial tone. The purpose of the present study was to shed light on the role of thromboxane A2 in postischemic brain injury.. We evaluated the effects of S-1452, a novel thromboxane A2 receptor antagonist, on brain edema, infarct areas, and survival rate in rats with middle cerebral artery occlusion. A transient middle cerebral artery occlusion model was produced by inserting a piece of silicon-coated nylon thread into the internal carotid artery.. The ratio of plasma thromboxane B2 to 6-keto-prostaglandin F1 alpha significantly rose at 0 hour (P < .05), 1 hour (P < .01), 3 hours (P < .05), and 12 hours (P < .05) and then nearly returned to the normal level at 24 hours after reperfusion following 1-hour occlusion. Pretreatment with S-1452 (5, 10, or 50 mg/kg PO) significantly attenuated the increase in postischemic water content in the cerebral cortex perfused by the anterior cerebral artery and the cerebral cortex perfused by the middle cerebral artery in a dose-dependent manner but slightly attenuated it in the caudate putamen 24 hours after reperfusion following 1-hour occlusion. Pretreatment with S-1452 (10 mg/kg PO) also significantly decreased the areas of infarction in the front parts of the cerebrum. The survival rate of animals after 2 hours of occlusion tended to be improved by treatment with S-1452 (10 mg.kg-1.d-1 PO), although there was no statistical significance.. Our results suggest that thromboxane A2 is closely related to postischemic brain injury in the early phase of recirculation and that S-1452 may have a protective effect on postischemic brain injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Water; Brain; Bridged Bicyclo Compounds; Cerebral Infarction; Fatty Acids, Monounsaturated; Ischemic Attack, Transient; Male; Rats; Rats, Wistar; Receptors, Thromboxane; Reperfusion Injury; Survival Analysis; Thromboxane A2; Thromboxane B2; Time Factors

Exposure of isolated perfused rabbit lungs (IPL) to ischemia-reperfusion causes a transient increase in pulmonary arterial (PA) pressure at the onset of reperfusion. Because thromboxane A2 (TxA2) is a potent vasoconstrictor, we hypothesized that it may contribute to the ischemia-reperfusion-induced pressor response. To evaluate this hypothesis, we exposed IPL perfused with a cell-free solution to 40 min of warm ischemia followed by reperfusion and measured perfusate immunoreactive thromboxane B2 (iTxB2) and 6-ketoprostaglandin F1 alpha (i6-keto-PGF1 alpha). We observed that ischemia-reperfusion IPL compared with controls had an increase in PA pressure (40.2 +/- 4.8 vs. 9.3 +/- 0.3 mmHg, P < 0.05), lung edema (29.3 +/- 6.3 vs. -0.2 +/- 0.2 g, P < 0.05), iTxB2 perfusate levels (155 +/- 22 vs. < 50 pg/ml, P < 0.05), and i6-keto-PGF1 alpha (436 +/- 33 vs. 61 +/- 16 pg/ml, P < 0.05). In ischemia-reperfusion IPL, infusion of SQ 29548 (10(-6) M), a specific TxA2/prostaglandin H2 receptor antagonist, attenuated the PA pressor response and the degree of edema. We conclude that pulmonary hypertension associated with ischemia-reperfusion results in part from pulmonary release of TxA2. Furthermore, TxA2 directly through membrane effects or indirectly through hydrostatic mechanisms increases the severity of ischemia-reperfusion-induced lung edema.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Hypertension, Pulmonary; In Vitro Techniques; Ischemia; Lung; Organ Size; Pulmonary Circulation; Pulmonary Edema; Rabbits; Radioimmunoassay; Receptors, Thromboxane; Reperfusion Injury; Thromboxane A2; Thromboxane B2; Thromboxanes; Vasoconstriction

This study was carried out to investigate the proportion of the 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) and thromboxane B2 (TXB2) alteration that is due to ischemia in pancreas transplantation against the proportion due to reperfusion. For this purpose, Lewis rats were divided in three experimental groups: Group I = Control, Group II = Donor pancreas subjected to 15 minutes of cold ischemia, Group III = Same as group II but pancreas were transplanted to the recipient individual and then subjected to reperfusion. The results indicate that increases in pancreas 6-keto PGF1 alpha occur as a consequence of cold ischemia while TXB2 remains unchanged. When blood flow was restored, 6-keto PGF1 alpha remained unchanged compared to the ischemic group while pancreatic levels of TXB2 were significantly increased. These results suggest a different induction of prostanoid metabolism during ischemia and reperfusion in pancreatic tissue.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Ischemia; Male; Organ Preservation; Pancreas; Pancreas Transplantation; Rats; Rats, Inbred Lew; Reperfusion Injury; Thromboxane B2

Thirty three New Zealand rabbits were randomly divided into three groups, i.e. the control group, the high atmospheric pressure. (HAP) group and the hyperbaric oxygenation (HBO) group. The experimental animals were made into the models of reperfusion for acute incomplete cerebral ischemia. The blood-gas analyses drawn from the common carotid arteries and the internal jugular veins were carried out, and the 6-keto-PGF1a and TXB2 in the brain tissues determined. The results showed that the contents of 6-keto-PGF1a in the brain tissues of the HBO groups were significantly increased (P less than 0.01). While those of TXB2 were significantly decreased (P less than 0.01). The po2 in both the arterial and the venous blood were obviously elevated in the HBO group. Pathological examination showed that the brain tissue damages in the HBO group were the slightest among the three groups. It was postulated that the effect of HBO on 6-keto-PGF1a and TXB2 might reflect one of the mechanisms of HBO for the treatment of acute cerebral ischemia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Gas Analysis; Brain Ischemia; Hyperbaric Oxygenation; Rabbits; Reperfusion Injury; Thromboxane B2

Derivatives of arachidonic acid have been found to play a role in the reperfusion injury of various tissues. These compounds have a broad spectrum of activity, including modulation of white blood cell response to injured tissue. This study was designed to determine the effect of thromboxane and lipoxygenase derivatives on the local and systemic response to ischemia and reperfusion of skeletal muscle. Fifteen dogs were separated into three groups and subjected to gracilis muscle ischemia followed by 2 hours of reperfusion. One group served as controls, one group was treated with OKY-046 (a thromboxane synthetase inhibitor), and one group was treated with diethylcarbamazine (a lipoxygenase inhibitor). White blood cell activation as measured by superoxide anion production, and eicosanoid levels were measured both in the gracilis venous effluent and central venous circulation. These results were compared to infarct size in the gracilis muscle. OKY-046 significantly reduced thromboxane production in both the central venous (102 +/- 30 to 31 +/- 9 pg/ml, p less than 0.05) and gracilis samples (107 +/- 22 to 25 +/- 6 pg/ml, p less than 0.005). This was accompanied by a reduced white cell activation in the central venous blood (15 +/- 1 to 10 +/- 1 nmol O2-, p less than 0.05), but did not affect infarct size or white cell activation in the gracilis. Conversely, diethylcarbamazine significantly reduced both white cell activation (16 +/- 1 to 10 +/- 1 nmol O2-, p less than 0.005) and infarct size in the gracilis muscles (61.6% +/- 4.5% to 28.5% +/- 8.6%, p less than 0.01), as well as reduced systemic white blood cell activation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acids; Cell Survival; Diethylcarbamazine; Dogs; Female; Ischemia; Leukotriene B4; Male; Methacrylates; Muscles; Neutrophils; Reperfusion Injury; Superoxides; Thromboxane B2; Thromboxane-A Synthase

The effects of platelet-activating factor (PAF) on prostanoid release during mesenteric ischemia-reperfusion-induced shock were investigated in anesthesized dogs 1) by measuring plasma levels of prostaglandin (PG)F2 alpha, 6-keto-PGF1 alpha and thromboxane (TX)B2 in the superior mesenteric vein during reperfusion following 2 hr occlusion of the superior mesenteric artery; 2) by monitoring the effects of BN 52021, a specific PAF receptor antagonist and indomethacin on hemodynamic parameters and prostanoid levels; and 3) by studying circulatory responses to PAF and PGF2 alpha injected into the superior mesenteric vein in the presence of BN 52021 or indomethacin. Restoration of the blood flow following 2 hr ischemia resulted in an immediate dramatic decrease in mean arterial blood pressure, with a concomitant increase in mean portal venous pressure, hematocrit values, and plasma prostanoid levels. Pretreatment of the animals either with BN 52021 (4 mg.kg-1) or indomethacin (2 mg.kg-1 plus 3 mg.kg-1hr-1) prevented the circulatory collapse and the increase in prostanoid levels during reperfusion. Administration of exogenous PAF (0.1 micrograms.kg-1) or PGF2 alpha (10 micrograms.kg-1) into the superior mesenteric vein evoked hypotension similar to that observed during reperfusion. Pretreatment of the animals with BN 52021 completely prevented the effects of PAF but failed to modify the responses to PGF2 alpha. Indomethacin at a dose that inhibited prostanoid formation was highly effective to attenuate the hypotensive response to exogenous PAF. These data suggest that prostanoid formation may be secondary to PAF release in circulatory collapse evoked by intestinal ischemia-reperfusion and give further support to the notion of the importance of PAF prostanoid interaction during ischemia-reperfusion-induced shock.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprost; Diterpenes; Dogs; Ginkgolides; Hemodynamics; Indomethacin; Lactones; Male; Mesenteric Arteries; Mesenteric Veins; Platelet Activating Factor; Prostaglandins; Reperfusion Injury; Shock; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Cell Count; Blood Pressure; Cardiac Output; Heart Rate; Hemodynamics; Indomethacin; Liver Transplantation; Reperfusion Injury; Swine; Syndrome; Thromboxane B2

We investigated if cyclooxygenase metabolites of arachidonic acid were involved in ischemia-reperfusion lung injury by determining if inhibition of their production attenuated the injury. Isolated rat lungs were perfused with physiologic salt solution osmotically stabilized with Ficoll until circulating blood elements were not detected in lung effluent. Ischemia was induced by stopping ventilation and perfusion for 90 min. Lung ventilation and perfusion were then resumed. Ischemia-reperfusion resulted in the production of prostacyclin and thromboxane assessed by lung effluent and tissue measurements of their respective stable metabolites, 6-keto-PGF1 alpha thromboxane B2 (TxB2). In contrast, prostaglandin F2 alpha did not increase. Ischemia-reperfusion also caused lung injury as assessed by increased lung 125I-BSA accumulation compared with nonischemic control lungs. Addition of the cyclooxygenase inhibitors, indomethacin, or flubiprofen to the lung perfusate before and after ischemia inhibited lung injury as well as the production of 6-keto-PGF1 alpha and TxB2. Addition of a thromboxane synthetase inhibitor (U 63557A) reduced lung injury as well as TxB2 formation without affecting the production of 6-keto-PGF1 alpha. The attenuation of lung injury was not explained by direct H2O2 removal by indomethacin, flubiprofen, or U 63557A because the concentrations of the inhibitors used in the isolated lung experiments did not remove exogenously added H2O2 from buffer in vitro. We conclude that cyclooxygenase metabolites of arachidonic acid are involved in ischemia-reperfusion injury to isolated rat lungs.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Benzofurans; Blood Pressure; Cyclooxygenase Inhibitors; Dinoprost; Flurbiprofen; Hydrogen Peroxide; Indomethacin; Lung; Male; Prostaglandin-Endoperoxide Synthases; Pulmonary Artery; Rats; Rats, Inbred Strains; Reperfusion Injury; Thromboxane B2; Thromboxane-A Synthase

Significant increases of TXB2 and PGE2 are reported to occur in pancreas transplantation. These increases are prevented with scavengers of oxygen-free radicals. In this communication, we report on changes of prostacyclin metabolites such as tissue 6-keto prostaglandin F1 alpha and urinary 2,3-dinor 6-keto prostaglandin F1 alpha in rats subjected to pancreas transplantation after different periods of organ cold preservation ischemia as well as the effect of superoxide dismutase (SOD) on these changes. For this purpose, male Lewis rats were classified as follows: Group I, Control; Group II, syngenic pancreas transplantation after 15 min of organ preservation in Collins solution at 4 degrees C; Group III, same as II but with 12 hours of organ preservation; Group IV, same as III, but with SOD pretreatment. Results have shown significant posttransplantation increases of both tissue 6-keto PGF1 alpha and urinary 2, 3 dinor 6-keto PGF1 alpha, the latter being a useful marker to evaluate systemic prostacyclin (PGI2) production by rat pancreas. This effect was prevented when the organ had been exposed to SOD during the period of cold preservation ischemia. These results confirm the implication of oxygen-free radicals (OFR) in the ischemia-reperfusion process associated to rat pancreas transplantation leading to enhanced arachidonic acid metabolism.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Chromatography, High Pressure Liquid; Cold Temperature; Ischemia; Male; Pancreas; Pancreas Transplantation; Radioimmunoassay; Rats; Rats, Inbred Lew; Reperfusion Injury; Superoxide Dismutase

Although the specific cause(s) of inflammatory bowel diseases (IBD) has not been identified, one theory suggests ischemia as the early event that occurs in IBD and reperfusion causes sustained release of oxyradicals, leading to inflammation and ulceration. In this study, we have confirmed that H2O2 in the concentration seen during ischemia/reperfusion is primarily responsible for cellular membrane damage in the rat colonic fragments in vitro. Hydrogen peroxide caused a time and dose-dependent increase in 6-keto-PGF1 alpha and TXB2 release. Hydrogen peroxide-stimulated 6-keto-PGF1 alpha release was blocked (50%) by phospholipase A2 (PLA2) inhibitors quinacrine and dimethyleicosadienoic acid at 5 min. Hydrogen peroxide-stimulated 6-keto-PGF1 alpha release was completely blocked by indomethacin, significantly blocked (69%) by nordihydroguiaretic acid, and completely blocked by catalase. Superoxide dismutase and uric acid failed to inhibit H2O2-stimulated 6-keto-PGF1 alpha release. Endogenous catalase inhibitors 3-aminotriazole and sodium azide further enhanced the release of 6-keto-PGF1 alpha stimulated by H2O2 by 29% and 73%, respectively. Xanthine-xanthine oxidase also increased 6-keto-PGF1 alpha release from the fragments by 110%. This release was not inhibited by superoxide dismutase and uric acid, but was completely inhibited by catalase. These studies suggest a direct effect of H2O2 on colonic fragments leading to submicroscopic cellular membrane damage and excess prostanoid production utilizing a PLA2/cyclooxygenase and catalase-sensitive pathway without the formation of toxic hydroxyl ions. The quick release of 6-keto-PGF1 alpha also suggests an early manifestation of H2O2-induced damage in rat colonic fragments.

Topics: 6-Ketoprostaglandin F1 alpha; Adrenal Cortex Hormones; Animals; Antioxidants; Calcimycin; Colon; Epithelium; Hydrogen Peroxide; Indomethacin; Intestinal Mucosa; Male; Organ Culture Techniques; Oxidation-Reduction; Phospholipases A; Phospholipases A2; Rats; Rats, Inbred Strains; Reperfusion Injury; Thromboxane B2; Uric Acid

The correlation between protective effect of ginsenosides Rb + R0 and brain endogenously-derived prostacyclin synthesis, thromboxane A2 formation and lipid peroxidation were estimated in rats. Ginsenosides Rb + R0 100 mg/kg iv 30 min before 4-vessel occlusion elevated 6-keto-PGF1 alpha level, declined thromboxane B2 and brain edema formation, reduced the rise of lipid peroxides and suppressed the reduction in both creatine phosphokinase (CK) and superoxide dismutase (SOD) activities in brain tissue after 40-min ischemia followed by 1-h reperfusion. Furthermore, these improvements were partially abolished by pretreating with iv indomethacin. It is concluded that ginsenosides possess protective effect on cerebral ischemia-reperfusion injury of rats and ginsenosides Rb + R0 are the active principles. The underlying mechanism of protection is ascribed partially or mainly to the facilitated synthesis and release of prostacyclin, reduced formation of thromboxane A2 and inhibited generation of free radicals and subsequent lipid peroxidation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Creatine Kinase; Female; Ginsenosides; Ischemic Attack, Transient; Lipid Peroxidation; Male; Malondialdehyde; Panax; Plants, Medicinal; Rats; Rats, Inbred Strains; Reperfusion Injury; Saponins; Superoxide Dismutase; Thromboxane B2

This study tests the role of white blood cells (WBC) and leukotrienes in mediating the increased microvascular permeability following ischemia and reperfusion. Anesthetized dogs (n = 23) underwent 2 hours of hind limb ischemia induced by tourniquet inflation to 300 mmHg. In untreated animals (n = 7), tourniquet release led after 5 minutes to a rise in plasma thromboxane (Tx) B2 levels from 360 to 1702 pg/ml (p less than 0.05); after 2 hours, lymph TxB2 concentration had risen from 412 to 1598 pg/ml (p less than 0.05). There were decreases in circulating WBC from 11,766 to 6550/mm3 and platelets from 230 to 155 x 10(3)/mm3. During reperfusion, popliteal lymph flow (QL) increased from 0.07 to 0.24 ml/hour (p less than 0.05), while the lymph/plasma (L/P) protein ratio was unchanged from 0.39, changes consistent with increased microvascular permeability. WBC depletion (n = 7) to 302/mm3 by hydroxyurea or nitrogen mustard attentuated (p less than 0.05) the reperfusion induced rise in plasma TxB2 from 91 to 248 pg/ml and prevented the increase in lymph TxB2 concentration. Within 5 minutes of tourniquet release WBC counts further decreased to 191/mm3 (p less than 0.05) and platelets declined from 175 to 93 x 10(3)/mm3 (p less than 0.05). QL increased from 0.07 to 0.12 ml/hour (p less than 0.05), lower than untreated animals (p less than 0.05), and the L/P protein ratio declined from 0.49 to 0.37 (p less than 0.05), dilutional changes consistent with increased filtration pressure but not permeability to protein. Pretreatment with the lipoxygenase inhibitor diethylcarbamazine (DEC) (n = 8) prevented the reperfusion-induced increase in plasma and lymph TxB2 levels (p less than 0.05) and the fall in WBC counts (p less than 0.05), while platelet counts declined from 381 to 210 x 10(3)/mm3 (p less than 0.05). QL rose from 0.09 to 0.23 ml/hour (p less than 0.05) during reperfusion, and the L/P protein ratio of 0.3 remained unchanged, a value lower than in untreated dogs (p less than 0.05). In two animals of each group, vascular recruitment was induced by tourniquet inflation to 50 mmHg. This led to a high QL of 0.25 ml/hour and a low L/P ratio of 0.18. In untreated animals during reperfusion, QL further increased to 1.3 ml/hour, and L/P ratio rose to 0.44, documenting increased vascular permeability. In contrast, reperfusion in leukopenic or diethylcarbamazine (DEC)-treated dogs with vascular recruitment, was not associated with increases in QL or the L/P protein ratio

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Capillary Permeability; Diethylcarbamazine; Dogs; Hindlimb; Ischemia; Leukocyte Count; Leukocytes; Leukotrienes; Lymph; Platelet Count; Reperfusion Injury; Thromboxane B2