Gross-total hematoma removal of hypertensive basal ganglia hemorrhages: a long-term follow-up.

BACKGROUND AND PURPOSE: Hypertensive basal ganglia hemorrhage (HBGH) accounts for 35%-44% of cases of hypertensive intracranial hemorrhage (ICH), which is one of the most devastating forms of cerebrovascular disease. In this study, intracerebral hematoma was evacuated with a burr hole craniectomy. The relationships of residue hematoma volume to brain edema, inflammation factors and the long-term prognosis of HBGH patients were studied. METHODS: One hundred and seventy-six patients with HBGH were randomly divided into gross-total removal of hematoma (GTRH) and sub-total removal of hematoma (STRH) groups. The pre-operative and post-operative data of the patients in the two groups were compared. The pre-operative data included age, sex, hematoma volume, time from the ictus to the operation, Glasgow Coma Scale (GCS) scores, and the European Stroke Scale (ESS) scores. The post-operative information included edema grade, level of thromboxane B2 (TXB2), 6-keto-prostaglandin F1a (6-K-PGF1a), tumor necrosis factor-a (TNF-a) and endothelin (ET) in hematoma drainage or cerebral spinal fluid (CSF), ESS and Barthel Index (BI). RESULTS: There was no statistical difference between the two groups (P>0.05) in the pre-operative data. The levels of TXB2, 6-K-PGF1a, TNF-a and ET in the GTRH group were significantly lower than those in the STRH group at different post-operative times. The ESS in the GTRH group increased rapidly after the operation and was higher than that in the STRH group. There was a significant difference between the two groups (P<0.05). The post-operative CT scan at different times showed that the brain edema grades were better in the GTRH group than in the STRH group. The BI was higher in the GTRH group than in the STRH group (P<0.05). CONCLUSIONS: GTRH is an effective method to decrease ICH-induced injury to brain tissue. Such effect is related to decreased perihematomal edema formation and secondary injury by coagulation end products activated inflammatory cascade.

Carbon monoxide-prostaglandin E2 interaction in the hypothalamic circulation.

The heme oxygenase (HO)-carbon monoxide pathway was earlier shown to increase hypothalamic blood flow after inhibition of nitric oxide synthesis in rats. We hypothesized that this effect is mediated by prostaglandin E2 (PGE2). Inhibition of constitutive HO activity decreased cerebral PGE2 production and simultaneously increased hypothalamic nitric oxide synthase (NOS) activity without changing hypothalamic blood flow. Furthermore, HO blockade induced cyclooxygenase-dependent decrease and NOS-mediated increase of the hypothalamic blood flow after inhibition of NOS and cyclooxygenase, respectively. Therefore, constitutive carbon monoxide release seems to have two indirect effects on the hypothalamic circulation: vasodilation mediated by PGE2 and vasoconstriction as a result of NOS inhibition.

Nimesulide 90 mg orally twice daily does not influence postoperative morphine requirements after major chest surgery.

BACKGROUND: Cyclooxygenase 2 inhibition has proven analgesic efficacy in a variety of surgical procedures. We postulated that perioperative cyclooxygenase 2 inhibition significantly reduces postoperative morphine requirements after major thoracic surgery and investigated the site of this potential analgesic effect. METHODS: Ninety-two patients participated in this single-center, double-blind, randomized, placebo-controlled, parallel-group trial. Patients between the ages of 18 and 80 yr undergoing a thoracotomy or median sternotomy were randomized to receive either nimesulide or placebo in combination with a standard analgesic regimen perioperatively. Nimesulide was administered orally the evening before surgery and at 12-h intervals for 5 days postoperatively. The primary efficacy variables were morphine consumption and pain scores for the first 48 h postoperatively. The secondary efficacy variable was the effect of nimesulide on cyclooxygenase activity in cerebrospinal fluid (CSF). RESULTS: Pain scores at rest or with movement, and total morphine consumption for the first 48 h postoperatively, were not statistically different between the groups. The mean difference in total morphine consumption up to 48 h postoperatively between the nimesulide and placebo group was a 9.0 mg reduction (95% CI: -28.9 to 10.9 mg) (P = 0.37). Adjusted mean (se) CSF 6-keto-PGF1alpha (6-keto-PGF1alpha) concentrations increased by 54.7 (25.7) pg/mL from preoperatively to Day + 2 postoperatively in the placebo group, whereas adjusted mean (se) CSF 6-keto-PGF1alpha concentration decreased by 0.6 pg/mL (18.2 pg/mL) in the nimesulide group. These changes were not statistically different between the groups (P = 0.095). CONCLUSION: Nimesulide, at a dose of 90 mg twice daily in combination with a standard analgesic regimen, does not influence pain scores, morphine requirements, or CSF prostaglandin levels after major thoracic surgery.

Clinical implication of the changes of cAMP, TXA2 and PGI2 in CSF of asphyxiated newborns.

To evaluate the changes of 3', 5'-cyclic adenosine monophosphate (cAMP), thromboxane A2(TXA2) and prostacyclin (PGI2) in cerebrospinal fluid (CSF) in the asphyxiated newborn and explore their roles in hypoxic-ischemic brain damage (HIBD). Thirty-six full term newborns were divided into 3 groups, including 12 with moderate-severe hypoxic-ischaemic encephalopathy (HIE), 13 with mild HIE, 11 without HIE (control group). The levels of cAMP, TXB2 (TXA2 metabolite) and 6-keto-PGF1 alpha (PGI2 metabolite) in CSF and plasma were measured 36-72 h after birth by RIA, and the concentrations were expressed as nM/L (cAMP), ng/L(TXB2 and 6-keto-PGF1 alpha). The infants were followed-up at 6 and 12 month of age and Mental Development Index (MDI) and Psychomotor Development Index (PDI) were measured using Bayley Scales of Infant Development (BSID). The CSF cAMP level in moderate-severe HIE group was 8.60 +/- 2.40, significantly lower than that of the mild HIE group (14.83 +/- 2.84) and the control group (24.43 +/- 2.39) (for both P < 0.01). The levels of TXB2 and 6-keto-PGF1 alpha in CFS in the moderate-severe HIE group (206.06 +/- 29.74, 168.47 +/- 23.02, respectively) were significantly higher than in the mild HIE group (83.37 +/- 28.57, 131.42 +/- 16.57, respectively, P < 0.01) and the control group (41.77 +/- 21.58, 86.23 +/- 13.05, respectively, P < 0.01). The level changes of cAMP, TXB2 and 6-keto-PGF1 alpha in plasma in all groups were similar to those in CSF, but no significant difference was found between mild HIE group and the control group (P > 0.05). The follow-up results showed that MDI and PDI of the moderate-severe HIE group were the lowest (84.79 +/- 13.34, 83.50 +/- 13.28, respectively), followed by mild HIE group (102.19 +/- 7.02, 99.94 +/- 9.08, respectively), with the control group being the highest (116.63 +/- 12.08, 116.69 +/- 10.87, respectively). Univariate analysis showed some significant difference (the moderate-severe HIE group vs. the mild HIE group or the control group, P < 0.01; the mild HIE group vs. the control group P < 0.05). The results suggested that the concentration of cAMP, TXA2 and T/K ratio in CSF after neonatal asphyxia might be sensitive markers in evaluating the severity of brain damage in early stage and predicting the future outcome.

Indomethacin prevents the development of experimental ammonia-induced brain edema in rats after portacaval anastomosis.

Patients with fulminant hepatic failure (FHF) die with brain edema, exhibiting an increased cerebral blood flow (CBF) at the time of cerebral swelling. Mild hypothermia prevents brain edema in experimental models and in humans with FHF, an effect associated with normalization of CBF. To study the effects of alterations of CBF on the development of brain edema, we administered intravenous (IV) indomethacin to rats receiving an ammonia infusion after portacaval anastomosis. This model predictably develops brain edema and a marked increase in CBF at 3 hours of infusion. Brain water was measured with the gravimetry technique; CBF was monitored with both laser Doppler flowmetry and radioactive microspheres, whereas intracranial pressure (ICP) was monitored with a cisterna magna catheter. Coadministration of indomethacin prevented the increase in CBF seen with ammonia alone (110 +/- 19% vs. -2 +/- 9%) as well as the increase in brain water (80.86 +/- 0.12% vs. 80.18 +/- 0.06%) and the increase in ICP. Plasma ammonia and brain glutamine levels were markedly elevated in the ammonia-infused group and unaffected by indomethacin. However, ammonia uptake by the brain was significantly reduced by indomethacin. Levels of 6-keto-PGF(1alpha), a stable metabolite of prostacyclin, were reduced in the cerebrospinal fluid (CSF) of indomethacin-treated animals. As with mild hypothermia, avoiding cerebral vasodilatation with indomethacin will prevent the development of brain edema in this hyperammonemic model. Cerebral vasoconstriction reduces cerebral ammonia uptake and, if selective to the brain, may be of benefit in FHF.

Cerebral arteriolar dilation to hypoxia: role of prostanoids.

Experiments addressed the hypothesis that dilator prostanoids contribute to maintenance of low cerebral microvascular tone during hypoxia in the newborn. Anesthetized newborn pigs equipped with closed cranial windows were used to measure responses of pial arterioles (approximately 60 microns) to treatments. Hypoxia (Pao2 approximately equal to 25 mmHg) caused dilation of pial arterioles (approximately 50% increase in diameter). Hypoxia (5 min) caused an increase in cortical cerebrospinal fluid 6-ketoprostaglandin F1 alpha concentration from 907 +/- 171 (normoxia) to 1,408 +/- 213 pg/ml (hypoxia). Pretreatment with indomethacin (5 mg/kg) did not affect pial arteriolar dilation to hypoxia. Conversely, indomethacin treatment during hypoxia caused a rapid decrease in arteriolar diameter to nearly the normoxia diameter within 3 min, returning to the original hypoxia diameter by 10 min. Ibuprofen treatment (30 mg/kg) had no effect on pial arteriolar diameter during normoxia or hypoxia, and pretreatment did not alter dilation to hypoxia. However, pretreatment with ibuprofen abolished the constrictor effect of indomethacin given during hypoxia. These data suggest that the primary mechanism by which hypoxia produces cerebral vasodilation does not involve prostanoids, but prostanoids can contribute to cerebral vasodilation in response to hypoxia.

Experimental and clinical studies of eicosanoids in cerebrospinal fluid after spinal cord injury.

OBJECTIVE: In an attempt to elucidate a possible role for eicosanoids in the pathogenesis of spinal cord injury (SCI), we measured the concentration of leukotriene (LT) C4, thromboxane B2, and 6-keto-prostaglandin F1 alpha in cerebrospinal fluid in both a canine experimental model and 11 patients with SCIs. METHODS: The eicosanoid concentration in cerebrospinal fluid was measured by radioimmunoassay. Neurological severity was assessed according to the grading system of Frankel et al.. Control samples were obtained from 20 patients without SCIs. RESULTS: In the canine model, a significant increase in all eicosanoid levels was found on Days 1 to 7, which subsequently returned to the control levels. In the clinical study, the highest mean (+/- standard error of the mean) concentrations of LTC4, thromboxane B2, and 6-keto-prostaglandin F1 alpha in the acute stage of SCI were 95.9 +/- 10.7, 175.2 +/- 38.2, and 167.5 +/- 39.9 pg/ml, respectively. These concentrations were five to nine times higher than control levels. There was a good correlation between cerebrospinal fluid LTC4 levels and the neurological severity. The time-dependent change in LTC4 concentrations in seven patients with SCIs was similar to that observed in the canine model. In addition, the highest mean concentrations of the eicosanoids measured in patients with complete paralysis was also similar to those of the canine model. The eicosanoid concentrations in five patients with SCI were measured more than 6 months after the onset of injury. Although all eicosanoid levels had elevated in the acute stage of injury, they were not elevated and showed the same levels as the controls at the chronic stage. CONCLUSION: The findings suggest that enhanced arachidonate metabolism occurs in humans and support the evidence from animal experiments that emphasizes the importance of eicosanoids in the secondary processes mediating ischemia and edema.

Repeated cocaine administration reduces bradykinin-induced dilation of pial arterioles.

Using the acute cranial window technique in rabbits under surgical anesthesia, we tested the vasoactivity of acetylcholine (ACh, 10(-8)-10(-5) M), bradykinin (BK, 10(-8)-10(-5) M), and asphyxia (10% O2, 9% CO2, balance N2) after subchronic pretreatment with cocaine. After repeated administration of cocaine (20 mg.kg-1.day-1 sc x 7 days), the BK-induced dilation of pial arterioles was reduced by 51%. Previous work showed that BK produces dilation of pial arterioles by a cyclooxygenase-dependent oxygen radical-mediated mechanism and that in rabbits the BK-induced dilation is dependent on both vascular and nonvascular cyclooxygenase. Selective blockade of vascular cyclooxygenase, in addition to cocaine treatment, did not produce any greater inhibition of the BK-induced dilation. The dilation in response to ACh and asphyxia was unaltered by cocaine. Levels of cerebrospinal fluid prostaglandins suggest cocaine pretreatment may inhibit cerebral vascular prostaglandin production. Together, cerebrospinal fluid prostaglandin and vasoreactivity data indicate cocaine pretreatment selectively inhibits the vascular cyclooxygenase-dependent mechanism mediating the BK-induced dilation. This decreased response to BK in cocaine-treated rabbits may result from decreased oxygen radical production concomitant with decreased vascular prostaglandin production. Alternatively, oxygen radical scavenging may be increased after cocaine treatment. We speculate that cocaine-induced alterations in cerebrovascular function and metabolism may be related to the increased incidence of stroke reported to occur in human cocaine users.

Relationship between opioids and prostaglandins in hypoxia-induced vasodilation of pial arteries in the newborn pig.

Previously, it has been observed that methionine enkephalin and leucine enkephalin contribute to hypoxia-induced pial artery dilation in the newborn pig. It has also been observed that the cyclooxygenase inhibitor indomethacin attenuates hypoxic hyperemia in piglets. The present study was designed to determine the relationship between opioids and prostaglandins in hypoxia-induced pial artery dilation. Newborn pigs equipped with closed cranial windows were used to measure pial artery diameter and collect cortical periarachnoid cerebrospinal fluid (CSF) for assay of opioids and prostaglandins. Hypoxia-induced artery vasodilation was mildly attenuated during moderate hypoxia (PaCO2 approximately 35 mm Hg), while this response was blunted during severe hypoxia (PaO2 approximately 25 mm Hg) by indomethacin, 5 mg/kg iv (23% +/- 1 % vs 18% +/- 1% and 33% +/- 2% vs 21% +/- 2% for moderate and severe hypoxia in the absence and presence of indomethacin, respectively). Hypoxic dilation was accompanied by increased CSF prostaglandin E2 (PGE2) concentration (1260 +/- 37 vs 1734 +/- 67 and 1256 +/- 33 vs 2859 +/- 189 pg/ml for moderate and severe hypoxia, respectively). Similar changes in CSF 6 keto PGF1alpha concentration during hypoxia were also observed. Topical PGE2 (10,100 ng/ml) increased CSF methionine enkephalin (874 +/- 35, 1290 +/- 44, and 1791 +/- 143 pg/ml for control, 10 and 100 ng/ml PGE2 respectively). Similar increases in CSF methionine enkephalin concentration were observed for topical PGI2. Additionally, these two prostaglandins also increased CSF leucine enkephalin concentration. Furthermore, while indomethacin had no effect on the release of CSF methionine enkephalin during moderate hypoxia, it attenuated the release of this opioid during severe hypoxia (786 +/- 27 and 2633 +/- 74 vs 781 +/- 51 and 2467 +/- 52; 926 +/- 15 and 3489 +/- 156 vs 898 +/- 11 and 2314 +/- 124 pg/ml for control and moderate/severe hypoxia before and after indomethacin, respectively). Similar effects of indomethacin on hypoxic release of leucine enkephalin were also observed. These data indicate that prostaglandins contribute to hypoxic pial dilation. Additionally, these data show that prostaglandins release the opioids methionine enkephalin and leucine enkephalin. Finally, these data suggest that elevated prostaglandin concentrations during severe hypoxia release opioids which in turn contribute to hypoxic pial dilation.

Interleukin-1 beta peptides induce cerebral pial arteriolar dilation in anesthetized newborn pigs.

Inflammatory cytokines may affect cerebral circulation under pathological conditions. Responses of cerebral pial arterioles to one such cytokine, interleukin (IL)-1 beta and its inhibitor [soluble IL-1 receptor (sIL-1R)] were examined in anesthetized newborn pigs using closed cranial windows. Levels of prostanoids and cyclic nucleotides in periarachnoid cerebral spinal fluid (CSF) were measured. To examine the structure-activity relationship of the parent IL-1 beta molecule, two IL-1 beta fragments with amino acid sequences of 187-204 [IL-1 beta-(187-204)] and 208-240 [IL-1 beta-(208-240)] were tested for their effects on pial arterioles. Diameter changes of pial arterioles were sequentially recorded every 5 min for 30 min after topical application of IL-1 peptides. CSF was sampled at the end of the 30 min. IL-1 beta dose dependently induced arteriolar dilation and increased prostaglandin E2 (PGE2), 6-keto-PGF1 alpha adenosine 3',5'-cyclic monophosphate (cAMP), and guanosine 3',5'-cyclic monophosphate (cGMP). Intravenous indomethacin blocked the IL-1 beta-induced vasodilation, the increased prostanoids, and the increased cAMP, but not the increased cGMP. Neither heat-inactivated IL-1 beta nor IL-1 beta vehicle affected arteriolar diameter or CSF levels of prostanoids. The sIL-1R blocked the IL-1 beta-induced vasodilation and the increased CSF prostanoids. IL-1 beta-(208-240) also induced pial arteriolar dilation; however, its vasodilatory potency was 1,000 times less than that of the whole IL-1 beta molecule. IL-1 beta-(187-204) did not induce pial arteriolar dilation even when its dose was increased to the level of IL-1 beta-(208-240). These results suggest that IL-1 beta, through the activation of membrane-bound IL-1 beta receptors, induces pial arteriolar dilation via mechanisms that involve prostanoids and cyclic nucleotides. The results also indicate that the 208-240 amino acid sequence of IL-1 beta has a sequence-specific physiological function.

Effect of intraventricular haemorrhage and rebleeding following subarachnoid haemorrhage on CSF eicosanoids.

CSF eicosanoid levels are raised following subarachnoid haemorrhage but not sufficiently to be vasoactive per se within the cerebral circulation. Rebleeding and intraventricular haemorrhage are two factors associated with a worse outcome after aneurysmal SAH. We have examined the effects of these two factors on the CSF levels of TXB2 (TXA2 metabolite), PG6-keto F1 alpha (prostacyclin metabolite), PGF2 alpha and PGE2 in 44 patients following subarachnoid haemorrhage. In 15 patients who had received no non-steroidal anti-inflammatory agent or dexamethasone, intraventricular haemorrhage increased the median levels of all four eicosanoids in ventricular CSF by 2.1-5.1-fold. In 4 patients who rebled, the CSF median levels of all four eicosanoids were raised up to 250-fold over the normal range. These concentrations are just sufficient to have cerebrovascular and neuromodulatory effects.

Subarachnoid blood causes pial arteriolar constriction in newborn pigs.

BACKGROUND AND PURPOSE: The present study was designed to determine in newborn animals the delayed effect of subarachnoid blood on pial arteriolar diameter and eicosanoid concentrations in cortical periarachnoid fluid. METHODS: Forty-eight to 96 hours after subarachnoid blood installation, closed cranial windows were implanted over the cerebral area exposed to blood in anesthetized, artificially ventilated newborn piglets. All pial arterioles greater than 60 microns in diameter were measured, and cortical periarachnoid fluid was collected for the determination of eicosanoids. RESULTS: Subarachnoid blood resulted in a 20% to 30% decrease in the average diameter of pial arterioles exposed to blood for 48 to 96 hours, a decreased number of large pial arterioles (greater than 200 microns), and an increased number of small arterioles (60 to 100 microns). No changes in dilator prostanoids (prostacyclin [as 6-keto-prostaglandin F1 alpha] and prostaglandin E2) were detected. Concentrations of vasoconstrictor prostanoids in cortical cerebrospinal fluid increased. Thromboxane B2 increased to 430 +/- 70 pg/mL, and prostaglandin F2 alpha increased to 1370 +/- 180 pg/mL compared with 250 +/- 20 and 860 +/- 70 pg/mL, respectively, in the control group. The concentration of peptidoleukotrienes increased to 400 to 600 pg/mL 72 to 96 hours after blood installation, while the level in the control group was less than 80 pg/mL. CONCLUSIONS: The altered balance between vasodilator and vasoconstrictor eicosanoids could contribute to cerebral vasoconstriction after subarachnoid blood installation in newborn pigs.

Prostanoids promote pial arteriolar dilation and mask constriction to oxytocin in piglets.

We determined effects of oxytocin on piglet pial arterioles and the role of prostanoids in mediating arteriolar responses. Anesthetized piglets were equipped with closed cranial windows, and arteriolar diameter was measured using intravital microscopy. Pial arterioles were exposed to 10(-10) to 10(-4) M oxytocin. Cerebrospinal fluid (CSF) levels of prostaglandin E2 (PGE2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) were determined using radioimmunoassay. Baseline diameter was 110 +/- 4 microns and increased to 120 +/- 6 microns at 10(-8) M (9 +/- 3%, n = 20). CSF levels of PGE2 were 697 pg/ml during baseline and increased to 1,685 +/- 316 pg/ml during 10(-6) M, 2,243 +/- 327 pg/ml during 10(-5) M, and 2,941 +/- 500 pg/ml during 10(-4) (n = 6). CSF levels of 6-keto-PGF1 alpha were 354 +/- 73 pg/ml during baseline and increased to 734 +/- 168 pg/ml at 10(-5) M and to 836 +/- 167 pg/ml at 10(-4) M (n = 5). After inhibition of prostaglandin synthesis by indomethacin (5 mg/kg i.v.), oxytocin constricted at all doses, starting at 10(-10) M (5 +/- 2%) and continuing to constrict at 10(-4) M (24 +/- 2%, n = 14). We conclude that: 1) piglet pial arterioles respond to relatively low levels of oxytocin, 2) local presence and/or production of prostanoids promotes dilation, and 3) endogenous prostanoids prevent constriction of pial arterioles to oxytocin. Our results suggest that oxytocin could play a role in the regulation of cerebral hemodynamics.

Effects of trigeminal neurotransmitters on piglet pial arterioles.

We investigated effects of calcitonin gene-related peptide (CGRP), substance P (SP), and neurokinin A (NKA) on pial arterioles in newborn pigs. Pial arteriolar diameter was determined using a closed cranial window and intravital microscopy. Initial diameters were approximately 100 microns. Calcitonin-gene related peptide dilated pial arterioles by 22 +/- 8% at 10(-9)M and by 34 +/- 6% at 10(-8)M (n = 8), and this response was not significantly altered by prior administration of indomethacin (5mg/kg, iv) (n = 6) or administration of NG-methyl-L-arginine (5mg/kg, iv, and 10(-3)M in CSF) (n = 10). Substance P dilated arterioles at 10(-10)M through 10(-5)M (maximal response = 23 +/- 3%) (n = 6), and this response was unaffected by indomethacin administration (n = 6). In contrast, NG-methyl-L-arginine blocked much of the pial arteriolar dilation to SP. Unlike the other two peptides, NKA did not change pial arteriolar diameter. Radioimmunoassay determinations indicated that cerebrospinal fluid levels of 6-keto-prostaglandin F1 and prostaglandin E2 did not change appreciably during application of CGRP or SP. We conclude that CGRP and SP but not NKA are dilator stimuli in the piglet pial circulation. Dilation by CGRP probably involves direct activation of receptors on vascular smooth muscle, while SP probably partially dilates pial arterioles via release of an endothelium-dependent relaxing factor.

Effect of dexamethasone on cerebral prostanoid formation and pial arteriolar reactivity to CO2 in newborn pigs.

This study investigates the effect of glucocorticoid treatment on the relationship between arteriolar PCO2 and cortical prostanoid production and on cerebrovascular responsiveness to elevated CO2 in newborn piglets. The response of pial arteries to hypercapnia (fractional inspired CO2 = 0.035 and 0.07) was studied in 18 anesthetized newborn piglets, 9 of which were pretreated with dexamethasone (2 mg.kg-1.day-1 for 36-48 h). Pial arterioles (77-122 microns diam) were monitored using a closed cranial window and intravital microscopy. Perivascular cerebrospinal fluid (CSF) was sampled from the cortical surface and analyzed for 6-keto-prostaglandin F1 alpha and thromboxane B2 (TxB2) using radioimmunoassay. In the dexamethasone-treated animals the increase in arteriolar diameter to CO2 was diminished by approximately 50% for each respective CO2 concentration vs. the control group. Acute sympathetic denervation did not restore the CO2 dilator response. Dexamethasone did not alter baseline cortical CSF prostanoid concentrations but abolished the CO2-induced increase in CSF prostanoids. The dilator response to exogenously applied prostaglandin E2 was inhibited in dexamethasone-treated animals. However, the dilator response to exogenous adenosine and the contractile response to prostaglandin F2 alpha were not altered in the dexamethasone-treated piglets. The data support the concept that metabolites of arachidonic acid participate in the cerebrovascular response to CO2 and suggest that glucocorticoid treatment may influence cerebrovascular tone via this mechanism.

Effect of hydrocephalus on prostaglandins and thromboxane B2 in ventricular cerebrospinal fluid.

The concentrations of prostaglandin F2 alpha, prostaglandin E2, 6-ketoprostaglandin F1 alpha (prostacyclin metabolite), and thromboxane B2 were assayed in ventricular cerebrospinal fluid obtained from 28 patients with hydrocephalus (17 obstructive, 11 communicating). Seven patients received dexamethasone or hydrocortisone on the day of sampling. No patient received nonsteroidal anti-inflammatory compounds for 48 hours before sampling. The median values did not differ significantly between the two types of hydrocephalus or from the concentrations in lumbar cerebrospinal fluid obtained from patients without intracranial pathology during lumbar myelography for possible lumbar disc disease. Hence, there is no evidence that eicosanoids accumulate in the ventricles in hydrocephalus, and it is unlikely that they have a significant role in its symptomatology.

Metabolism of central neurotransmitters during development of tolerance to the anticonvulsant effect of clonazepam and of physical dependence on the drug in dogs.

In previous studies, development of functional tolerance to the anticonvulsant effect of clonazepam and physical dependence on the drug have been demonstrated. In the present study, dogs were treated for 6 weeks with clonazepam 0.5 mg/kg b.i.d. Under methohexital anesthesia, cerebrospinal fluid samples were taken before treatment, at 3 days (acute effect), 4 and 5 weeks (tolerance) after the start of treatment, 2 and 8 days after withdrawal and 5 weeks after the end of treatment as another control. The following transmitters or metabolites were determined: HVA, VMA, 5-HIAA, GABA, PGE2, TXB2 and 6-keto PGF1 alpha. 5-HIAA levels showed a significant rise, indicating an increased activity of the serotonergic system in the brain during development both of tolerance and withdrawal. Dopaminergic activity was not altered during treatment, but was increased after cessation of treatment, as indicated by a significant increase in HVA concentrations.

Eicosanoid levels in CSF of premature infants with posthemorrhagic hydrocephalus.

The cerebrospinal fluid (CSF) of 11 premature infants suffering from posthemorrhagic hydrocephalus was examined by radioimmunoassay for prostaglandin (PG) E2, PGF2 alpha, PGD2, 6-keto PGF1 alpha, thromboxane B2 (TxB2) and peptidoleukotrienes (LTC4/LTD4). The LTs were detected in the CSF of more of these patients (70%) than any of the other eicosanoids, and usually in the highest concentration. Among the 11 posthemorrhagic patients CSF eicosanoid levels were highest when determined soon after injury. Moreover, the variety of eicosanoids present, as well as concentrations, in these infants decreased with time. The types of eicosanoids most evident in the CSF of patients who required shunting were TxB2 and LTs, being present together in 5 of 6 (83%) of these infants. In contrast, 1 of 5 (20%) of the patients who did not require this neurosurgical intervention contained both TxB2 and LTs, the remaining having only one or neither eicosanoid. The highest average concentration for each eicosanoid studied was (pg/ml): PGE2, 628; PGF2 alpha, 985; PGD2, 1410; 6-keto PGF1 alpha, 544; TxB2, 486 and LTs, 1229. This study is the first to demonstrate that the CSF of preterm infants may contain a wide variety of eicosanoids and indicates that these lipids are a manifestation of neurological assault.

Dilator effects of amino acid neurotransmitters on piglet pial arterioles.

We examined the effects of topically applied amino acids (glutamate, aspartate, glycine, and taurine) and a synthetic glutamate analogue [N-methyl-D-aspartate (NMDA)] on pial arteriolar tone and cortical surface cerebrospinal fluid (CSF) dilator prostanoid concentrations in anesthetized newborn pigs. We also determined whether prolonged contact of pial arterioles with glutamate (10(-3) M) and aspartate (10(-3) M) would alter arteriolar responses to exogenous isoproterenol or norepinephrine. Vascular responses were determined using the closed cranial window technique and intravital microscopy. Concentrations of prostaglandin E2 and 6-ketoprostaglandin F1 alpha in CSF under the cranial window were determined using radioimmunoassay. At the highest dose tested (10(-3) M), NMDA dilated arterioles by 30 +/- 4% (n = 8), glutamate by 21 +/- 5% (n = 6), aspartate by 28 +/- 10% (n = 5), and taurine by 21 +/- 2% (n = 7). Glycine application did not change pial arteriolar diameter significantly (n = 8). The amino acids tested (NMDA and glutamate) did not increase CSF levels of dilator prostagnoids, and intravenous indomethacin trihydrate did not change vascular responsiveness to NMDA. Furthermore, dilator responsiveness to isoproterenol and constrictor responsiveness to norepinephrine were not affected significantly after 30 min of topical application of glutamate and aspartate to the pial surface (n = 4). We conclude that these amino acids are potent dilators of the neonatal cerebral circulation. The mechanism of dilation in the cases of NMDA and glutamate does not appear to involve dilator prostanoids. Furthermore, prolonged contact with excitatory amino acids under these conditions does not alter subsequent cerebrovascular responsiveness.

Prevention of chronic cerebral vasospasm in dogs with ibuprofen and high-dose methylprednisolone.

Severe chronic cerebral vasospasm was produced in dog basilar arteries by two injections, 2 days apart, of autologous blood into the cisterna magna of 25 dogs. Treatment with ibuprofen (n = 8) or high-dose methylprednisolone (n = 8) after the first injection of blood prevented or reduced angiographic vasospasm. Cerebrospinal fluid concentrations of prostaglandin E2, prostaglandin F2 alpha, 6-ketoprostaglandin F1 alpha (a metabolite of prostacyclin), and thromboxane B2 (a metabolite of thromboxane A2) were measured in both treated and untreated (n = 7) dogs. In untreated dogs, the level of prostaglandin E2 increased 94-fold by Day 8 after the first injection of blood and was strongly and positively correlated with the degree of angiographic vasospasm. Treatment with ibuprofen and high-dose methylprednisolone prevented or significantly reduced this increase in prostaglandin E2 concentration. Smaller increases in cerebrospinal fluid concentrations of thromboxane B2 and 6-ketoprostaglandin F1 alpha occurred after experimental subarachnoid hemorrhage; the magnitude of these increases was also reduced by ibuprofen or high-dose methylprednisolone treatment. In contrast, prostaglandin F2 alpha levels were not significantly altered during the study. These data show that enhanced prostaglandin E2 synthesis occurs during experimental subarachnoid hemorrhage, and the by-products generated in its synthesis may play a role in the pathogenesis of cerebral vasospasm.