Effects of subarachnoid hemorrhage and a thromboxane A2 synthetase inhibitor on intracranial prostaglandins

The effects of subarachnoid hemorrhage (SAH) on intracranial prostaglandins (PGs) were studied in canines. Subarachnoid hemorrhage was produced by the "two hemorrhage" method. Basilar artery caliber and regional cerebral blood flow (rCBF) in the occipital cortex were reduced by 42% and 43% during delayed vasospasm, respectively. Once delayed vasospasm had developed, intravenous infusion of OKY-046, a selective inhibitor of thromboxane (TX) A2 synthetase, induced no significant change in angiographic vasospasm but caused a significant increase in rCBF. In delayed vasospasm, cortical levels of PGF2 alpha were significantly decreased, whereas plasma levels of PGF2 alpha and TXB2 in the transverse sinus were significantly increased. The intravenous infusion of OKY-046 in delayed vasospasm induced a significant increase in cortical PGF2 alpha and PGE in the occipital cortex, and caused a significant increase in plasma 6-keto-PGF1 alpha and a significant decrease in plasma TXB2 in the transverse sinus. In delayed vasospasm, decreased cortical levels of PGF2 alpha may reflect a decrease in rCBF and increased plasma PGF2 alpha and TXB2 levels may reflect enhancement of intravascular coagulation. These PGs have very strong and various biological activities. The results suggest that SAH induces complicated changes of intracranial PGs and OKY-046 can improve these pathological changes.     

Changes in renal prostanoid synthesis induced by potassium loading in rats

Previous works have demonstrated changes in the urinary excretion of prostaglandins (PG) in response to changes in potassium (K) or sodium (Na) intake. In the present study, the production of PGE2, PGF2 alpha, 6-keto-PGF1 alpha and thromboxane B2 (TXB2) by isolated glomeruli, cortical homogenates, medullary and papillary slices was measured in K-loaded rats on either a normal or a low Na intake. In glomeruli, K loading increased selectively PGE2 synthesis. In Na-depleted animals, all prostanoids were elevated and K loading did not induce a further increase. In cortical and medullary preparations, PGE2 was decreased by K loading irrespective of the state of Na balance. In papilla, PGE2 decreased (in all K-loaded rats) and PGF2 alpha increased (only in rats with normal Na intake). 6-Keto-PGF1 alpha and TXB2 did not change significantly. No correlation was present between changes of PG synthesis and urinary kallikrein excretion. The results demonstrate a specific effect of K on PGE2 and PGF2 alpha, and suggest a role for these substances in K homeOstasis.     

Barrier disruption in the major cerebral arteries during the acute stage after experimental subarachnoid hemorrhage

The effects of experimental subarachnoid hemorrhage (SAH) on the blood-arterial wall barrier in the basilar arteries were studied during the acute stage after SAH. SAH was induced in rats by injecting fresh autologous blood into the cisterna magna. Horseradish peroxidase (HRP) was given intravenously before killing the animals to assess the integrity of the barrier. In the basilar arteries taken from the animals that were killed 30 minutes after the cisternal injection of either mock cerebrospinal fluid or arterial blood, HRP reaction products were diffusely observed in the subendothelial spaces and smooth muscle layers. At 5 hours after the blood injection, no permeation of HRP into the subendothelial space was observed. Endothelial cell transcytosis seemed to be the important mechanism for HRP permeation into the subendothelial space rather than the opening of interendothelial junctions. The disruption of the blood-arterial wall barrier in the major cerebral arteries after SAH may be involved in the pathogenesis of vasospasm.     

Overexpression of cyclooxygenase-2 in rabbit basilar artery endothelial cells after subarachnoid hemorrhage

OBJECTIVE: We investigated the expression in rabbit basilar arteries of cyclooxygenase (COX)-2, which is the inducible isoform of the enzyme of prostaglandin (PG) production, and the concentrations of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) and representative PGs in the cerebrospinal fluid (CSF) after experimental subarachnoid hemorrhage (SAH). METHODS: Seven sets of basilar arteries were removed from control rabbits and from rabbits killed 1 and 3 days after induced SAH. The arteries were subjected to identical simultaneous immunolabeling for examination with a confocal microscope. One-half of each artery was stained for the constitutive form COX-1 and the other half for COX-2. CSF was sampled in control animals and at 6 hours, 1 day, and 3 days for assays of TNFalpha, PGE2, and 6-keto-PGF1 (metabolite of PGI2). RESULTS: COX-1 immunoreactivity in the endothelial layer was similar in the three groups. Weak endothelial COX-2 immunoreactivity was found in arteries of control animals. COX-2 staining was higher in the group killed at 3 days compared with the control group (P < 0.05). The levels of PGE2 and 6-keto-PGF1alpha in the CSF peaked significantly at 6 hours, then decreased at 3 days to the basal level (PGE2) or significantly lower (6-keto-PGF1). TNFalpha was undetectable in control CSF, significantly higher (P < 0.001) at 6 hours, and undetectable at 3 days. CONCLUSION: After SAH, endothelial COX-1 immunoreactivity does not change, whereas overexpression of COX-2 occurs at 3 days. This induction does not seem linked to TNFalpha production, nor is it responsible for early raised levels of PGE2 and PGI2 in the CSF. We suggest that the role of induced COX-2 may be to modify gene expression and hence alter the properties of the vessel wall after SAH.     

Barrier disruption in the major cerebral arteries after experimental subarachnoid hemorrhage in spontaneously hypertensive and normotensive rats

The effects of experimental subarachnoid hemorrhage (SAH) on the blood-arterial wall barrier in the major cerebral arteries were studied in 24 spontaneously hypertensive rats (SHR) and 13 Sprague-Dawley rats (SDR). Horseradish peroxidase (HRP) was given intravenously before killing the animals to assess the integrity of the barrier. In the acute experimental group, transient elevation of intracranial pressure (ICP) and systemic arterial pressure produced by cisternal injection of whole blood, saline solution, or Elliott's B solution resulted in extensive disturbance of the blood-arterial wall barrier. In the chronic group, only the cisternal injection of whole blood in SHR brought about an extensive and marked disturbance of the arterial permeability. These results suggest that: (a) early breakdown of the blood-arterial wall barrier seems to be due to a sudden rise in the ICP or arterial pressure; (b) in the chronic experiments, the subarachnoid clot is the most important factor responsible for the permeability changes; and (c) in the chronic SAH experiments, the blood-arterial wall barrier seems to be more vulnerable in SHR than in Sprague-Dawley rats. Due to the well-known similarities between SHRs and hypertensive human beings, patients with chronic hypertension should be considered at high risk after SAH for extensive blood-arterial wall barrier disturbances.     

Urinary prostaglandins and thromboxane in patients with chronic glomerulonephritis

To evaluate the potential contribution of prostaglandins (PGs) and thromboxane (TX) to the development of chronic glomerulonephritis, we measured the urinary excretion of PGE, PGF2 alpha, 6-keto-PGF1 alpha and TXB2 by radioimmunoassay in 36 patients with chronic glomerulonephritis. In patients with nephrotic syndrome, urinary excretion of PGE and TXB2 was highly increased, whereas that of PGF2 alpha and 6-keto-PGF1 alpha remained normal. In patients with non-nephrotic chronic glomerulonephritis, urinary excretion of TXB2 was significantly increased, whereas that of PGE and 6-keto-PGF1 alpha remained normal and that of PGF2 alpha was significantly decreased. In patients with chronic renal failure, the urinary excretion of all PGS and TX was markedly decreased presumably due to a decrease in the number of cells which can metabolize arachidonic acid. These results suggest that TXA2 plays an important role as an exaggerating factor in the development of chronic glomerulonephritis, particularly that accompanying nephrotic syndrome, and that renal synthesis of PGE is compensatorily increased to maintain renal function in nephrotic syndrome.     

Changes of plasma thromboxane level in subarachnoid haemorrhage

Changes of plasma thromboxane level in subarachnoid haemorrhage (SAH) were studied clinically and experimentally using 11-dehydro-thromboxane B2 (11 DTX) as a measuring index. 11 DTX is a major long-lived metabolite formed from thromboxane (TX) B2, and is said to be a more reliable parameter for detecting TXA2 production in biological systems. In this clinical study, blood was sampled from the cubital vein of 10 SAH patients on the earliest possible day (day 0 or 1), during the vasospasm predilection period (day 7 approximately 11) and in the chronic stage (day 16 approximately 32). Plasma concentrations of 11 DTX and 6-keto-PGF 1 alpha were measured in clinical cases. A canine SAH model was produced by the two haemorrhage methods and blood was sampled from the superior sagittal sinus before and on day 4 of the first cisternal blood injection. 11 DTX, TXB2 and platelet function were examined in each sample. In the clinical studies, plasma 11 DTX levels tended to be higher in the early stage of SAH but decreased thereafter to the normal or lower level. Plasma concentrations of 6-keto-PGF1 alpha tended to decrease mildly during the vasospasm predilection period. In the experimental study, neither definite change of plasma 11 DTX level nor neurological deficit could be induced by the mimic SAH, while an increase in platelet aggregability and narrowing of the basilar artery were observed. 11 DTX was inferred to be a more reliable parameter of TX biosynthesis than TXB2.     

Superoxide dismutase activity in cisternal cerebrospinal fluid after aneurysmal subarachnoid haemorrhage

Summary It has been recognised that the level of superoxide dismutase (SOD) significantly increases in CSF as the result of cerebral ischaemic damage. The aim of this study was to correlate the CSF levels of SOD enzymatic activity to the patterns of subarachnoid haemorrhage with regards to ischaemic complications due to vasospasm.A series of 78 patients operated on for intracranial aneurysms was studied; all patients were monitored with serial TCD measurements every second day after SAH. CSF samples were obtained at surgery by cisternal puncture of the subarachnoid cistern nearest to the aneurysm. SOD activity was assayed spectrophotometrically.Mean cisternal CSF level of SOD in 12 control cases (12.99±2.33 U/ml) is significantly higher (p < 0.01) than in 26 patients operated on between day 1 and 3 from last SAH episode (4.44±0.7 U/ml) and in 40 patients treated by delayed surgery (7.64±0.92 U/ml). In 13 patients presenting neurological deterioration related to arterial vasospasm mean cisternal SOD level was 12.23±1.86 U/ml; in 27 cases without vasospasm mean level was 5.43±0.7 U/ml (p < 001).The present results suggest that (a) cisternal CSF levels of SOD significantly decreases after SAH, probably in relation to an impaired synthesis in the brain compartment and that (b) a substantial elevation of SOD levels is evident in patients suffering ischaemic complications vasospasm-related. Biochemical events in the brain compartment could influence the expression and release of anti-oxidant enzymes in CSF after SAH.     

Barrier disruption in the major cerebral arteries following experimental subarachnoid hemorrhage

The effects of experimental subarachnoid hemorrhage (SAH) on the blood-arterial wall barrier in the major cerebral arteries were studied in 20 normotensive dogs. Horseradish peroxidase (HRP) was given intravenously before the animals were sacrificed to assess the integrity of the barrier. Transient elevation of intracranial pressure (ICP) produced by cisternal injection of saline solution resulted in HRP leakage at the branching points of the major cerebral arteries. Extensive disturbance of the blood-arterial wall barrier was consistently observed in the major cerebral arteries after SAH, with or without elevation of ICP. These results suggest that both subarachnoid clot and a sudden rise in the ICP are important factors causing the breakdown of the blood-arterial wall barrier, but that the effect of the clot is the most profound. Electron microscopy revealed that opening of the interendothelial junctions is one of the important mechanisms responsible for the HRP leakage in the major cerebral arteries following SAH. Disturbance of arterial permeability in the major cerebral arteries following SAH probably accounts for the abnormal post-contrast enhancement that occurs in patients who are prone to develop vasospasm following aneurysm rupture, and is probably involved in the pathogenesis of vasospasm.     

Comparison of intimal platelet accumulation in cerebral arteries in two experimental models of subarachnoid hemorrhage

Intimal accumulation of indium-111-labeled platelets in the middle cerebral arteries was examined in two different models of experimental subarachnoid hemorrhage (SAH) in the cat. SAH was produced in 7 subjects by a transorbital rupture of the right middle cerebral artery (RMCA) and in 10 subjects by the transorbital cisternal injection of 2 ml of autologous arterial blood around the RMCA. Animals in both experimental groups were sacrificed at 2, 4, 24, and 48 hours after SAH. The radioactivity (in counts per minute) of the RMCA segment was divided by that of the left middle cerebral artery (LMCA) to produce a radioactivity ratio (RMCA/LMCA). This radioactivity ratio was determined for each animal and was scored as positive if it was 1.25 or greater, and as negative if it was less than 1.25. The scores derived from the radioactivity ratios in both experimental SAH groups were mostly positive (86 and 70%, respectively) and were significantly different (P less than 0.05) from those of intact controls (n = 7) or sham-operated controls (n = 5; n = 4). There was, however, no significant difference (P = 0.35) between the scores of the two experimental groups in the first 48 hours after SAH. The results indicate that subarachnoid blood placed upon the adventitial surface of intact cerebral arteries activates platelet aggregation to a degree comparable to that which occurs after mechanical vessel rupture in the acute stages of SAH. We suggest that the noxious agents responsible for arterial injury and subsequent intimal platelet aggregation after SAH exert their influence primarily from the abluminal surface of the cerebral artery.     

Cerebral arterial responses to induced hypertension following subarachnoid hemorrhage in the monkey.

Regional cerebral blood flow (rCBF), angiographic cerebral arterial caliber, and cerebrospinal fluid (CSF) pressure were measured in rhesus monkeys to determine the effect of experimentally induced subarachnoid hemorrhage (SAH) on cerebral arterial responses to graded increases in blood pressure. These measurements were also performed in a control group of monkeys subjected to a mock SAH by injection of artificial CSF into the cerebral space. Before subarachnoid injection of blood or artificial CSF, graded increases in mean arterial blood pressure (MABP) to a level 40% to 50% above baseline values had no effect on rCBF. The major cerebral arteries constricted and CSF pressure remained unchanged. Similar responses were observed after injections of artificial CSF. When MABP was increased in animals that had been subjected to subarachnoid injection of blood, rCBF increased and was associated with dilatation of the major cerebral arteries and moderate increases in CSF pressure. These results demonstrate that cerebral arterial responses to increases in blood pressure may be abnormal in the presence of subarachnoid blood. The manner in which abnormal cerebral arterial reactivity, changes in blood pressure, and vasospasm combine to determine the level of cerebral perfusion following SAH is postulated.     

Regional disparity in the vascular response to subarachnoid hemorrhage--relationship between alteration of the concentration of eicosanoids and electron microscopic findings

In an attempt to document the apparent regional disparity of the vascular response to subarachnoid hemorrhage (SAH), the authors measured the concentrations of eicosanoids in various arterial segments corresponding to alterations observed on electron microscopy, using cats with experimentally produced SAH. The level of thromboxane B2 was elevated in both the arterial walls and cerebral cortices, particularly in the latter, on day 7 after SAH production. The 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) levels in the SAH group were decreased in the basilar and pial arteries after the production of SAH. The mean concentration of 6-keto-PGF1 alpha in the cerebral cortices showed only slight, erratic changes. Ultrastructural observations revealed that the vessels of smaller diameter, such as the pial vessels, underwent more marked spastic changes than did those of larger diameter. These results suggest that the ischemic events following SAH may have been induced by vasospasm and increased coagulability caused by changes in the concentrations of arachidonic acid metabolites in arteries of relatively small diameter.     

Mesangial cells release untransformed prostaglandin H2 as a major prostanoid

BACKGROUND: Prostaglandin H2 (PGH2) is the precursor of the other prostanoids and exhibits a vasoconstricting activity. Glomerular mesangial cells are an important source of vasoactive prostanoids in kidney. Hence, the present investigation focused on the release of untransformed PGH2 by rat glomerular mesangial cells (RGMCs). METHODS: Synthesis of prostanoid by resting and interleukin-1beta (IL-1beta)-treated (overnight) RGMCs from exogenous or endogenous arachidonic acid (AA) was assessed by high-performance liquid chromtography or enzyme immunoassay, respectively. Cyclo-oxygenase isoforms were determined by Western blotting. Release of untransformed PGH2 from exogenous AA was evaluated in RGMCs and intact glomeruli as the difference of PGF2alpha formed in the incubations performed in the presence and in the absence of SnCl2 or measuring the ability of aspirin-treated platelets to form thromboxane B2 (TXB2) in mixed incubations of platelets and RGMCs or glomeruli. RESULTS: The prostanoids formed by RGMCs were PGE2, PGF2alpha, PGI2 and PGD2. SnCl2 totally deviated formation of PGE2 and PGD2 toward PGF2alpha in resting RGMCs, whereas PGE2 was only partially deviated toward PGF2alpha in IL-1beta-treated RGMCs. The PGE2/PGD2 ratio in resting RGMCs was similar to that expected for nonenzymatic isomerization of PGH2, whereas this ratio was higher in IL-1beta-treated RGMCs, suggesting the induction of PGE synthase by IL-1beta. Aspirin-treated platelets formed TXB2 when either RGMCs or intact glomeruli were present in the incubation and formation of TXB2 was approximately fourfold higher with IL-1beta-treated RGMCs or glomeruli. CONCLUSIONS: RGMCs and intact glomeruli released substantial amounts of untransformed PGH2, which was enhanced following exposure to IL-1beta.     

Correlation between blood prostaglandins and blood pressure in chronic renal failure

Plasma prostaglandins (PGs; PGE2, PGF2 alpha, 6-keto-PGF 1 alpha and TXB2) and plasma renin activity (PRA) were measured in 94 end-stage renal disease (ESRD) patients including 15 undialyzed, 74 maintenance-hemodialyzed and 5 anephric patients, and in 27 healthy controls. In the healthy controls, 6-keto-PGF 1 alpha inversely correlated with age, while TXB2 and the TXB2/6-keto-PGF 1 alpha ratio correlated with age. In the ESRD patients, 6-keto-PGF 1 alpha showed a tendency to decrease with age, and the TXB2/6-keto-PGF 1 alpha ratio significantly correlated with age. The undialyzed group showed significantly higher blood pressure and TXB2 but significantly lower 6-keto-PGF1 alpha compared to the other groups. In the dialyzed group, PGE2 and 6-keto-PGF1 alpha tended to be lower and TXB2 higher compared to the healthy control group. In the dialyzed group, 6-keto-PGF1 alpha correlated inversely with blood pressure independently from PRA. As for PGF2 alpha, it was higher in the undialyzed, dialyzed and anephric groups than in the healthy control group. These results suggested that PGs were involved in blood pressure abnormalities, and that PGI2 played an important role in controlling blood pressure in ESRD patients as one of the depressor factors.     

Alterations of monoamine metabolites and of tryptophan in the basal cisternal CSF of patients after subarachnoid haemorrhage

Summary Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and tryptophan (TRP) were measured in the CSF obtained from the basal cistern of 20 patients, who had undergone surgical obliteration of bleeding aneurysms within 3 days after subarachnoid haemorrhage (SAH). The concentrations of these substances, which were assayed by high performance liquid chromatography (HPLC), were the highest on days 3 or 4, and thereafter showed a gradual decrease with an increase in time. The cisternal CSF in patients who had severe pre-operative clinical grades of SAH or vasospasm contained relatively higher concentrations of HVA, 5-HIAA and TRP than those contained in patients who did not. It is proposed that SAH stimulates the release of monoamines from the brain with the resultant extracellular accumulation of their metabolites and their diffusion into CSF during the acute stage. This stimulatory effect of SAH on the brain monoamine system may be consistent with those previously reported in cases of cerebral haemorrhage or infarction.     

Role of eicosanoids of the contralateral kidney in maintenance of two-kidney, one-clip renovascular hypertension in rats

OBJECTIVE: To elucidate the role of the eicosanoids prostaglandin E(2) (PGE(2)), 6-keto-prostaglandin F(1a) (PGF(1a)) and thromboxane B(2) (TXB(2)) in the maintenance of two-kidney, one-clip renovascular hypertension in rats. MATERIAL AND METHODS: The right renal artery was constricted by a silver clip in 63 male Sprague-Dawley rats to induce hypertension, while a sham operation was performed in 17 control rats. Six months after the induction of hypertension, nephrectomy of the clipped kidney was performed. Nephrectomy was followed by a period of high sodium intake. Blood pressure and eicosanoid excretion were measured before and after nephrectomy of the clipped kidney, as well as during high sodium intake. RESULTS: During the chronic phase of Goldblatt hypertension, the amount of vasoconstrictive TXB(2) excreted by the contralateral kidney increased compared to that in the controls, whereas PGE(2) excretion was unaffected. Eicosanoid excretion before and after removal of the clipped kidney did not differ between post-Goldblatt hypertensive and post-Goldblatt normotensive animals. During the period of high sodium intake, PGE(2) excretion increased only in control rats, being unaltered in Goldblatt hypertensive rats. CONCLUSIONS: In the chronic phase of two-kidney, one-clip renovascular hypertension, the contralateral kidney of post-Goldblatt hypertensive and post-Goldblatt normotensive rats excretes more vasoconstrictive thromboxane in comparison to controls, whereas excretion of vasodilatory prostaglandin is not elevated. However, increased TXB(2) excretion and the absence of an increase in PGE(2) excretion from the contralateral kidney do not appear to be important for the maintenance of high blood pressure in this model of renovascular hypertension.     

Effects of nicardipine on the ex vivo release of eicosanoids after experimental subarachnoid hemorrhage

The activation of lipid peroxidation and the enhancement of arachidonic acid metabolism have been demonstrated as indicators of brain damage after subarachnoid hemorrhage (SAH). Meanwhile, the final common pathway of neuronal damage seems to be related to the impaired homeostasis of Ca++. The present study evaluated the effect of the calcium-antagonist nicardipine on arachidonate metabolism after experimental induction of SAH. The ex vivo release of four eicosanoids (prostaglandin (PG)D2, PGE2, 6-keto-PGF1 alpha, and leukotriene (LT)C4) was measured at different intervals after SAH induction. Rats were separated into the following three groups: a sham-operated group, an SAH group (rats were injected with 0.3 ml autologous arterial blood), and an SAH-treated group (after SAH induction, rats were treated with nicardipine 1.2 mg/kg intraperitoneally). Nicardipine significantly decreased the ex vivo release of PGD2 at 48 hours after SAH (p less than 0.01). The release of PGE2 was significantly enhanced at 6 hours after SAH, while in the nicardipine-treated group PGE2 release is significantly reduced. Nicardipine also affects the lipoxygenase pathway, reducing the release of LTC4 at 1, 6, and 48 hours after SAH induction. The results of the present study show that nicardipine treatment exerts an inhibitory effect on both biochemical pathways of arachidonic acid metabolism; aside from vascular effects, nicardipine could exert a protective role against the release of arachidonate metabolites, which could play a significant role in the pathogenesis of brain damage after SAH.     

Interleukin-6 and Development of Vasospasm after Subarachnoid Haemorrhage

Summary  The authors characterized the role of interleukins in the cerebrospinal fluid (CSF) in the development of vasospasm after subarachnoid haemorrhage (SAH), particularly interleukin-6 (IL-6).  Concentrations of interleukin-1β (IL-1 β), IL-6, and interleukin-8 (IL-8) were measured serially in CSF of 24 patients and in serum of 9 patients with SAH and correlated clinically. Additionally, the effects of the same cytokines on the cerebral arteries of dogs were analyzed on angiograms after intracisternal injection. Changes in levels of eicosanoids, angiogenic factors, and soluble cell adhesion molecules were investigated in the CSF of injected dogs.  CSF concentrations of IL-6 and IL-8 were elevated significantly above control levels from the acute stage of SAH until the chronic stage. Patients with symptomatic vasospasm had significantly higher levels of IL-6 as well as IL-8 in CSF on days 5 and 7. Intracisternal injection of IL-6 induced long-lasting vasoconstriction in five out of eight dogs, while IL-8 did not. The diameter of canine basilar artery after IL-6 was reduced 29±5% from pretreatment diameter at 8 hours. Prostaglandins E₂ and I₂ were elevated in CSF for the first 4.5 hour of this IL-6-induced vasospasm. Neither angioenic factors such as platelet-derived growth factor-AB and vascular endothelial growth factor nor soluble cell adhesion molecules were significantly elevated in CSF.  IL-6, which increases to very high concentrations in CSF after SAH, may be important in inducing vasospasm, as IL-6 produced long-lasting vasoconstriction in the canine cerebral artery, which may be partly related to activation of the prostaglandin cascade.     

CSF leukotriene C4 following subarachnoid hemorrhage

Leukotrienes derive from arachidonic acid metabolism via the lipoxygenase pathway and modulate several cellular events. In the central nervous system, leukotrienes are mainly synthesized in the gray matter and in vascular tissues. Their production is enhanced in ischemic conditions and in experimental subarachnoid hemorrhage (SAH). Previous studies have indicated the ability of the leukotrienes C4 and D4 to constrict arterial vessels in vivo and in vitro and have suggested their involvement in the pathogenesis of cerebral arterial spasm. In the present study, the authors measured lumbar and cisternal cerebrospinal fluid (CSF) levels of leukotriene C4 in 48 patients who had suffered aneurysmal SAH. In 12 of the cases, symptomatic and radiological spasm was evident. The mean lumbar CSF level of immunoreactive-like activity of leukotriene C4 (i-LTC4) was significantly higher (p less than 0.005) than in control cases, while the cisternal CSF level was higher than the lumbar mean concentration (p less than 0.005). Patients presenting with vasospasm had significantly higher levels of i-LTC4 compared to patients without symptomatic vasospasm. This is the first report concerning monitoring of i-LTC4 levels in the CSF after SAH. The results of this study suggest that: 1) metabolism of arachidonic acid via the lipoxygenase pathway is enhanced after SAH; 2) the higher cisternal CSF levels of i-LTC4 may be part of the biological response in the perianeurysmal subarachnoid cisterns after the hemorrhage; and 3) the higher CSF levels of i-LTC4 in patients presenting with vasospasm suggest that a relationship exists between this compound and arterial spasm and/or reflect the development of cerebral ischemic damage.