ozagrel and Reperfusion-Injury

Platelet activation and subsequent aggregation play a key role in the pathogenesis of ischemic brain damage. Recent studies revealed that enhanced platelet activation is also observed after ischemia, suggesting that secondary thrombus formation might participate in the development of cerebral infarction. The binding of platelet glycoprotein GPIIb/IIIa (integrin alpha(IIb)beta3) to fibrinogen is the final common pathway in platelet aggregation. Therefore, GPIIb/IIIa antagonists might be useful in acute ischemic stroke as well as in the secondary prevention of ischemic stroke. In the present study, we evaluated the effect of three compounds, FK419 ((S)-2-acetylamino-3-[(R)-[1-[3-(piperidin-4-yl) propionyl] piperidin-3-ylcarbonyl] amino] propionic acid trihydrate), a novel nonpeptide GPIIb/IIIa antagonist, ozagrel, a selective thromboxane A(2) synthase inhibitor, and argatroban, a thrombin inhibitor, on middle cerebral artery (MCA) patency and ischemic brain damage using photochemically induced MCA thrombosis model in guinea pigs. FK419, ozagrel, or argatroban was administered 5 min after the termination of photoirradiation. FK419 dose-dependently improved MCA patency by decreasing the total occlusion time, time to continuous reperfusion, and the number of cyclic flow reductions, at doses that inhibited ADP-induced platelet aggregation ex vivo. In contrast, ozagrel only improved total occlusion time, and argatroban showed no improvement in MCA patency. FK419 also reduced ischemic brain damage in a dose-dependent fashion, whereas ozagrel and argatroban did not. Finally, FK419 ameliorated neurological deficits, whereas ozagrel and argatroban did not. These results indicate that FK419, a GPIIb/IIIa antagonist, ameliorates ischemic brain damage by improving MCA patency after occlusion and that FK419 is a promising candidate for the treatment of acute ischemic stroke.

Topics: Animals; Antithrombins; Arginine; Blood Coagulation; Blood Platelets; Brain Ischemia; Disease Models, Animal; Guinea Pigs; Infarction, Middle Cerebral Artery; Male; Methacrylates; Pipecolic Acids; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Reperfusion Injury; Sulfonamides; Thromboxane B2

The study investigated the possibility of pharmacologically modulating hepatic allograft function from non-heart-beating donors (NHBDs) using male Lewis rats. The donors were divided into 4 groups: Group 1 in which the vehicle was administered, Group 2 in which FK506 (tacrolimus; a powerful immunosuppressive agent) was administered, Group 3 in which OKY046 (a specific thromboxane synthetase inhibitor) was administered and Group 4 in which FK506 and OKY046 were administered. The recipients received orthotopic liver transplantation. The survival rates differed significantly between the recipients that had received liver transplantation from Groups 1 and 4. The serum liver enzyme and inflammatory cytokine concentrations of the recipients which had received liver transplantation from Groups 2, 3 and 4 were significantly lower than those of the recipients that had received liver transplantation from Group 1. Although there was no significant difference, all parameters were better in the recipients that had received transplantation from Group 4 than those that had received transplantation from Groups 2 and 3. The action mechanisms of FK506 and OKY046 are completely different. Therefore, concomitant use of FK506 and OKY046 might have additive effects on liver transplantation from NHBDs. In conclusion, we demonstrated that pretreatment of NHBDs using FK506 and OKY046 ameliorated graft viability.

Topics: Animals; Enzyme Inhibitors; Graft Survival; Immunosuppressive Agents; Liver; Liver Transplantation; Male; Methacrylates; Rats; Rats, Inbred Lew; Reperfusion Injury; Tacrolimus; Thromboxane-A Synthase; Tissue Donors; Transplantation, Homologous

The effects of ozagrel (CAS 82571-53-7), a thromboxane A2-synthetase inhibitor, and norphenazone (CAS 89-25-8), a free-radical scavenger, on cerebral infarction were assessed using the suture-induced middle cerebral artery occlusion (MCAO) model and a microthrombosis model. In the former model, the middle cerebral artery was occluded for 2 h, and the infarction area and volume were evaluated 24 h after the start of reperfusion. In the latter model, microthrombosis were induced by two injections of sodium laurate (interval, 2 days) into the internal carotid artery, and the neurologic deficits were evaluated on the day afer the 2nd injection. Ozagrel at 3 mg/kg decreased both the area and volume of the cortical infarction after ischemia-reperfusion of the middle cerebral artery. Ozagrel also had suppressive effects on the neurologic deficits in the microthrombosis model. Norphenazone at 1 and 3 mg/kg had no clear effects in either model. Since the suture-induced MCAO model and the microthrombosis model are models for occlusion-reperfusion of the major cerebral arteries and lacunar infarction, respectively, these results suggest a highly beneficial effect of ozagrel in the clinical therapy for stroke.

Topics: Animals; Antipyrine; Edaravone; Enzyme Inhibitors; Free Radical Scavengers; Infarction, Middle Cerebral Artery; Male; Methacrylates; Middle Cerebral Artery; Optic Chiasm; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Thrombosis; Thromboxane-A Synthase

The neuroprotective property and the effects on hemodynamics of hydroxy fasudil, an active metabolite of an antispastic drug, fasudil, were examined. In rats, hydroxy fasudil was found following intravenous infusion or intraperitoneal administration of fasudil, and the maximum plasma concentration of hydroxy fasudil was approximately 25 or 40% of the parent drug, respectively. The i.v. administration of hydroxy fasudil produced significant increases in regional cerebral blood flow in dogs. Hydroxy fasudil relaxed the KCl, PGF2alpha or U-46619-induced contraction in canine basilar or middle cerebral arterial strips, concentration-dependently. The neuroprotective property of hydroxy fasudil was examined on delayed neuronal death in gerbils. Hydroxy fasudil (3 mg/kg) significantly protected against the ischemia-induced neuronal loss. To further clarify the effect on neurological impairments, hydroxy fasudil was tested in a rat model of microembolization stroke. Intravenous administration of hydroxy fasudil improved neurological functions, significantly reduced the size of the infarct area and prevented the accumulation of neutrophils. The present findings suggest that hydroxy fasudil has an efficacy to improve the hemodynamic function and to inhibit neutrophil-mediated damage, and contributes to the potency and long duration of the cytoprotective properties of fasudil on ischemic brain damage, and also suggest a critical role for rho kinase in the pathogenesis of cerebral ischemic injury, and the potential utility of rho kinase inhibitor as a therapeutic agent in stroke.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Brain; Brain Ischemia; Cerebral Arteries; Dogs; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Gerbillinae; Hemodynamics; In Vitro Techniques; Infusions, Intravenous; Injections, Intraperitoneal; Intracellular Signaling Peptides and Proteins; Male; Methacrylates; Muscle Contraction; Muscle, Smooth, Vascular; Neuroprotective Agents; Protein Serine-Threonine Kinases; Rats; Regional Blood Flow; Reperfusion Injury; rho-Associated Kinases

Ischemia reperfusion injury (IRI) contributes significantly to posttransplant graft dysfunction. An emphasis, therefore, has been directed toward the identification of novel renoprotective agents. In this study, the renoprotective effect of tetrodotoxin (TTX) alone, or in combination with a thromboxane synthetase inhibitor (OKY-046), was investigated in a 60-min warm ischemia, 72-h reperfusion, IRI rodent model. Unilateral nephrectomized rats were treated with the test vehicle alone, 1, 2, or 4 microgram/kg of TTX or 2 mg/kg of OKY-046 intravenously, either 15 min pre- or postischemia, or 2 microgram/kg TTX administered simultaneously with OKY-046 (2 mg/kg), following the ischemic interval. Baseline, 24, and 72 h mean plasma creatinine (Cr) and urea nitrogen (BUN) were compared. Maximal renoprotection was demonstrated by significantly improved 72-h Cr and BUN levels with the 2 microgram/kg of TTX or with 2 mg/kg of OKY-046, each administered after ischemia (ischemic control Cr = 8. 01 +/- 1.07 mg/dl vs TTX = 3.84 +/- 0.80 mg/dl, P = 0.008; vs OKY-046 = 4.0 +/- 1.5, P + 0.008; ischemic control BUN = 241.3 mg/dl +/- 32.8 vs TTX = 85.7 mg/dl +/- 18.7, P < 0.008; vs OKY-046 = 52.6 +/- 22.5, P = 0.008). The combination therapy utilizing TTX with OKY-046 resulted in reduced animal survival, demonstrating no renoprotection as measured with the biochemical parameters. These results support the renoprotective effects of TTX in a severe, rodent IRI model. The exact mechanism of action, as well as the therapeutic potential of TTX in preservation/transplantation, warrants further study.

Topics: Animals; Blood Urea Nitrogen; Creatinine; Drug Therapy, Combination; Enzyme Inhibitors; Kidney; Male; Methacrylates; Organ Size; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Survival Rate; Tetrodotoxin; Thromboxane-A Synthase; Time Factors

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

The efficacy of post-ischemic treatment with AJ-3941 ((+/-)-(E)-1-(3-fluoro-6,11-dihydrodibenz[b,e]-oxepine-11-yl )-4-(3-phenyl-2- propenyl)-piperazine dimaleate, CAS 143110-70-7), a cerebrovascular selective Ca2+ channel antagonist, on brain infarction induced by focal ischemia-reperfusion in rats was evaluated. Focal ischemia was induced by transient occlusion of middle cerebral artery (MCA) with a 3-0 nylon monofilament for 90 min. One day after MCA occlusion (MCAo), brain infarct size was determined by measuring 2,3,5-triphenyltetrazonium chloride-negative stained area of the serial brain sections. The development of cerebral infarction was observed in both regions of cortex and subcortex, such as striatum, caudatum, putamen, hippocampus and corpus callosum. Post-ischemic treatment with AJ-3941 (1 or 3 mg/kg p.o., 10 min and 3 h after the occlusion) significantly reduced the infarct size and volume in the ipsilateral hemisphere in a dose-dependent manner, compared to the solvent control. The reducing effect was observed mainly in the cortical region, and a significant reduction of the subcortical infarct volume was found at the higher dose (3 mg/kg). Post-ischemic treatment with the thromboxane A2 synthetase inhibitor, sodium ozagrel (150 micrograms/kg/min i.v. infusion, between 1 h and 24 h after the MCAo) did not reduce the infarct volume in the hemisphere after ischemia-reperfusion. AJ-3941 had only minimum effect on the elevation of body temperature during ischemia-reperfusion. These results indicate that post-ischemic treatment with AJ-3941 may ameliorate the brain injury after the transient focal cerebral ischemia, and they suggest that AJ-3941 has beneficial effects for treatment of ischemic cerebral damage, such as stroke.

Topics: Animals; Body Temperature; Brain; Calcium Channel Blockers; Cerebral Cortex; Cerebral Infarction; Dibenzoxepins; Enzyme Inhibitors; Ischemic Attack, Transient; Male; Methacrylates; Piperazines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Thromboxane-A Synthase

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

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

There are multiple causes of liver graft nonfunction in the early post-transplant period. Since a severe microcirculatory disturbance based on ischemia-reperfusion liver injury is considered to be the main underlying pathophysiology, it is suspected that various vasoactive substances are liberated after reperfusion of the graft. In order to investigate this matter, we conducted an experimental study with pig liver allotransplantation. Two groups of animals received donor grafts with or without thromboxane synthase inhibitor (sodium ozagrel), 1.25 mg/ kg body weight intravenously, given at the time of liver harvesting. All of the recipient animals in the treatment group (n = 10) survived longer than 7 days whereas three of ten animals in the control group died within 7 days. Serum lactate dehydrogenase (LDH) in the recipient serum at 1 h after reperfusion was significantly lower in the treatment group (915.1 +/- 167.3 U/l) than in the control group (1264.4 +/- 134.7 U/l). Serum thromboxane B2 (2261.7 +/- 1055.7 pg/ml) and endothelin-1 (6.3 +/- 2.2 pg/ml) after reperfusion in the treatment group were significantly lower than those in the control group (4220.0 +/- 1711.0 pg/ml and 11.2 +/- 3.1 pg/ml, respectively). Although serum angiotensin II after reperfusion tended to be lower in the treatment group than in the controls serum renin activity was less than 3 ng/ml in both groups of animals. There were no differences in the plasma endotoxin levels between the two groups. We conclude that the administration of sodium ozagrel to the donor animals provided better graft function in recipients than no such treatment. We speculate that the inhibition of thromboxane A2 production suppresses the liberation of other vasoconstrictive substances, preventing microcirculatory disturbance and, thereby, contributing to improved graft function after liver transplantation.

Topics: Angiotensin II; Animals; Aspartate Aminotransferases; Cardiovascular Agents; Endothelins; Endotoxins; Enzyme Inhibitors; Female; L-Lactate Dehydrogenase; Liver Transplantation; Methacrylates; Prostaglandins F; Reperfusion Injury; Swine; Thromboxane B2; Thromboxane-A Synthase

This study was designed to investigate the possible involvement of the thromboxane A2 (TXA2)-TXA2 receptor (TXA2R) system of the hepatic sinusoid in cold preservation/reperfusion injury in liver grafts. Rat livers were preserved in cold University of Wisconsin solution for either 6 or 24 hr. The number of TXA2Rs in sinusoidal endothelial cells isolated from 0-, 6-, and 24-hr preserved liver specimens was 22.50 +/- 1.80 x 10(3)/cell, 12.66 +/- 1.00 x 10(3)/cell, and 4.17 +/- 0.65 x 10(3)/cell, respectively. Kd and Bmax at 0 hr, 6 hr, and 24 hr of preservation were 8.54 +/- 1.26 nM and 37.34 +/- 3.01 fmol/10(6) cells, 7.08 +/- 1.14 nM and 12.66 +/- 1.00 fmol/10(6) cells, and 1.91 +/- 0.10 nM and 3.88 +/- 0.59 fmol/10(6) cells, respectively. The administration of OKY-046 (inhibitor of TXA2 synthesis) to the University of Wisconsin solution suppressed this reduction in TXA2R number. Furthermore, the concentration of TXA2 in hepatic sinusoid was decreased by OKY-046. In a reperfusion experiment, liver tissue preserved for 24 hr exhibited a higher reperfusion pressure, and effluent levels of both aspartate aminotransferase and lactate dehydrogenase were markedly elevated. The addition of OKY-046 to the preservation solution, however, prevented the rise in reperfusion pressure almost completely and the increase in effluent enzyme levels. This study showed that the TXA2Rs in sinusoidal endothelial cells were internalized through binding with TXA2 during cold preservation, causing activation of the TXA2-TXA2R system. This activation apparently induces an increase in reperfusion pressure, possibly due to sinusoidal contraction, resulting in microcirculatory disturbances.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aspartate Aminotransferases; Cryopreservation; Endothelium, Vascular; Female; L-Lactate Dehydrogenase; Liver; Liver Transplantation; Methacrylates; Microcirculation; Organ Preservation; Rats; Rats, Wistar; Receptors, Thromboxane; Reperfusion Injury; Thromboxane A2; Thromboxane-A Synthase

Prostanoids such as prostacyclin and thromboxane A2 have recently been suggested to play important roles in cold ischemia/reperfusion injury. The purpose of this study was to investigate the effect of thromboxane A2 synthetase inhibitor (OKY-046) on cold-stored livers of the rat using an ex vivo perfusion system. Addition of OKY-046 to preservation solution and the perfusate of livers stored cold (4 degrees C) in lactated Ringer's solution resulted in significantly lower glutamic pyruvic transaminase release (3.01 +/- 0.86 IU/g liver vs. 1.79 +/- 1.08 IU/g liver at 120 min after perfusion; P < 0.05), reduced perfusate ammonia levels (8.51 +/- 2.51 micrograms/dl/g liver vs. 3.62 +/- 1.71 micrograms/dl/g liver at 60 min; P < 0.05 and thereafter), lower perfusate taurocholate levels (0.63 +/- 0.10 vs. 0.18 +/- 0.05 at 15 min; P < 0.01 and thereafter), perfusate hyaluronic acid clearance (0.934 +/- 0.132 vs. 0.76 +/- 0.127 at 30 min; P < 0.05 and thereafter), and a reduced number of trypan blue-positive sinusoidal lining cells (50.1 +/- 9.9%; vs. 17.4 +/- 7.0%; P < 0.01). Histologically, the liver preserved for 6 hr in simple cold lactated Ringer's solution exhibited interstitial edema, various degrees of hepatocyte swelling, and sinusoidal stenosis, as well as dilatation, while the livers treated with OKY-046 demonstrated much less hepatocyte swelling, and change in sinusoidal width was nearly absent. We conclude that OKY-046 reduces post-preservation reoxygenation injury by protecting sinusoidal endothelial cells and hepatocytes.

Topics: Alanine Transaminase; Ammonia; Animals; Cell Survival; Cryopreservation; Hyaluronic Acid; Liver; Male; Methacrylates; Organ Preservation; Perfusion; Prostaglandins; Rats; Rats, Inbred Lew; Reperfusion Injury; Taurocholic Acid; Thromboxane-A Synthase

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

Topics: Animals; Eicosanoids; Hydantoins; Indoles; Leukotriene Antagonists; Liver Transplantation; Male; Methacrylates; Platelet Aggregation Inhibitors; Rats; Rats, Inbred Lew; Receptors, Thromboxane; Reperfusion Injury; Thromboxane A2; Thromboxane-A Synthase

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