Lipoxygenase metabolites of arachidonic acid and the development of ischaemic cerebral oedema

This study examined the changes in cerebral blood flow, water content, and lipoxygenase metabolites (leukotrienes) following bilateral carotid artery occlusion (BCO) and reperfusion in the gerbil. The effect of inhibiting lipoxygenase with nordihydroguaretic acid (NDGA) was also examined. BCO caused cerebral blood flow (measured using H2 clearance) to decline from 23.5 +/- 1.9 to 4.5 +/- 1.9 ml/min/100 gm. Reperfusion increased flow to 27.9 +/- 4 ml/min/100 gm at 10 min, which declined to 13.7 +/- 1.3 ml/min/100 gm at 50 min. Concomitant oedema measurement revealed brain specific gravity decreasing to 1.0402 +/- 0.0014 at 10 min and to 1.0325 +/- 0.0006 at 50 min reperfusion (nonoccluded controls). Leukotriene B4 (LTB4) increased from 26.8 +/- 4.6 to 33.5 +/- 2.1 pg/mg protein 10 min after reperfusion (p less than 0.05), but declined to 21.8 +/- pg/mg protein by 100 min (vs nonischaemic control = 21.3 +/- 2.9 pg/mg protein). Activation of arachidonate metabolism was confirmed by significantly increased 6 keto PGF1 alpha. Pretreatment of the animals with NDGA did not alter CBF, but increased specific gravity above saline-treated controls at 50 min of reperfusion (NDGA = 1.0370 +/- 0.002 vs control = 1.0325 +/- 0.0006, p less than 0.05). Similarly, NDGA blunted the increase in LTB4 formation 10 min after reperfusion (control = 26.8 +/- 4.6 pg/mg protein vs NDGA = 29.7 +/- 2.9 pg/mg protein, p = N.S.). These findings indicate that LTB4 production is stimulated by BCO and reperfusion in the gerbil, and that this stimulation occurs early on in the reperfusion. Further, we observe that the lipoxygenase inhibitor NDGA limits the formation of ischaemic cerebral oedema.(ABSTRACT TRUNCATED AT 250 WORDS)     

Brain ornithine decarboxylase activity following transient cerebral ischaemia: relationship to cerebral oedema development

Ornithine decarboxylase (ODC) activity, the first and generally rate-limiting enzyme for polyamine synthesis, is stimulated in permanent focal cerebral ischaemia in areas of incomplete ischaemia which are developing ischaemic brain oedema. As polyamines are ubiquitous ornithine-derived molecules which are obligatory in cold-induced vasogenic oedema, we studied the effect of transient dense cerebral ischaemia with reperfusion on ischaemic oedema development and ODC activity. Fifty-nine Mongolian gerbils were anaesthetized with ketamine hydrochloride (160 mg/kg i.p. plus supplementation as needed). Both common carotid arteries were isolated and a tracheotomy placed in position. EEG was monitored with needle electrodes and temperature maintained at 37-38°C. Twenty-nine gerbils underwent 40 min of bilateral carotid artery occlusion followed by reperfusion times of 10 min, 1, 2, 4, 6 or 8 h. Non-ischaemic control groups were monitored for equal intervals. At sacrifice, the brain was rapidly removed and forebrain samples analysed for ODC activity (enzymatic assay) and cerebral oedema (gravimetric determination). Marked loss of EEG amplitude was noted in all gerbils subjected to bilateral carotid artery occlusion. Ischaemia produced significant levels of cortical oedema throughout the reperfusion period (maximal decrease in specific gravity at 4 h postischaemia; control: 1.0456 ± 0.0013; ischaemia: 1.0355 ± 0.0021, mean ± SD; p > 0.0001). Significant subcortical oedema was produced at 10 min, 2 and 4 h postischaemia. A biphasic response was observed in brain ODC activity. Throughout the first 2 h of reperfusion, ODC activity was significantly depressed in ischaemic versus control animals (10 min: 1423 ± 824 versus 3049 ± 1019; 1 h: 704 ± 635 versus 2621 ± 902; 2 h: 348 ± 184 versus 3654 ± 2072 pmoles/g tissue/60 min; p > 0.05). This difference was no longer detectable by 4 h postischaemia and by 6 h, ODC levels were significantly higher in ischaemic animals (ischaemia: 9314 ± 2652; control: 3065 ± 2000 pmoles/g tissue/60 min; p > 0.01). Although not significant, ODC was also greater in ischaemic animals at 8 h postischaemia. ODC levels at 6 and 8 h postischaemia were significantly higher (p > 0.05) than ODC levels at 10 min, 1 and 2 h postischaemia among ischaemic animals. These data indicate that transient ischaemia initially suppresses then stimulates ODC activity over the initial 8 h following transient global ischaemia in the gerbil. Since stimulation of ODC activity does not occur until early cerebral oedema is established, it is unlikely that polyamines are involved in the early cytotoxic oedema. Later stages of ischaemic oedema, however, with mixed cytotoxic and vasogenic components may be affected by the delayed rise in ODC activity after transient ischaemia.     

Amelioration of ischaemic cerebral oedema by a free radical scavenger,AVS: 1,2-bis(nicotinamido)-propane. An experimental study using a regional ischaemia model in cats

The effect of a free radical scavenger, AVS: 1,2-bis(nicotinamido)-propane, on the blood f1ow, oedema, and energy metabolites in the cortical area rendered ischaemic by the occlusion of the middle and the internal cerebral arteries was studied using cats. The development of cortical oedema was assessed by the changes in the specific gravity as well as the water and electrolyte contents of the cortical samples obtained 4 h after the arterial occlusion. Compared to the control group receiving saline, the AVS group exhibited a significant amelioration of cortical oedema, whereas no effect of AVS on the cortical blood flow was observed. The decrease of the energy charge and the increase of lactate in the ischaemic cortical area were less pronounced in the AVS groups. These data indicate that AVS possesses an action to mitigate the development of cortical oedema following regional ischaemia. The possible mechanism of action of AVS is discussed in reference to the free radical hypothesis.     

Toxicity of glutathione depletion in mesencephalic cultures: a role for arachidonic acid and its lipoxygenase metabolites

The contribution of arachidonic acid (AA) release and metabolism to the toxicity that results from glutathione (GSH) depletion was studied in rat mesencephalic cultures treated with the GSH synthesis inhibitor l-buthionine sulfoximine. Our data show that GSH depletion is accompanied by increased release of AA, which is phosholipase A2 (PLA2) dependent. Exogenous AA is toxic to GSH-depleted cells. This toxicity is prevented by inhibition of lipoxygenase activity, suggesting participation of toxic byproducts of AA metabolism. Hydroxyperoxyeicosatetraenoic acid (HPETE), one of the primary products of AA metabolism by lipoxygenase is also toxic to GSH-depleted cells, whereas hydroeicosatetraenoic acid (HETE) is not. Cell death caused by GSH depletion is prevented by: (i) replenishment of GSH levels with GSH-ethyl ester; (ii) inhibition of PLA2 activity; (iii) inhibition of lipoxygenase activity; and (iv), treatment with ascorbic acid. These data suggest that the following events likely contribute to cell death when GSH levels become depleted. Loss of GSH results in increased release of AA, which is PLA2 dependent. Metabolism of arachidonic acid via the lipoxygenase pathway results in generation of oxygen free radicals possibly produced during conversion of HPETE to HETE, which contribute to cellular damage and death. Our study suggests that limiting AA release and metabolism may provide benefit in conditions with an existing depletion of GSH, such as Parkinson's disease.     

Effects of cervical spinal cord stimulation in experimental ischaemic oedema

Abstract

Cervical spinal cord stimulation (SCS) has been used in an animal model of acute ischaemic brain oedema. In anaesthetized rats a temporary carotid bilateral occlusion of 60 minutes was carried out, followed by a reperfusion period of 30 minutes before sacrifice. Two electrodes were placed in each side of the duramater at C2 level. SCS was started either 60 minutes before ischaemia or at the beginning of the reperfusion period. The parameters of stimulation were: pulse width 0.1 ms; frequency of 25 cps; intensity at one third of the threshold which produced motor responses. The specific gravity of the brain was measured at different areas using a microgravimetric technique in a bromobenzene-petroleum column. Our results indicate that: 1) cervical SCS reduces ischaemic cerebral oedemai, 2) the effect is more prominent using stimulation during the reperfusion period, and 3) there were no differences in mortality rates or in the pathological study.     

Effect of Nimodipine on arachidonic acid metabolites after subarachnoid hemorrhage

Arachidonic acid metabolites are under investigation as possible vasoactive agents involved in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage. Prostaglandins, as well as other vasoactive compounds, activate contractile proteins through utilization of extracellular bound Ca++ to the intracytoplasmic free fraction. Recently, calcium-antagonists, mainly Nimodipine, have been proposed for the prophylaxis and/or reversal of the ischemic damage caused by vasospasm. Nimodipine failed to reduce vasospasm incidence in a series of 30 patients admitted with diagnosis of subarachnoid hemorrhage from ruptured intracranial aneurysm. Nimodipine failed to reduce level of four arachidonate metabolites measured (prostaglandin D2, prostacyclin, thromboxane B2 and leukotriene C4) in lumbar and cisternal CSF. After subarachnoid hemorrhage there is a significant increase of CSF levels of arachidonate metabolites; in perianeurysmic cisterns level of prostaglandin D2, thromboxane B2 and leukotriene C4 are significantly higher than lumbar CSF levels. Moreover, cisternal CSF level of prostaglandin D2 and leukotriene C4 are significantly higher in patients with symptomatic vasospasm. Nimodipine did not significantly modify CFS level of arachidonate metabolites: this suggests that Nimodipine treatment, which definitely improves long-term results of patients for intracranial aneurysms, could exert its pharmacological action reducing Ca++ intake from the extracellular compartment and preventing a direct toxic effect of calcium, without a direct action against the release of vasoactive compounds.     

Attitudes in the management of acute ischaemic cere-brovascular accident and cerebral haemorrhage in Latin America: a multinational study

ABSTRACT— Eleven neurologists (the Collaborative Group) from 7 Latin American countries interviewed 73 of their peers (respondents) with a questionnaire containing points on history-taking, investigations performed, and treatment. The obvious methodological pitfalls of this method are discussed. It was felt, nevertheless, that with judicious interpretation of the answers a fair reflection of reality can be obtained. Items in the history which are less frequently enquired for were alcohol intake just before a stroke, known abnormalities in the blood picture, and intermittent claudication. Amongst less frequently performed investigations were Doppler study of carotids, angiography, lumbar puncture, echocardiography ordered without the indication of a cardiologist, and EEG. Regarding treatment, steroids were preferred by a large majority in the treatment of cerebral oedema. In other items two thirds or more of respondents reached agreement except when dealing with high blood pressure on admission, the use of aspirin in acute ischaemic non-cardiogenic stroke and the use of anticoagulants in stroke considered to be progressing. No differences by country or years of experience were found. The management of affluent and poorer patients was more even than might be expected, most telling differences being CT scanning and anticoagulation.     

Immunosuppression by whole-body irradiation and its effect on oedema in experimental cerebral ischaemia

The effect of global immunosuppression by sublethal whole body X-irradiation on the development of cerebral oedema was assessed 24 h after right middle cerebral artery occlusion in the rat. Irradiation produced a significant leukopenia and thrombocytopaenia, and significantly reduced cortical oedema when compared to non-irradiated control animals.     

Role of cerebral endothelium in brain oedema

Abstract

The view that cerebral endothelial cells represent the cellular basis of the blood-brain barrier has been generally accepted. The regulation of transport processes operating in the cerebral endothelial cells is currently of great interest. Our knowledge of these regulatory mechanisms is briefly reviewed here with special regard to the molecular processes involved in the formation of brain oedema and emphasis on new therapeutic means for its prevention.     

The influence of MK-801 on the hippocampal free arachidonic acid level and Na+,K+-ATPase activity in global cerebral ischemia-exposed rats

The influence of 20 min global cerebral ischemia on the free arachidonic acid (FAA) level and Na⁺,K⁺-ATPase activity in the rat hippocampus at different time points after ischemia was examined. In addition, the effect of MK-801 on mentioned parameters was studied. Animals were exposed to 20 min global cerebral ischemia and were sacrificed immediately, 0.5, 1, 2, 6, 24, 48, 72, and 168 h after ischemic procedure. The level of the FAA and the Na⁺,K⁺-ATPase activity was measured during all reperfusion periods examined. Various doses of MK-801 (0.3, 1.0, 3.0, and 5.0 mg/kg) had been injected 30 min before ischemic procedure started. It was found that 20 min global cerebral ischemia induces a statistically significant increase of the FAA level immediately after ischemia and during the first 0.5 h of reperfusion. After a transient decrease, the level of FAA level increased again after 24 and 168 h of recirculation. Treatment with 3.0 mg/kg of MK-801 significantly prevented the FAA accumulation immediately and 0.5 h after ischemic insult while application of 5.0 mg/kg of MK-801 exerted a protective effect during the first 24 h. Global cerebral ischemia induces the significant decline in the Na⁺,K⁺-ATPase activity in the hippocampus starting from 1 to 168 h of reperfusion. Maximal inhibition was obtained 24 h after the ischemic damage. Application of 3.0 mg/kg of MK-801 exerted statistically significant protection during the first 24 h while the treatment with 5.0 mg/kg of MK-801 prevented fall in enzymatic activity during all reperfusion periods examined. Our results suggest that, in spite of different and complex pathophysiological mechanisms involved in the increase of FAA level and the decrease of the Na⁺,K⁺-ATPase activity, blockade of NMDA receptor subtype provides a very important strategy for the treatment of the postischemic excitotoxicity.     

Eicosapentaenoic acid potentiates the production of prostacyclin-like material in the arachidonic acid perfused human umbilical vein

The production of prostacyclin (PGI2)-like material in human umbilical veins perfused continuously at 37 degrees C with Hanks buffer solution with 1% human albumin (HBA) was studied by bioassay. Subsequent perfusion resulted in a time dependent significant decrease in production of PGI2-like material. After addition of 20 mumol/l arachidonic acid (HBA-AA) the production of PGI2-like material increased significantly. The production of PGI2-like material was significant greater when the vein was perfused with HBA-AA than when perfused with HBA with 20 mumol/l eicosapentaenoic acid (HBA-EPA). Examination of the HBA-EPA perfusate by thin layer chromatography showed that it contained a substance that comigrated with genuine 6-keto-PGF1 alpha and a substance that comigrated with delta 17-6-keto-PGF1 alpha. Finally, perfusion with HBA containing 10 mumol/l AA plus 10 mumol/l EPA resulted in a significant greater production of PGI2-like material than perfusion with HBA-AA alone. These results support the hypothesis that EPA has beneficial antithrombotic properties in human.     

Platelet adenine nucleotides and arachidonic acid metabolism in the myeloproliferative disorders

Platelet aggregation to collagen, adenosine diphosphate and arachidonic acid has been investigated in 17 patients with various myeloproliferative states. Ten patients who had abnormalities of aggregation to collagen and/or ADP were also all found to have diminished intracellular and releasable adenine nucleotides but aggregation to arachidonic acid was normal. Seven other patients who had normal aggregation responses had normal platelet adenine nucleotides. In the ten patients with abnormal platelet function platelet cyclo-oxygenase activity was normal but in two patients platelet lipoxygenase activity was reduced. Thromboxane B₂ production during collagen stimulation was found to be normal suggesting normal release of endogenous arachidonic acid. These findings suggest that the platelet defect in myeloproliferative states is due to an acquired storage pool disease.     

In vivo 31phosphorus spectroscopy during transient cerebral ischaemia in the gerbil

The depletion of the high energy phosphates; phosphocreatine and ATP, during cerebral ischaemia disrupts normal cellular function and can lead to cerebral infarction. Using in vivo nuclear magnetic resonance spectroscopy; the metabolic effects of the gerbil model of transient bilateral carotid artery occlusion were quantified. By examining the changes in the inorganic phosphate (Pi), phosphocreatine (PCr) and μ-ATP peaks, the PCr/Pi ratio, the PCr/μ-ATP ratio and intracellular pH (pHi) before, during and after an ischaemic insult were calculated. Preischaemic values for these parameters were: PCr/Pi = 2.466 ± 0.130, PCr/μ-ATP = 1.691 ± 0.053, pHi = 7.112 ± 0.021. By the end of 20 min of global ischaemia, the PCr and μ-ATP peaks fell to levels similar to background in most animals. Calculated values were: PCr/Pi = 0.488 ± 0.126, PCr/μ-ATP = 1.833 ± 0.179, pHi = 6.551 ± 0.258. With reperfusion, PCr/Pi increased rapidly back towards preischaemic levels but pHi improvement was delayed 10 min after that of PCr/Pi. By 1 h of reperfusion, both PCr/Pi and pHi were statistically equivalent to preischaemic values. During ischaemia, ATP was lost more rapidly than the storage form, PCr, but recovery of both was parallel. This suggested an intact ability to store such energy. These data indicate that the gerbil brain recovers normal high energy phosphate levels within an hour following a 20 min ischaemic insult, but that initial reperfusion does not immediately correct intracellular acidosis. Such a delay may prove a useful marker of those animals with more severe ischaemic injury.     

动脉瘤性蛛网膜下腔出血后脑血管痉挛与血浆花生四烯酸代谢产物的关系

目的探讨动脉瘤性蛛网膜下腔出血(aSAH)病人血浆花生四烯酸代谢产物的含量与脑血管痉挛(CVS)发生、发展之间的关系。方法选取34例aSAH病人作为研究组,在aSAH后第1、3、7、14天抽取外周静脉血测定血栓素B2(TXB2)和6-酮-前列腺素F1α(6-Keto-PGF1α)的含量。另选取同时期健康成人6例作为对照组,进行对比研究。结果研究组发生CVS 23例,其中表现为迟发性缺血性神经功能障碍(DIND)的症状性CVS 10例,无症状性CVS(无DIND)13例。与对照组相比,研究组各时间点血TXB2含量均明显升高,而血6-Keto-PGF1α含量变化无显著性差异;与无CVS病人相比,CVS病人血TXB2含量在各时间点均明显升高,而血6-Keto-PGF1α含量仅在第7天时明显降低;与无DIND病人相比,DIND病人血6-Keto-PGF1α含量在第1、3、14天明显降低,而血TXB2含量仅在第3天时明显升高。结论 aSAH后CVS、DIND的发生、发展与血TXB2、6-Keto-PGF1α含量变化可能存在相关性。     

Ethanol alters the transfer of arachidonic acid to ethanolamine plasmalogens in C-6 glioma cells

In this study, the effects of ethanol exposure on uptake and metabolism of arachidonic acid by C-6 glioma cells in culture was examined. Labeled arachidonic acid was effectively taken up by the phospholipids of these cells and radioactivity was initially incorporated into phosphatidylinositols and phosphatidylcholines, reaching a peak between 4 and 6 hours. However, the labeling of ethanolamine plasmalogens continued to show an increase with time after labeled arachidonic acid has been exhausted in the medium. Since over 90% of labeled arachidonic acid was already taken up by the cells after 4 hours of exposure, the continued increase in labeling of ethanolamine plasmalogens is attributed to a transacylation mechanism. Cells grown in 150 mM ethanol for 2 days did not show a change in the overall incorporation of labeled arachidonic acid into phospholipids but showed a significant increase in labeling of ethanolamine plasmalogens, which was marked by a concomitant decrease in labeling of phosphatidylcholines. Ethanol exposure also resulted in a significant increase in the transfer of labeled arachidonic acid to triacylglycerols. Changes in phospholipid and triacylglycerol labeling pattern positively correlated with increasing ethanol concentration from 75 to 300 mM. Besides, most ethanol effects were readily noticeable after 24 hours of exposure. These data suggest a specific effect of ethanol on promoting the transacylase process for biosynthesis of ethanolamine plasmalogens as well as the acyltransferase for biosynthesis of triacylglycerols.     

Vascular lipoxygenase activity: synthesis of 15-hydroxyeicosatetraenoic acid from arachidonic acid by blood vessels and cultured vascular endothelial cells

Although indirect pharmacologic evidence has suggested the presence of a lipoxygenase pathway of arachidonic acid (AA) metabolism in blood vessels, direct biochemical evidence has been difficult to demonstrate. We have investigated lipoxygenase metabolism in both fresh vessel preparations and cultured vascular cells from various sources and species. Lipoxygenase-derived [³H]HETE (composed of 12-HETE, 15-HETE and 5-HETE), which was abolished by ETYA but not by aspirin, was formed when [³H]AA was incubated with fresh sections of rat aorta. Lipoxygenase activity was lost following deendothelialization. A single peak of [³H]15-HETE was produced by cultured bovine aortic and human umbilical vein endothelial cells (EC) in response to exogenous [³H]AA or from [³H]AA released by ionophore A23187 from endogenous EC membrane phospholipid pools. Cultured bovine, rabbit or rat aorta smooth muscle cells had no detectable 15-lipoxygenase activity. ¹⁴C]Linoleic acid was converted by EC to its 15-lipoxygenase metabolite, [¹⁴C]13-hydroxyoctadecadienoic acid. These results indicate that blood vessels from different sources and species have a 15-lipoxygenase system, and this activity resides predominantly in the endothelial cells.     

Blood volume expansion with hetastarch in acute ischaemic stroke: the effects on local cerebral blood flow and computer mapped EEG

Focal cerebral ischaemia was induced in seven anaesthetized monkeys by unilateral middle cerebral artery (MCA) occlusion. Local cerebral blood flow (CBF) and computer mapped EEG (CME) changes were then studied as blood volume and cardiac output (CO) were varied. CO was increased by colloidal volume expansion and decreased by exsanguination. Local CBF fell to 24 ± 9% of control values in ischaemic areas following MCA occlusion and increased to 43 ± 19% of control values (p < 0.01) when CO was increased by 130 ± 70% with colloid infusion. Local CBF to nonischaemic regions was not altered significantly by blood volume expansion. Exsanguination led to return of CO to control levels and was associated with reduction of local CBF in ischaemic regions to 24 ± 12% of control values (p < 0.05).

CME showed bifrontal or ipsilateral slow wave foci (delta) following MCA occlusion. Blood volume expansion brought about a marked reduction of this slow wave activity and exsanguination led to recurrence of the slow wave foci.

This data demonstrated that colloidal blood volume expansion induced an increase in local CBF and improved neuroelectric status of ischaemic brain following MCA occlusion. It was also shown that a reduction of blood volume and cardiac output resulted in a reduction in local CBF and a worsening of neuroelectric status in ischaemic areas. This study supports the contention that blood volume and cardiac output maintenance is extremely important in the management of acute ischaemic stroke.     

Nitric oxide responsible for NMDA receptor-evoked inhibition of arachidonic acid incorporation into lipids of brain membrane

The activation of the glutamatergic NMDA receptor has no effect on arachidonic acid release from cortical synaptoneurosomal lipids prelabeled with [1-¹⁴C]arachidonic acid ([¹⁴C]AA). However, activation of NMDA receptor leads to the reduction of AA incorporation into rat brain cortex synaptoneurosomal membrane phosphatidylinositol (PI). The competitive NMDA receptor antagonist, 2-amino-5-phosphovaleric acid (APV), completely eliminates the effect of NMDA on this process. More precise analysis of the sequence of events leading to NMDA-induced decrease of AA incorporation indicates that this process is significantly blocked by voltage-gated sodium and calcium channels inhibitors, such as tetrodotoxin (TTX) and ω-conotoxin (CTX), respectively. Then the antagonist of inositol trisphosphate receptor, TMB-8, totally abolishes the effect of NMDA on AA incorporation into PI. The lowering of AA incorporation evoked by NMDA is significantly diminished by nitric oxide (NO) synthase inhibitor,N ^G-nitro-l-arginine (NNLA). Further studies were carried out with NO donor(s) to explain the mechanism of NO action in the inhibition of AA incorporation into PI. Our results suggest the following sequence of events: opening of voltage-dependent sodium and calcium channels, subsequent activation of PI-4,5-bisphosphate-specific phospholipase C (PLC), elevation of inositol trisphosphate (IP₃)-sensitive calcium ions, stimulation of NO production and NO-mediated S-nitrosylation, or free radical effect on enzymes involved in AA incorporation. Our data suggest that NO-mediated events may be responsible for NMDA-evoked inhibition of AA incorporation into PI of synaptoneurosomal membrane.     

Increase of plasma methionine-enkephalin level in patients at the acute stage of cerebral infarction

We investigated the participation of endogenous opioid peptide in cerebral ischaemia. In 13 patients with supratentorial infarction, the plasma immunoreactive methionine-enkephalin concentration at the acute stage (30.77 ± 3.54 pg/ml) was significantly higher than that at the chronic stage (20.37 ± 2.07 pg/ml) or that of the control subjects (19.64 ± 1.71 pg/ml). However; it was unrelated to infarct size or patient severity. The increased methionine-enkephalin, which appears to originate from the sympatho-adrenal system or infarcted brain, may play a role in the evolution of cerebral ischaemia.     

Effects of eicosapentaenoic acid on arachidonic acid metabolism in cultured vascular cells and platelets: Species difference

The metabolism of eicosapentaenoic acid (EPA) in cultured vascular smooth muscle cells isolated from human, rat, rabbit and miniture pig and bovine endothelial cells were studied. EPA was not able to be converted to any prostaglandins (PGs) in murine and porcine smooth muscle cells. However, in human and rabbit smooth muscle cells and bovine endothelial cells EPA was easily converted to Δ 176-ketoPGF_1α, which is a stable metabolite of PGI₃. Cyclooxygenase and 12-lipoxygenase activities in platelets isolated from human citrated blood were almost completely inhibited by EPA at the dose over 4 μg. But in platelets isolated from rat the inhibitory effects of EPA on arachidonic acid (AA) metabolism were much smaller than that in human platelets. In rat, EPA was not only being converted to no PGI₃, but also being a blocker to PGI₂ synthesis in vascular cells. Moreover, in rat EPA has much less activity in inhibiting thromboxane A₂ (TXA₂) synthesis in platelets. On the contrary, in human EPA was not only easily converted to PGI₃ in vascular cells, but also blocking TXA₂ synthesis in platelets.Thus, anti-aggregatory effects of EPA was positive in human and negative in rat perhaps due to species difference in sensitivity to EPA.