Elevated Body Fat in Rats by the Dietary Nitric Oxide Synthase Inhibitor,L-Nω Nitroarginine

The influence of the dietary nitric oxide (NO) synthase inhibitor, L-N^ω nitroarginine (L-NNA) on body fat was examined in rats. In experiment 1, all rats were fed with the same amount of diet with or without 0.02% L-NNA for 8 wk. L-NNA intake caused elevations in serum triglyceride and body fat, and reduction in serum nitrate (a metabolite of nitric oxide). The activity of hepatic carnitine palmitoyltransferase was reduced by L-NNA. In experiment 2, rats were fed for 8 wk with the same amount of diets with or without 0.02% L-NNA supplemented or not with 4% L-arginine. The elevation in body fat, and the reductions in serum nitrate and in the activity of hepatic carnitine palmitoyltransfererase by L-NNA were all suppressed by supplemental L-arginine. The results suggest that lower NO generation elevated not only serum triglyceride, but also body fat by reduced fatty acid oxidation.     

Feeding the nitric oxide synthase inhibitor L-N(omega)nitroarginine elevates serum very low density lipoprotein and hepatic triglyceride synthesis in rats

This study was conducted to study the influence of dietary L-N(omega)nitroarginine (L-NNA), a nitric oxide (NO) synthase inhibitor, on serum lipids and lipoproteins and on the activities of enzymes related to lipid metabolism in rats. Feeding rats a diet containing 0.2 g/kg L-NNA for 5 weeks elevated serum concentrations of triglyceride, cholesterol, phospholipid, and free fatty acid and reduced serum nitrate (an oxidation product of NO). The elevation in serum triglyceride was mainly due to the elevation in very low density lipoprotein (VLDL) triglyceride. Contents of cholesterol and phospholipid in the VLDL fraction also were elevated by L-NNA. L-NNA treatment caused significantly higher activity of hepatic microsomal phosphatidate phosphohydrolase (the rate-limiting enzyme in triglyceride synthesis) and lower activity of hepatic carnitine palmitoyltransferase (the rate-limiting enzyme in fatty acid oxidation). Activities of hepatic enzymes responsible for fatty acid synthesis such as glucose-6-phosphate dehydrogenase, malic enzyme, and fatty acid synthase were unaffected by L-NNA. The activity of hepatic microsomal phosphocholine cytidyltransferase (the rate-limiting enzyme in phosphatidylcholine synthesis) was reduced significantly by L-NNA. Our results suggest that lower NO production caused the elevations in hepatic triglyceride synthesis by higher esterification of fatty acid and lower fatty acid oxidation, leading to an enrichment of VLDL triglyceride.     

Hypolipidemic and antiperoxidative effect of coconut protein in hypercholesterolemic rats

Effect of coconut protein in rats fed high fat cholesterol containing diet on the metabolism of lipids and lipid peroxides was studied. In addition, effect of coconut protein were compared with rats fed L-arginine. The results indicate that those fed coconut protein and those fed L-arginine showed significantly lower levels of total cholesterol, LDL+ VLDL cholesterol, Triglycerides and Phospholipids in the serum and higher levels of serum HDL cholesterol. The concentration of total cholesterol, triglycerides and phospholipids in the tissues were lower in these groups. There was increased hepatic cholesterogenesis which is evident from the higher rate of incorporation of labeled acetate into free cholesterol. Increased conversion of cholesterol to bile acids and increased fecal excretion of bile acids were observed. Feeding coconut protein results in decreased levels of Malondialdehyde in the heart and increased activity of Superoxide dismutase and Catalase. Supplementation of coconut protein causes increased excretion of urinary nitrate which implies higher rate of conversion of arginine into nitric oxide. In the present study, the arginine supplemented group and the coconut protein fed group produced similar effects. These studies clearly demonstrate that coconut protein is able to reduce hyperlipidemia and peroxidative effect induced by high fat cholesterol containing diet and these effects are mainly mediated by the L-arginine present in it.     

Regulation of lipid flux between liver and adipose tissue during transient hepatic steatosis in carnitine-depleted rats

Rats with carnitine deficiency due to trimethylhydrazinium propionate (mildronate) administered at 80 mg/100 g body weight per day for 10 days developed liver steatosis only upon fasting. This study aimed to determine whether the transient steatosis resulted from triglyceride accumulation due to the amount of fatty acids preserved through impaired fatty acid oxidation and/or from up-regulation of lipid exchange between liver and adipose tissue. In liver, mildronate decreased the carnitine content by approximately 13-fold and, in fasted rats, lowered the palmitate oxidation rate by 50% in the perfused organ, increased 9-fold the triglyceride content, and doubled the hepatic very low density lipoprotein secretion rate. Concomitantly, triglyceridemia was 13-fold greater than in controls. Hepatic carnitine palmitoyltransferase I activity and palmitate oxidation capacities measured in vitro were increased after treatment. Gene expression of hepatic proteins involved in fatty acid oxidation, triglyceride formation, and lipid uptake were all increased and were associated with increased hepatic free fatty acid content in treated rats. In periepididymal adipose tissue, mildronate markedly increased lipoprotein lipase and hormone-sensitive lipase activities in fed and fasted rats, respectively. On refeeding, carnitine-depleted rats exhibited a rapid decrease in blood triglycerides and free fatty acids, then after approximately 2 h, a marked drop of liver triglycerides and a progressive decrease in liver free fatty acids. Data show that up-regulation of liver activities, peripheral lipolysis, and lipoprotein lipase activity were likely essential factors for excess fat deposit and release alternately occurring in liver and adipose tissue of carnitine-depleted rats during the fed/fasted transition.     

Increased hepatic activity of inducible nitric oxide synthase in rats fed on a high-fat diet

The effects were examined of the dietary level of fat on the activity of inducible nitric oxide synthase (iNOS) in the liver of rats. In experiment 1, rats were fed on a diet containing 5% or 20% beef tallow or safflower oil for 32 d. The animals were given a subcutaneous injection of the carcinogen, 1,2-dimethylhydrazine (DMH), on d 4. The activity of hepatic iNOS was significantly elevated by the high-fat diet, but was unaffected by the dietary source of the fat examined. In experiment 2, rats were fed on a 5% or 20% beef tallow diet for 11 d or 32 d with or without the DMH treatment. Feeding the high-fat diet and DMH treatment caused higher activity of hepatic iNOS. In experiment 3, the high-fat diet elevated hepatic iNOS activity and the amount of its protein in the lipopolysaccharide-treated rats. The results suggest that hepatic NO production is enhanced by a high-fat diet.     

Effect of methotrexate on long-chain fatty acid metabolism in liver of rats fed a standard or a defined, choline-deficient diet

The effect of methotrexate on lipids in serum and liver and key enzymes involved in esterification and oxidation of long-chain fatty acids were investigated in rats fed a standard diet and a defined choline-deficient diet. Hepatic metabolism of long-chain fatty acids were also studied in rats fed the defined diet with or without choline. When methotrexate was administered to the rats fed the standard diet there was a slight increase in hepatic lipids and a moderate reduction in the serum level. The palmitoyl-CoA synthetase activity and the microsomal glycerophosphate acyltransferase activity in the liver of rats were increased by methotrexate. The data are consistent with those where the liver may fail to transfer the newly formed triacylglycerols into the plasma with a resultant increase in liver triacylglycerol content and a decrease in serum lipid levels. Fatty liver of methotrexate-exposed rats can not be attributed simply to a reduction of fatty acid oxidation as the carnitine palmitoyltransferase activity was increased. The methotrexate response in the rats fed the defined choline-deficient diet was different. There was a reduction in both serum and hepatic triacylglycerol and the glycerophosphate acyltransferase and palmitoyl-CoA synthetase activities. The carnitine palmitoyltransferase activity was unchanged. Hepatomegaly and increased hepatic fat content, but decreased serum triacylglycerol, total cholesterol and HDL cholesterol were found to be related to the development of choline deficiency as the pleiotropic responses were almost fully prevented by addition of choline to the choline-deficient diet. Addition of choline to the choline-deficient diet normalized the total palmitoyl-CoA synthetase and carnitine palmitoyltransferase activities. In contrast to methotrexate exposure, choline deficiency increased the mitochondrial glycerophosphate acyltransferase activity. The data are consistent with those of where fatty liver induction of choline deficiency may be related to an enhanced esterification of long-chain fatty acids concomitant with a reduction of their oxidation.     

Randomly interesterified triacylglycerol containing medium- and long-chain fatty acids stimulates fatty acid metabolism in white adipose tissue of rats

We have reported previously that randomly interesterified triacylglycerol containing medium- and long-chain fatty acids in the same glycerol molecule (MLCT) resulted in significantly lower body fat accumulation and higher hepatic fatty acid oxidation than from long-chain triacylglycerol (LCT) in rats. To understand the metabolic changes occurring in white adipose tissue, the fatty acid oxidation and synthesis, and the adipocytokine level were measured in rats fed with MLCT or LCT for 2 weeks. In comparison with LCT, MLCT lowered not only the fatty acid synthase and glycerol-3-phosphate dehydrogenase activities in perirenal adipose tissue, but also the serum insulin and leptin levels, in addition to significantly reducing the body fat accumulation. In contrast, fatty acid oxidation measured as the carnitine palmitoyltransferase activity in the tissue was significantly higher in the MLCT-fed rats than in the LCT-fed rats. It seems that the altered fatty acid metabolism in adipose tissue per se was also responsible for the lower adiposity by dietary MLCT.     

Effect of Cheonggukjang supplementation upon hepatic acyl-CoA synthase, carnitine palmitoyltransferase I, acyl-CoA oxidase and uncoupling protein 2 mRNA levels in C57BL/6J mice fed with high fat diet

This study investigated the effect of Cheonggukjang on mRNA levels of hepatic acyl-CoA synthase (ACS), carnitine palmitoyltransferase I (CPT-I), acyl-CoA oxidase (ACO) and uncoupling protein 2 (UCP2), and on serum lipid profiles in C57BL/6J mice. Thirty male C57BL/6J mice were divided into three groups; normal diet (ND), high fat diet (HD) and high fat diet with 40% Cheonggukjang (HDC). Energy intake was significantly higher in the HDC group than in the ND and HD groups. The HDC group normalized in weight gain, epididymal and back fat (g/100 g) accumulation which are increased by high fat diet. Serum concentrations of triglyceride and total cholesterol in the HDC were significantly lower than those in the HD group. These results were confirmed by hepatic mRNA expression of enzymes and protein (ACS, CPT-1, ACO, UCP2) which is related with lipid metabolism by RT-PCR. Hepatic CPT-I, ACO and UCP2 mRNA expression was increased by Cheonggukjang supplementation. We demonstrated that Cheonggukjang supplement leads to increased mRNA expressions of enzymes and protein involved in fatty acid oxidation in liver, reduced accumulation of body fat and improvement of serum lipids in high fat diet fed mice.     

一氧化氮参与低氧脑血管张力调节

本工作是初生小牛基底动脉血管条上,用一氧化氮合成酶抑制剂－Ｌ－硝基精氨酸研究ＮＯ及内皮细胞在低氧脑血管扩张机制中的作用。实验结果表明,Ｌ－ＮＮＡ可减弱低氧扩血管作用,但减少的值要小于常氧下相同浓度Ｌ－ＮＮＡ所引起的作用。     

The influence of nitric oxide on basal and cholecystokinin-8-induced proliferation and apoptosis in the rat pancreas

Nitric oxide (NO) is formed by different cell types in the pancreas. In this study, inhibition of endogenous nitric oxide by N(omega)-nitro-L-arginine (L-NNA) reduced the urinary excretion of NO(2)/NO(3) and raised serum L-arginine and the NO donator S-nitroso-N-acetylpenicillamine (SNAP) increased the urinary excretion of NO(2)/NO(3). The peptide cholecystokinin-8 (CCK-8) has a strong influence on exocrine pancreatic proliferation. Rat pancreas was excised and studied with regard to tissue weight, protein and DNA contents after 3 days of treatment with saline, L-NNA or SNAP given separately or combined with CCK-8. Further, proliferation of different pancreatic cells was studied with [3H]-thymidine incorporation and apoptotic activity was studied by analysing caspase-3 activity and histone-associated DNA fragments. The effects of L-NNA indicate that endogenous nitric oxide formation has a tonic inhibition on apoptosis in the pancreas during both basal condition and growth stimulation by CCK-8. In CCK-induced hyperplasia, NO inhibits the proliferation of acinar cells but stimulates ductal cells. Endogenous NO may regulate the balance between proliferation and apoptosis and in a situation of growth stimulation by CCK-8, it has a tonic inhibition on both mitogenesis and apoptosis thus slowing down the acinar cell turnover in the pancreas.     

Effect of L-arginine and the nitric oxide synthase blocker L-NNA on calcium capacity in rat liver mitochondria with differing resistance to hypoxia

The effect of L-arginine and blockator of nitric oxide synthase L-NNA on processes of calcium mitochondrial capacity in liver with different resistance to hypoxia in the experiments with Wistar rats has been studied using the followrng substrates of energy support: succinic, alpha-ketoglutaric acids, alpha-ketolutarate and inhibitor succinatedehydrogenase malonate. As well we used substrates mixtures combination providing for activation of aminotransferase mechanism: glutamate and piruvate, glutamate and malate. It has been shown that L-arginine injection increases calcium mitochondrial capacity of low resistant rats using as substrates the succinate and alpha-ketoglutarate to control meanings of high resistance rats. Effects of donors nitric oxide on this processes limit NO-synthase inhibitor L-NNA.     

Biometric evidence of diet-induced obesity in Lew/Crl rats

Although Lew/Crl rats are central to a classic model of renal transplantation and may provide a valid system for evaluating the effect of obesity on transplantation outcomes, their response to high-fat diet has not been evaluated sufficiently. The objective of this study was to evaluate biometric and basic metabolic data of Lew/Crl rats fed a 60% kcal, lard-based, very high-fat diet (HFD) compared with those fed a 10% kcal fat control diet (CD). Rats were maintained for 17 wk; body parameters and caloric intake were monitored weekly. Biometric data were collected and calculated before and after euthanasia. Serum was evaluated for liver enzyme activity and total bilirubin, glucose, triglyceride, cholesterol, insulin, leptin, and creatinine concentrations, and urine was evaluated for protein, glucose, specific gravity, and ketones. Tissues were harvested, weighed, and evaluated histologically. Compared with CD rats, HFD rats consumed more calories and weighed more after 3 wk. After 17 wk, HFD rats had significantly increased body weight, girth, volume, epididymal fat pad weight, omental weight, and body fat. In addition, HFD rats had mild elevations in some liver enzymes and a lower serum triglyceride concentration than did CD rats. Histologic assessment and other metabolic markers of disease were not different between the 2 groups. Lew/Crl rats fed a 60% kcal HFD become obese, but they lack significant metabolic abnormalities frequently associated with obesity in other rat strains.     

Increased L-arginine uptake and inducible nitric oxide synthase activity in aortas of rats with heart failure

L-Arginine crosses the cell membrane primarily through the system y(+) transporter. The aim of this study was to investigate the role of L-arginine transport in nitric oxide (NO) production in aortas of rats with heart failure induced by myocardial infarction. Tumor necrosis factor-alpha levels in aortas of rats with heart failure were six times higher than in sham rats (P < 0.01). L-Arginine uptake was increased in aortas of rats with heart failure compared with sham rats (P < 0.01). Cationic amino acid transporter-2B and inducible (i) nitric oxide synthase (NOS) expression were increased in aortas of rats with heart failure compared with sham rats (P < 0.05). Aortic strips from rats with heart failure treated with L-arginine but not D-arginine increased NO production (P < 0.05). The effect of L-arginine on NO production was blocked by L-lysine, a basic amino acid that shares the same system y(+) transporter with L-arginine, and by the NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Treatment with L-lysine and L-NAME in vivo decreased plasma nitrate and nitrite levels in rats with heart failure (P < 0.05). Our data demonstrate that NO production is dependent on iNOS activity and L-arginine uptake and suggest that L-arginine transport plays an important role in enhanced NO production in heart failure.     

Influence of nitric oxide synthase inhibitors on the vasopressin-induced pituitary-adrenocortical activity and hypothalamic catecholamine levels.

In the present study the role of endogenous nitric oxide (NO) in the vasopressin-induced ACTH and corticosterone secretion was investigated in conscious rats. Vasopressin (AVP 5 microg/kg i.p.) considerably augmented ACTH and corticosterone secretion. L-arginine (120 and 300 mg/kg i.p.) did not significantly alter the AVP-induced secretion of those hormones. Nitric oxide synthase (NOS) blockers N(omega)-nitro-L-arginine (L-NNA) and its methyl ester (L-NAME) given i.p. 15 min before AVP markedly increased the AVP-induced ACTH secretion. L-NNA (2 mg/kg) more potently and significantly increased the AVP-induced ACTH secretion, whereas L-NAME elicited a weaker and not significant effect. Both those NOS antagonists intensified significantly and to a similar extent the AVP-induced corticosterone secretion. L-arginine (120 mg/kg i.p.) reversed the L-NNA-induced rise in the AVP-stimulated ACTH secretion and substantially diminished the accompanying corticosterone secretion. Neither vasopressin alone nor in combination with L-arginine and L-NAME evoked any significant alterations in the hypothalamic noradrenaline and dopamine levels. L-NNA (2 and 10 mg/kg i.p.) elicited a dose dependent and significant decrease in the hypothalamic noradrenaline level. The hypothalamic dopamine level was not significantly altered by any treatment. These results indicate that in conscious rats endogenous NO has an inhibitory influence on the AVP-induced increase in ACTH and corticosterone secretion. L-NNA is significantly more potent than L-NAME in increasing the AVP-induced ACTH secretion. This may be connected with a considerable increase by L-NNA of hypothalamic noradrenergic system activation which stimulates the pituitary-adrenal axis in addition to specific inhibition of NOS.     

The effect of nitric oxide donors and L-arginine on the gastric electrolyte barrier.

The potential difference across the stomach wall (PD) is determined by the gastric mucosal barrier. The decrease in the PD evoked by "the barrier breakers", e.g. aspirin, ethanol or bile acids is believed as a sensitive index of the mucosal damage. The effect of glyceryl trinitrate (GTN), isosorbide dinitrate (IDN) and molsidomine (MOL)--all exogenous donors of nitric oxide (NO), as well as L-arginine (L-ARG), which is a substrate for NO-synthase and Nomega-nitro-L-arginine (L-NNA), a non-selective NO synthase inhibitor on the gastric electrolyte barrier were studied against the gastric damage induced by ethanol. All NO donors given intragastrically alone caused only moderate, not significant changes in the PD and failed to affect the mucosal barrier, while L-NNA slightly decreased the PD. The NO donors and L-arginine applied as pretreatment prior to ethanol resulted in diminishing of its damaging action that was similar for all these drugs, while L-NNA intensified both the injury and the drop in the PD values caused by ethanol. In summary, our results showed the protective effect of endogenous nitric oxide from L-ARG and that originating from GTN, MOL and IDN on the gastric electrolyte barrier, supporting involvement of nitric oxide in the mechanism of gastric protection in the stomach.     

Role of nitric oxide in hypoxia inhibition of fever.

Hypoxia causes a regulated decrease in body temperature (T(b)), and nitric oxide (NO) is now known to participate in hypoxia-induced hypothermia. Hypoxia also inhibits lipopolysaccharide (LPS)-induced fever. We tested the hypothesis that NO may participate in the hypoxia inhibition of fever. The rectal temperature of awake, unrestrained rats was measured before and after injection of LPS, with or without concomitant exposure to hypoxia, in an experimental group treated with N(omega)-nitro-L-arginine (L-NNA) for 4 consecutive days before the experiment and in a saline-treated group (control). L-NNA is a nonspecific NO synthase inhibitor that blocks NO production. LPS caused a dose-dependent typical biphasic rise in T(b) that was completely prevented by hypoxia (7% inspired oxygen). L-NNA caused a significant drop in T(b) during days 2-4 of treatment. When LPS was injected into L-NNA-treated rats, inhibition of fever was observed. Moreover, the effect of hypoxia during fever was significantly reduced. The data indicate that the NO pathway plays a role in hypoxia inhibition of fever.     

Pressor effect of NG-nitro-L-arginine in pentobarbital-anesthetized rats

The pressor effect of NG-nitro-L-arginine (L-NNA), a potent inhibitor of nitric oxide (NO) synthesis, was studied in pentobarbital anesthetized rats. Iv injections of L-NNA from 0.25 to 8 mg/kg caused bradycardia and a dose-dependent increase in mean arterial pressure (MAP) with a maximal response of 43 +/- 5 mmHg and ED50 value of 1.3 +/- 0.2 mg/kg. The time course of the response to the injection of a single dose of L-NNA was also determined. Peak response was reached 60 min after the injection of a single dose (4 mg/kg, iv) and the effect lasted greater than 5 h. The rising phase of the pressor response was accompanied by slight bradycardia while the recovery phase was associated with significant tachycardia. Iv injections of L-arginine (12.5-200 mg/kg) caused transient dose-dependent reductions in MAP. The pressor effect of L-NNA (4 mg/kg, iv bolus) was dose-dependently attenuated by L-arginine. The results show that L-NNA is an efficacious and long-acting pressor agent and are consistent with the hypothesis that endogenous NO plays an important role in the regulation of blood pressure.     

Effect of L-arginine analogs and a calcium chelator on nitric oxide (NO) production by Leishmania sp

Leishmania amazonensis, L. braziliensis and L. chagasi promastigotes were grown in the presence of L-arginine analogs such as Nomega-nitro-L-arginine methyl ester (L-NAME), NG-nitro-L-arginine (L-NNA) and D-arginine (an inactive L-arginine isomer), besides an intracellular calcium chelator [ethylene glycol-bis (beta-aminoethyl ether)-N,N,N',N'-tetra acetic acid; EGTA] to verify the importance of L-arginine metabolism and the cofactors for these parasites. The parasite's growth curve was followed up and the culture supernatants were used to assay nitric oxide (NO) production by the Griess reaction. The results showed a significant effect of L-arginine analogs on NO production by all Leishmania species studied, especially L-NAME, an irreversible inhibitor of the constitutive nitric oxide synthase (cNOS). When L. amazonensis promastigotes were pre-incubated with L-NAME, the infection range of the murine macrophages was lowered to 61% in 24 h and 19% after 48 h. These data demonstrated that the parasite NO pathway is important to the establishment of the infection.     

Mechanisms of liver steatosis in rats with systemic carnitine deficiency due to treatment with trimethylhydraziniumpropionate

Rats with systemic carnitine deficiency induced by treatment with trimethylhydraziniumpropionate (THP) develop liver steatosis. This study aims to investigate the mechanisms leading to steatosis in THP-induced carnitine deficiency. Rats were treated with THP (20 mg/100 g) for 3 or 6 weeks and were studied after starvation for 24 h. Rats treated with THP had reduced in vivo palmitate metabolism and developed mixed liver steatosis at both time points. The hepatic carnitine pool was reduced in THP-treated rats by 65% to 75% at both time points. Liver mitochondria from THP-treated rats had increased oxidative metabolism of various substrates and of beta-oxidation at 3 weeks, but reduced activities at 6 weeks of THP treatment. Ketogenesis was not affected. The hepatic content of CoA was increased by 23% at 3 weeks and by 40% at 6 weeks in THP treated rats. The cytosolic content of long-chain acyl-CoAs was increased and the mitochondrial content decreased in hepatocytes of THP treated rats, compatible with decreased activity of carnitine palmitoyltransferase I in vivo. THP-treated rats showed hepatic peroxisomal proliferation and increased plasma VLDL triglyceride and phospholipid concentrations at both time points. A reduction in the hepatic carnitine pool is the principle mechanism leading to impaired hepatic fatty acid metabolism and liver steatosis in THP-treated rats. Cytosolic accumulation of long-chain acyl-CoAs is associated with increased plasma VLDL triglyceride, phospholipid concentrations, and peroxisomal proliferation.     

NO介质在大鼠红藻氨酸诱导癫痫发作中的作用

目的：进一步探讨脑内一氧化氮(NO)介质(NO或NO衍生物)在复杂部分性及全身强直阵挛性癫痫发作中的作用。方法：采用红藻氨酸(KA)诱导大鼠癫痫发作,以NO合酶抑制剂L-硝基精氨酸(L-NNA)或NO前体L-精氨酸(L-Arg)予以预处理,观察其癫痫发作行为及海马结构内NO含量(NO2^-/NO3^-)的变化。结果：给予大鼠惊厥剂量KA(10mg/kg),15min时出现湿狗样抖动(WDS),1～3h出现全身痉挛;经L-NNA(50mg/kg)或L-Arg(40mg/kg)预处理的大鼠,注射相同剂量的KA后,其癫痫行为发生明显变化,L-NNA预处理的大鼠癫痫发作行为明显加重,表现为全身痉挛的潜伏期缩短、时间延长、死亡率提高;L-Arg预处理的大鼠癫痫发作行为减弱,WDS和全身痉挛的潜伏期均延长,发作程度减轻、时间缩短,观察时间内无一例死亡。KA给药后30min海马结构内的NO2^-/NO3^-含量迅速增多,7d时仍持续增高;与NS预处理组相比,经L-Arg预处理的动物,KA给药后3h及3d,其NO2^-/NO3^-浓度升高明显。结论：兴奋诱导性癫痫发作过程中内源性NO介质的变化可能具有重要的抗发作作用。