Damage to the hemato-encephalic barrier during one-time immobilization stress

Intravenous injection of trypan blue followed by treatment of the brain according to the Falc-Hillarp was used for morphological study of the blood-brain barrier in control rats and in animals exposed to the 6.5-hour stress. The density of the blood-brain barrier as regards the macromolecules in control animals was found to be liable to noticeable areal variations. The zones of primary increased barrier permeability were found near the basal surface of the brain. Prolonged single immobilization stress gave rise to destructive changes in the blood-brain barrier in the reticular formations of the midbrain and medulla oblongata. Besides, in control animals, there was a slight increase in permeability of the brain areas marked by the reduced barrier density.     

艾灸对阿尔茨海默病模型大鼠血脑屏障结构与学习记忆功能的影响*

目的:探讨艾灸对阿尔茨海默病(AD)模型大鼠血脑屏障结构与学习记忆功能的影响。方法:48只SD大鼠随机分为4组:正常对照组、假手术组、模型组、艾灸组,模型组和艾灸组大鼠采用双侧海马一次性注射聚集态Aβ_25-35的方法建立AD大鼠模型,假手术组双侧海马区注射等量生理盐水,正常组不做处理。造模成功后,在艾灸组大鼠的“百会”、“肾俞”、“印堂”穴上方2～3 cm处施予艾条温和灸治疗,每穴10 min,每天1次,持续治疗21 d。采用Morris水迷宫实验评估各组大鼠的学习与记忆能力,伊文思蓝法检测血脑屏障通透性,电镜下观察血脑屏障的超微结构,免疫组化法检测海马区MMP-2和MMP-9阳性细胞数。结果:与正常对照组和假手术组比较,模型组大鼠逃避潜伏期时间显著增加(P＜0.01),空间探索时间显著下降(P＜0.01),学习记忆功能严重受损,脑内伊文思蓝含量显著增加(P＜0.01),血管周围水肿变大,血脑屏障结构功能受损,同时海马MMP-2和MMP-9阳性表达均显著增加(P＜0.01);与模型组比较,艾灸治疗组大鼠的学习与记忆能力均有所增强(P＜0.05),脑内伊文思蓝含量显著下降(P＜0.05),血管周围水肿程度减轻,血脑屏障损伤情况得到改善,海马MMP-2和MMP-9阳性表达显著降低(P＜0.05或P＜0.01)。结论:艾灸能减轻AD模型大鼠血脑屏障结构的损伤程度,从而改善大鼠的学习记忆能力,其机制可能与MMP-2和MMP-9被抑制有关。     

Mechanism of action of collagenase on the permeability of the blood-brain barrier

Some proteolytic enzymes are able to increase reversibly the permeability of the blood-brain barrier (BBB) to different tracers such as trypan blue. Intraventricularly injected collagenase is the most potent of the enzymes tested. It was assumed that collagenase acts on basement membrane collagen, the partial hydrolysis of which increases BBB permeability, and that the recovery of normal permeability requires resynthesis of the degraded substrate. In this paper, it is shown that injection of collagenase in lateral brain ventricles of rats increases the level of hydroxyproline (hypro) in the CSF, suggesting that collagen is indeed degraded by the enzyme. We also demonstrate that treatment with inhibitors of protein synthesis—puromycin and cycloheximide—delays considerably the recovery of normal BBB permeability, which occurs 140 h after collagenase treatment instead of 70–72 h without inhibitors. This fact indicates that protein synthesis is necessary for the recovery of normal BBB permeability. The demonstration of release of hypro in the cerebrospinal fluid (CSF) after collagenase action, and of the necessity of protein synthesis for the recovery of normal permeability, supports the above-mentioned hypothesis, according to which basement membrane collagen plays a role in the regulation of the permeability of the BBB.     

Magnesium sulfate attenuates increased blood-brain barrier permeability during insulin-induced hypoglycemia in rats

Magnesium probably protects brain tissue against the effects of cerebral ischemia, brain injury and stroke through its actions as a calcium antagonist and inhibitor of excitatory amino acids. The effects of magnesium sulfate on cerebrovascular permeability to a dye, Evans blue, were studied during insulin-induced hypoglycemia with hypothermia in rats. Hypoglycemia was induced by an intramuscular injection of insulin. After giving insulin, each animal received MgSO4 (270 mg/kg) ip, followed by a 27 mg/kg dose every 20 min for 2.5 h. Plasma glucose and Mg2+ levels of animals were measured. Magnesium concentrations increased in the serum following MgSO4 administration (6.05+/-0.57 vs. 2.58+/-0.14 mg/dL in the Mg2+ group, and 7.14+/-0.42 vs. 2.78+/-0.06 mg/dL in the insulin + Mg2+ group, P < 0.01). Plasma glucose levels decreased following hypoglycemia (4+/-0.66 vs. 118+/-2.23 mg/dL in the insulin group, and 7+/-1.59 vs. 118+/-4.84 mg/dL in the insulin + Mg2+ group, P < 0.01). Blood-brain barrier permeability to Evans blue considerably increased in hypoglycemic rats (P < 0.01). In contrast, blood-brain barrier permeability to Evans blue was significantly reduced in treatment of hypoglycemic rats with MgSO4 (P < 0.01). These results indicate that Mg2+ greatly reduced the passage of exogenous vascular tracer bound to albumin into the brain during hypoglycemia with hypothermia. Mg2+ could have protective effects on blood-brain barrier permeability against insulin-induced hypoglycemia.     

Abdominal vagal mediation of the satiety effects of CCK in rats

CCK type 1 (CCK1) receptor antagonists differing in blood-brain barrier permeability were used to test the hypothesis that satiety is mediated in part by CCK action at CCK1 receptors on vagal sensory nerves innervating the small intestine. Devazepide penetrates the blood-brain barrier; A-70104, the dicyclohexylammonium salt of N alpha-3-quinolinoyl-D-Glu-N,N-dipentylamide, does not. At dark onset, non-food-deprived control rats and rats with subdiaphragmatic vagotomies received a bolus injection of devazepide (2.5 micromol/kg i.v.) or a 3-h infusion of A-70104 (3 micromol.kg(-1).h(-1) i.v.) either alone or coadministered with a 2-h intragastric infusion of peptone (0.75 or 1 g/h). Food intake was determined from continuous computer recordings of changes in food bowl weight. In control rats both antagonists stimulated food intake and attenuated the anorexic response to intragastric infusion of peptone. In contrast, only devazepide was effective in stimulating food intake in vagotomized rats. Thus endogenous CCK appears to act both at CCK1 receptors beyond the blood-brain barrier and by a CCK1 receptor-mediated mechanism involving abdominal vagal nerves to inhibit food intake.     

Blood-brain barrier permeabilizing activity in sera of severe-burn patients

The relationship between the collagenolytic activity and the neurotoxic effects of sera from heavily burnt patients was investigated. Burn and control sera were submitted to alcoholic fractionation according to Cohn's method 6, and the collagenolytic activity of the individual fractions was investigated using a sensitive collagen-gel lysis method (5). Collagenolytic activity could be demonstrated in Cohn fractions I and II+III in all burn sera investigated and only occasionally in some other Cohn fractions. No such activity could be demonstrated in any of the fractions obtained from normal sera. The action of the serum fractions on the permeability of the blood-brain barrier (BBB) was also investigated using a previously described procedure (7). When injected intraventricularly to rats, Cohn fractions I and II+III from burn sera produced an increase of BBB permeability as determined by the penetration of intravenously injected trypan blue in the CNS. There was a strong and highly significant correlation between the collagenolytic activity of the Cohn fractions and their permeability increasing activity on the BBB. It is suggested that the highly increased level of serum collagenase activity is responsible for an increased permeability of the BBB of severely burnt patients, facilitating or enabling the entrance in the CNS of toxic substances such as the neurotoxic lipoproteins recently isolated from the sera of the same patients (1).     

Blood–Brain Barrier Permeability to Sodium. Modification by Glucose or Insulin?

In order to explore the pathogenetic mechanism underlying the changes in blood-brain barrier sodium transport in experimental diabetes, the effects of hyperglycemia and of hypoinsulinemia were studied in nondiabetic rats. In untreated diabetes, the neocortical blood-brain barrier permeability for sodium decreased by 20% (5.6 +/- 0.7 versus 7.0 +/- 0.8 X 10(5) ml/g/s) as compared to controls. Intravenous infusion of 50% glucose for 2 h was associated with a decrease in the blood-brain barrier permeability to sodium (5.4 +/- 1.2 X 10(5) ml/g/s), whereas rats treated with an inhibitor of insulin-secretion (SMS 201-995, a somatostatin-analogue) had normal sodium permeability (7.3 +/- 2.0 X 10(5) ml/g/s). Acute insulin treatment of diabetic rats normalized the sodium permeability within a few hours as compared to a separate control group (7.7 +/- 1.1 versus 6.9 +/- 1.4 X 10(5) ml/g/s). To elucidate whether the abnormal blood-brain barrier passage is caused by a metabolic effect of glucose or by the concomitant hyperosmolality, rats were made hyperosmolar by intravenous injection of 50% mannitol. Although not statistically significant, blood-brain barrier sodium permeability increased in hyperosmolar rats as compared to the control rats (8.3 +/- 1.0 and 7.0 +/- 1.9 X 10(5) ml/g/s, respectively). It is concluded that either hyperglycemia per se or a glucose metabolite is responsible for the blood-brain barrier abnormality which occurs in diabetes. Further, we suggest that the specific decrease of sodium permeability could be the result of glucose-mediated inhibition of the Na+K+-ATPase localized at the blood-brain barrier.     

The effect of administration of estradiol and testosterone on body growth of young male rats.

The influence of estradiol and testosterone on body growth of young male Wistar rats was investigated. In the first experiment, estradiol was given to intact ad libitum fed male rats at 32, 37 and 42 days of age. Moreover, two untreated groups of animals were used: one was fed restrictedly according to the food intake of animals receiving estradiol and another was fed ad libitum. The animals were sacrificed at 47 days of age. Both untreated groups of animals achieved significantly higher body weight and length of tibia than estradiol treated animals. Also the growth of the tail of untreated animals was more intensive than that of estradiol treated animals. In the second experiment, estradiol was given to intact ad libitum fed male rats at 30, 35 and 45 days of age. Moreover, testosterone was given to a half of these animals at 45, 50 and 55 days of age. The animals were sacrificed at 60 days of age. Administration of testosterone significantly increased the growth of the tail and tibia in comparison to the animals which did not receive testosterone after estradiol administration. The results of the present study show that the inhibitory effect of estradiol on body growth of young male rats is not only the result of decreased food intake and that testosterone can improve the skeletal growth of male rats altered by previously given estradiol.     

A GABA-EEG test of the blood-brain barrier near epileptic foci

The permeability of the blood-brain barrier (BBB) to gamma-aminobutyric acid (GABA) in the region of an epileptic focus may be assessed by infusing GABA and measuring a change in epileptic spike activity on the EEG. GABA does not cross the normal BBB but will suppress epileptic spike activity when it does cross where the BBB is damaged. 9 alumina-cobalt experimental epileptic foci were all initially suppressible, but 7 then became unsuppressible . When the foci were irradiated to lower the BBB, all 7 became temporarily suppressible. The experiments demonstrate that (1) epileptic foci can be equally active both with the BBB 'open' and 'closed'; (2) the intravenous GABA-EEG test can detect whether the BBB near the epileptic focus is open to GABA, and (3) anatomic tests of BBB integrity (in these experiments intravenous trypan blue) cannot determine if whether BBB near the focus is 'open' to GABA. Since the intravenous GABA-EEG test reveals the permeability of the BBB in the immediate environment of the epileptic focus, it may be very useful in the selection of a susceptible therapeutic group for inhibitory amino acid therapy.     

孕酮对新生大鼠低氧缺血性脑损伤中MMP-3表达的影响

目的：研究孕酮（PROG）对新生大鼠低氧缺血后脑内基质金属蛋白酶3（MMP-3）表达的影响。方法：建立新生大鼠低氧缺血性脑损伤动物模型,伊文思兰（EB）染色和电镜观察新生鼠低氧缺血性脑损伤血一脑屏障的通透性改变;免疫印迹（Western blot）方法检测大脑皮层MMP-3表达。结果：电镜显示低氧缺血组血-脑屏障完整性明显破坏：EB染色结果表明低氧缺血组血-脑屏障通透性明显高于假手术组,差异极显著（P〈0．01）,孕酮组血-脑屏障通透性明显低于低氧缺血组,有显著性差异（P〈0．05）;Western blot结果显示低氧缺血组MMP-3蛋白表达显著高于假手术组（P〈0．01）;孕酮组MMP-3蛋白表达显著低于低氧缺血组（P〈0．05）。结论：孕酮通过减少MMP-3的表达,降低血一脑屏障的损伤,这可能是其发挥脑保护作用的机制之一。     

Lifelong Consumption of Sodium Selenite: Gender Differences on Blood–Brain Barrier Permeability in Convulsive,Hypoglycemic Rats

The aim of this study was to compare the effects of hypoglycemia and induced convulsions on the blood-brain barrier permeability in rats with or without lifelong administration of sodium selenite. There is a significant decrease of the blood-brain barrier permeability in three brain regions of convulsive, hypoglycemic male rats treated with sodium selenite when compared to sex-matched untreated rats (p<0.05), but the decrease was not significant in female rats (p>0.05). The blood-brain barrier permeability of the left and right hemispheres of untreated, moderately hypoglycemic convulsive rats of both genders was better than their untreated counterparts (p<0.05). Our results suggest that moderate hypoglycemia and lifelong treatment with sodium selenite have a protective effect against blood-brain barrier permeability during convulsions and that the effects of sodium selenite are gender-dependent.     

Blunted febrile response to intravenous endotoxin in starved rats

The effects of fasting on the febrile responses to intravenous injection of bacterial lipopolysaccharide (LPS; endotoxin) of Escherichia coli were investigated in rats. Ad libitum-fed rats (C) produced a biphasic fever with an increase in the temperature difference between brown adipose tissue and colon and shivering activity (SA). Measurement by a direct calorimeter showed no particular changes in heat loss. Rats starved for 4 days (F4) responded to intravenous LPS with a monophasic fever accompanied by an increase in SA only. However the maximal rise in colonic temperature (Tco) did not differ from C rats. Subsequent 2-day fasting reduced SA and the maximal fever height. Endogenous pyrogen (EP) injected intravenously produced a prompt rise in Tco followed by prolonged hyperthermia in C rats. In the F4 rats, there was no such sustained rise in Tco as a result of intravenous EP. The response in Tco to intravenous prostaglandin E2 (PGE2) was the same in fed and starved rats. The administration of LPS, EP, and PGE2 into the lateral ventricle evoked a similar extent of hyperthermia in C and F4 rats. Because the second phase of fever has been shown to occur after pyrogens are translated into a febrile stimulus within the blood-brain barrier, it is assumed that the functional changes of the blood-brain barrier such as in the permeability of pyrogens or in the sensitivity of pyrogen receptors resulted in the absence of the second phase of fever in starved rats.     

Intracerebral Dialysis and the Blood-Brain Barrier

Abstract: The aim of the study was to evaluate how implantation of a dialysis probe influences the blood-brain barrier. Leakage of endogenous serum albumin was evaluated by Evans blue/albumin staining and by immunohistochemistry. The passage from blood to dialysate of two substances that normally do not pass into the brain, [³H]inulin and glutamate, was studied 3 and 24 h after insertion of a dialysis probe. Evans blue, given 20 min before rats were killed, was observed around the probe and surrounding brain tissue. Albumin immunoreactivity was seen at considerable distance from the probe with larger spread at 24 h than at 3 h after probe insertion. Glutamate and [³H]inulin were detected in the dialysate with no significant further increase of radioactivity after intracarotid infusion of protamine sulfate that enhances the permeability over the blood-brain barrier. When protamine was followed by infusion of glutamate, the concentrations of taurine increased in the dialysate in four of eight rats. That plasma constituents have access to the brain around the dialysis probe is essential to consider, particularly in studies using substances and drugs that do not pass an intact blood-brain barrier.     

Uptake of catecholamines and penetration of trypan blue after blood-brain barrier lesions

Summary Blood-brain barrier lesions were produced on rabbits which had been depleted of their endogenous monoamines with a large dose of reserpine. After the lesion, catecholamines and the blood-brain barrier indicator dye trypan blue were injected. After freeze-drying, the cellular distribution of the injected substances was observed in the fluorescence microscope.It was found that, in the injured areas, the monoamines and trypan blue had penetrated into the brain parenchyma, where the monoamines were taken up and concentrated in nerve terminals. Trypan blue was found diffusely in the neuropil, while the nerve cell bodies and axons exhibited no fluorescence of trypan blue. On the control side, this type of fluorescence of catecholamines or trypan blue could not be detected.The lesions applied seem to be quite specific for the blood-brain barrier, as an active and energy-dependent uptake of catecholamines could be demonstrated in central monoamine nerve terminals. Thus the results also show that these terminals have the same reserpine-resistant membrane pump in vivo as earlier demonstrated for peripheral adrenergic neurons, and for central neurons in vitro.This investigation has been supported by research grants (B 66-158 and B 66-257) from the Swedish Medical Research Council and by a Public Health Service Research Grant (NB 05236-02) from the National Institute of Neurological Diseases and Blindness. For generous supplies of drugs we thank the Swedish Ciba, Stockholm, Sweden for reserpine (Serpasil^®), the Swedish Pfizer, Stockholm, Sweden for nialamide (Niamid^®) and Hoechst Anilin AB, Göteborg, Sweden for -methylnoradrenaline (Corbasil^®).     

In Vivo Distribution of CGS-19755 Within Brain in a Model of Focal Cerebral Ischemia

The blood-brain barrier permeability of the competitive N-methyl-D-aspartate receptor antagonist CGS-19755 [cis-4-(phosphonomethyl)-2-piperidine carboxylic acid] was assessed in normal and ischemic rat brain. The brain uptake index of CGS-19755 relative to iodoantipyrine was assessed using the Oldendorf technique in normal brain. The average brain uptake index in brain regions supplied by the middle cerebral artery was 0.15 +/- 0.35% (mean +/- SEM). The unidirectional clearance of CGS-19755 from plasma across the blood-brain barrier was determined from measurements of the volume of distribution of CGS-19755 in brain. These studies were performed in normal rats and in rats with focal cerebral ischemia produced by combined occlusion of the proximal middle cerebral artery and ipsilateral common carotid artery. In normal rats the regional plasma clearance across the blood-brain barrier was low, averaging 0.015 ml 100 g-1 min-1. In ischemic rats this clearance value averaged 0.019 ml 100 g-1 min-1 in the ischemic hemisphere and 0.009 ml 100 g-1 min-1 in the nonischemic hemisphere. No significant regional differences in plasma clearance of CGS-19755 were observed in either normal or ischemic rats except in cortex injured by electrocautery where a 14-fold increase in clearance across the blood-brain barrier was measured. We conclude that CGS-19755 crosses the blood-brain barrier very slowly, even in acutely ischemic tissue.     

The blood-brain barrier: an alternative hypothesis

Brain blood vessels, unlike most vessels elsewhere in the body, exhibit a blood-brain barrier (BBB) to certain substances, e.g. trypan blue. Under some circumstances this barrier is no longer effective and the permeability of the vessels increases. Although capillarization is much less in the brain than in many other organs, e.g. heart muscle, total cerebral blood flow per minute is enormous. Consequently, to accommodate a large blood volume with a limited capillary bed, the velocity of blood through brain vessels must be extremely fast. The hypothesis presented in this paper is that this rapid flow results in a low or negative pressure on the endothelium, and plasma and trypan blue are prevented from passing through the wall. The tight junctions of cerebral endothelial cells may be able to withstand only a limited amount of pressure on their luminal surface. If the velocity of blood in brain capillaries decreases, pressure on the endothelium should increase, and brain vessels, like blood vessels elsewhere in the body, become permeable to vital dyes. Other conditions also increase capillary permeability, e.g. acute arterial hypertension or venous congestion. Although brain vessels can adapt to a moderate, gradual change in systemic pressure, when a significant rise in cerebral arterial pressure is abrupt, the compensatory changes in the postcapillary venous bed may be inadequate and consequently intracapillary pressure and vascular permeability are increased. Venous congestion increases intracapillary pressure by restricting capillary outflow as well as by reducing velocity through capillary beds. Under such conditions increased capillary permeability may be indicated by cerebral edema, and even, on occasion, by petechial hemorrhages. In short, if the flow is fast and unimpeded the BBB will be effective; if the velocity decreases, or intracapillary pressure increases for whatever reason, the permeability of the brain endothelium will be abnormally increased.     

Chronic maternal dietary iodine deficiency but not thiocyanate feeding affects maternal reproduction and postnatal performance of the rat

Iodine deficiency disorders affect reproductive performance in the afflicted populations. Environmental iodine deficiency (ID) and goitrogens are important in their aetiology. We observed earlier that chronic maternal dietary ID but not goitrogen feeding altered the blood-brain barrier nutrient transport in adult rats. Whether similar differences exist in their effects on reproduction of dams and postnatal performance of the offspring has been assessed. Inbred, female, weaning WNIN rats were rendered hypothyroid by feeding for 8-12 weeks, a low iodine test diet or a control diet with added potassium thiocyanate (KSCN) (@ 25 mg/rat/day). Following mating with control males, they continued on their respective diets till their pups were weaned. Indices of reproductive performance such as percentage of conception, mortality of dams during pregnancy and parturition, litter size, and survival of pups till weaning were affected markedly by ID but not thiocyanate feeding. Neither ID nor thiocyanate feeding from conception or parturition affected their reproductive performance. Nevertheless, postnatal weight gain of pups was less in all the three ID groups but not thiocyanate fed dams. Rehabilitation of chronically ID pregnant dams from conception or parturition did not improve their pregnancy weight gain, litter size or birth weight of pups but decreased abortion and mortality of mothers during pregnancy and parturition. Rehabilitation improved the pups' postnatal weight gain but the effect was only moderate. Based on the results of the present study it may be suggested that maternal ID but not thiocyanate feeding affects reproductive performance and postnatal performance of their offspring.     

Effects of peripheral CCK receptor blockade on food intake in rats

Type A cholecystokinin receptor (CCKAR) antagonists differing in blood-brain barrier permeability were used to test the hypothesis that satiety is mediated, in part, by CCK action at CCKARs located peripheral to the blood-brain barrier. At dark onset, non-food-deprived rats received a bolus injection of devazepide (2.5 micromol/kg iv), a 3-h infusion of A-70104 (1 or 3 micromol x kg-1 x h-1 iv), or vehicle either alone or coadministered with a 3-h infusion of CCK-8 (10 nmol x kg-1 x h-1 iv) or a 2-h intragastric infusion of peptone (1 g/h). Food intake was determined from continuous computer recordings of changes in food bowl weight. Devazepide penetrates the blood-brain barrier; A-70104, the dicyclohexylammonium salt of Nalpha-3-quinolinoyl-d-Glu-N,N-dipentylamide (A-65186), does not. CCK-8 inhibited 3-h food intake by more than 50% and both A-70104 and devazepide abolished this response. A-70104 and devazepide stimulated food intake and similarly attenuated the anorexic response to intragastric infusion of peptone. Thus endogenous CCK appears to act, in part, at CCKARs peripheral to the blood-brain barrier to inhibit food intake.     

Effect of moderate protein deficiency on reproduction in the female rat and on the development of the pups until weaning

Two groups of Wistar female rats were respectively fed ad libitum a standard stock diet containing 22 p. 100 protein (n = 93) and a diet containing 7.5 p. 100 protein (n = 189) for 8 weeks. They were mated with male rats of the same strain after 2 weeks of these diets. A small decrease (8 p. 100) in fecundity was observed but this moderate protein deprivation did not affect either the litter size (9.68 +/- 3.50 vs 9.61 +/- 3.69) or the percentage of stillborn pups (4.8 vs 4.9 p. 100). The postnatal mortality of the pups of deprived dams was much higher than that of pups from normal dams (11.2 vs 0.9 p. 100). During the suckling period, the 7.5 p. 100 protein diet did not cover the requirements of the dams. They lost 20 p. 100 of their weight, whereas the weight of the dams fed the 22 p. 100 protein diet remained stable. The weight deficit of the young rats born from deprived dams was about 10 p. 100 at birth but it rose to 50 p. 100 at weaning. During the gestation and suckling periods, the maternal body stores and tissues were mobilized to assure the growth of the young.     

Long-term L-NAME treatment potentiates the blood-brain barrier disruption during pentylenetetrazole-induced seizures in rats

We investigated whether the severity of blood-brain barrier disruption caused by pentylenetetrazole-induced seizures is modified by long-term nitric oxide synthase inhibition in rats. Rats were given N-omega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, in drinking water for 4 weeks, and then treated with pentylenetetrazole to induce seizures. Damage to the blood-brain barrier was investigated using Evans blue dye extravasation. Serum nitric oxide concentration was decreased in L-NAME-treated rats (P<0.01). L-NAME and/or pentylenetetrazole treatments elevated systolic blood pressure of animals (P<0.01). L-NAME caused an increase in the mortality rate after pentylenetetrazole injection leading to the death of animals at about 15 min after the onset of the seizure. Pentylenetetrazole-induced seizures in rats treated with L-NAME caused a significant increase in Evans blue dye extravasation into cerebral cortex, diencephalon and cerebellum, as compared with seizures evoked by pentylenetetrazole injection to L-NAME-untreated rats (P<0.01). Data presented here suggest that the degree of blood-brain barrier disruption induced by seizures is more pronounced in long-term nitric oxide deficiency.