Protective effect of oral -arginine administration on gentamicin-induced renal failure in rats

We investigated the effects of orally supplemented -arginine, the substrate of nitric oxide (NO) and N^ω-nitro- -arginine methyl ester ( -NAME), a nitric oxide-synthase inhibitor in gentamicin-induced renal failure. Rats were given gentamicin (100 mg/kg/day s.c.), gentamicin and -arginine (2 g/l, drinking water), gentamicin and -NAME (100 mg/l, drinking water) or gentamicin plus -arginine and -NAME. After 8 days, the gentamicin group developed marked renal failure, characterized by a significantly decreased creatinine clearance and increased blood creatinine, fractional excretion of sodium, fractional excretion of lithium, urine gamma glutamyl transferase, systolic blood pressure and daily urine volume when compared to controls. Renal histological analysis confirmed tubular necrosis. -arginine administration caused normalization of these parameters, whereas -NAME led to aggravation of the failure. Concomittant administration of -NAME and -arginine to gentamicin-treated rats caused no significant changes when compared to the rats receiving gentamicin alone. We conclude that -arginine supplementation has beneficial effects in gentamicin-induced renal failure in rats and that these effects are reversed by the NO-synthase inhibitor, -NAME.     

URINARY NO3− EXCRETION AS AN INDICATOR OF NITRIC OXIDE FORMATION IN VIVO DURING ORAL ADMINISTRATION OF l-ARGININE OR l-NAME IN RATS

• 1 Endothelium-derived nitric oxide (NO), a major modulator of vascular tone, is synthesized from the terminal guanidino nitrogen of l -arginine. This reaction is inhibited by analogues of l -arginine, such as N-nitro-l -arginine methyl ester (l -NAME). Many of the biological effects of NO are mediated by the second messenger cGMP. NO is rapidly oxidized to NO₃^? which, like cGMP, is eliminated via excretion into the urine. In a placebo controlled study, we investigated whether oral bolus administration of l -arginine and l -NAME affects the urinary excretion rates of NO₃^? and cGMP in Munich Wistar Frömmter (MWF) rats.
• 2 Twenty MWF rats were kept in metabolic cages and received l -arginine (3 g/kg body weight), l -NAME (50mg/kg), or placebo (0.9% saline) in randomized order. Urine samples were sequentially collected for 10 h and analysed for creatinine, NO₃^? and cGMP.
• 3 l -Arginine induced a slight, but prolonged increase in urine flow, whereas l -NAME induced an early, transient increase in urine flow which was followed by a decrease. Creatinine clearance decreased by 65% after l -NAME, but was not affected by l -arginine or placebo.
• 4 Urinary NO₃^? and cGMP excretion rates transiently increased after l -arginine (NO₃^?: + 29%; cGMP: + 16%) for 4–5h, whereas l -NAME induced an immediate, pronounced and lasting inhibition of urinary NO₃^? and cGMP excretion (NO₃^?:-76%; cGMP:-46%). Urinary NO₃^? and cGMP excretions were significantly correlated (r = 0.755; P< 0.001).
• 5 Urinary excretion rates of NO₃^? and cGMP, expressed as μmol/h, were correlated to urine flow (mL/h; r = 0.617 and 0.649, respectively; both P<0.05), whereas after correction by urinary creatinine (μmol/mmol creatinine) no correlation with urine flow was observed, indicating that these excretion rates were independent of renal excretory function. Thus we conclude that changes in the urinary excretion rates of NO₃^? and cGMP represent changes in NO production rates in vivo when expressed in relation to urinary creatinine. Urinary NO₃^? and cGMP excretion is modulated by acute NO synthase inhibition or substrate provision.

     

The Protective Effect of Glycine in Cisplatin Nephrotoxicity: Inhibition with NG-Nitro-l-arginine Methyl Ester

Abstract— The effect of glycine on the acute changes in renal haemodynamics and nephrotoxicity produced by cisplatin was investigated in the rat. Cisplatin (6·0 mg kg^?1, i.v.) injection in anaesthetized rats produced, over a period of 2 h, falls of approximately 50% in renal blood flow (RBF) and the clearance of [³H]inulin (CL_IN), effects which were prevented by co-administration of glycine (1·0 g kg^?1). Infusion of the nitric oxide (NO) synthase-inhibitor N^G-nitro-l -arginine methyl ester, l -NAME (10 μg min^?1 kg^?1, i.v.), abolished glycine's ability to maintain RBF in cisplatin-injected rats whilst partially inhibiting the ability of glycine to preserve CL_IN. Treatment of cisplatin-injected rats with glycine (1·0 g kg^?1, i.v.) significantly ameliorated the nephrotoxic effects of cisplatin (6·0 mg kg^?1) as judged by improvements in a range of indices of renal function which included plasma urea and creatinine concentrations, urine output, sodium excretion, CL_IN and the clearance of [¹⁴C]p-aminohippurate. Administration of l -NAME (1·0 mg kg^?1, i.v.) to rats which received cisplatin and glycine significantly inhibited the reno-protective effect of glycine. However, l -NAME administration to rats which were treated only with cisplatin did not result in any potentiation of cisplatin nephrotoxicity. The findings of this study suggest that glycine can block the acute falls in RBF and C_IN produced by cisplatin by a mechanism which involves the production of NO. Furthermore, the results indicate that these renal haemodynamic actions of glycine are responsible, at least in part, for the ability of this amino acid to ameliorate cisplatin nephrotoxicity.     

Nitric Oxide Modulates the Acute Increase of Gastrointestinal Transit Induced by Endotoxin in Rats: a Possible Role for Tachykinins

Because of the evidence that endogenous nitric oxide (NO) plays an essential role in the physiological regulation of gastrointestinal motility we have investigated, by use of the NO synthase inhibitor, N^G-nitro-l -arginine methyl ester (l -NAME), the role of endogenous NO in the acute endotoxin-induced changes of gastrointestinal transit. Pre-treatment with E. coli endotoxin (100 μg kg^?, i.v.) induced a significant increase in the gastrointestinal transit of a charcoal suspension in anaesthetized rats. Previous administration of the NO synthase inhibitor, l -NAME (10 mg kg^?, i.v.) significantly prevented the effects of endotoxin. l -arginine (200 mg kg^?, i.v.) and the substance P antagonist [d -Pro², d -Trp^7,9]-substance P (SPA), significantly reversed the effects of l -NAME on gastrointestinal transit in rats treated with endotoxin. Pre-treatment with dexamethasone (5 mg kg^?, s.c., twice), an inhibitor of the expression of inducible NO synthase, did not affect the increase in the gastrointestinal transit through constitutive NO synthesis. The results suggest that constitutive nitric oxide is involved in the increase of gastrointestinal transit induced by endotoxin and that the reduction in transit induced by l -NAME in endotoxin-treated rats is mediated by endogenous tachykinins.     

Involvement of nitric oxide in the response to 5-hydroxytryptamine in the rat in-vivo

Abstract— The involvement of nitric oxide (NO) in the effects of 5-HT on intestinal secretion and cardiovascular function in anaesthetized rats was investigated using N^G-nitro-l -arginine methyl ester (l -NAME), a specific NO-synthase antagonist, and its optical isomer d -NAME. l -NAME significantly reduced the prolonged hypotensive response to 5-HT. It also caused a small rightward shift in the colonic 5-HT dose-response curve. This suggests that NO plays a significant role in the prolonged hypotensive response to 5-HT, and may make a small contribution to the secretory response of the colon, but not that of the jejunum, in the rat in-vivo.     

NG-Nitro-l-arginine methyl ester inhibits the effect of an H3-histaminergic receptor agonist on NANC contraction in guinea-pig perfused bronchioles

Abstract— A role for nitric oxide in the H₃-histaminergic agonist-induced inhibition of the non-adrenergic, non-cholinergic (NANC) contraction has been studied in guinea-pig perfused bronchioles. (R)-α-Methylhistamine ((R)-α-MeHA), an agonist for H₃ receptors, inhibited the NANC contraction induced by electrical field stimulation. N^G-Nitro-l -arginine methyl ester (l -NAME) (50 μm ), an inhibitor of nitric oxide synthesis, blocked the effect of (R)-α-MeHA. The effect of l -NAME was reversed by l -arginine (50 μm ). l -NAME, l -arginine or (R)-α-MeHA were without effect on exogenous substance P- or neurokinin A-induced contractile responses of the perfused bronchioles. These results show that an H₃-agonist inhibited the release of neurotransmitters in NANC nerve endings of guinea-pig perfused bronchioles presumably by production of nitric oxide.     

EFFECTS OF FR139317 ON RENAL RESPONSES TO ACUTE NITRIC OXIDE BLOCKADE IN ANAESTHETIZED RATS

1. Effects of FR139317, an endothelin ET_A receptor antagonist, on renal haemodynamic and excretory responses to acute nitric oxide (NO) blockade were examined using anaesthetized rats. 2. Intrarenal arterial infusion of N^G-nitro-l -arginine (NOARG), the NO synthase inhibitor, at a rate of 40 μg/kg per min, produced a significant decrease in renal blood flow, with no change in systemic blood pressure. There were significant decreases in urine flow and urinary excretion of sodium during infusion of NOARG. In animals pretreated with FR139317, similar renal responses to the NOARG infusion were observed. 3. These results suggest that an action of endothelin-1 via ET_A receptors does not greatly contribute to the renal haemodynamic and excretory responses to acute blockade of renal NO production.     

NG-Nitro-L-Arginine-Methyl-Ester Protects against Ischaemia-Induced Biochemical Changes and Hippocampal Neurodegeneration in the Gerbil

To assess the effects of the nitric oxide inhibitor N^G-nitro-l -arginine methyl ester (L-NAME) on behavioural, biochemical and histological changes following global ischaemia, the Mongolian gerbil was used. Ischaemia was induced by bilateral carotid occlusion (BCO) for 5 min. N^G-nitro-l -arginine methyl ester was administered i.p. at 10 mg/kg 30 min, 6, 24, and 48 h after surgery. Results indicated that 5 min BCO caused a large increase in home cage activity. N^G-nitro-l -arginine methyl ester caused some attenuation in this hyperactivity. The activity of nitric oxide synthase (NOS) was increased in the cerebellum, brain stem, striatum, cerebral cortex and hippocampus of 5-min bilateral carotid occluded animals. N^G-nitro-l -arginine methyl ester reversed the increase in nitric oxide synthase activity in all brain regions. Extensive neuronal death was observed in the CA₁ layer of the hippocampus in 5-min BCO animals 96 h after surgery. N^G-nitro-l -arginine methyl ester significantly protected against the neuronal death of cells in the CA₁ layer.     

Distribution and metabolism of N G-nitro-l-arginine methyl ester in patients with septic shock

Objective: The pharmacokinetics of N ^G-nitro-l-arginine methyl ester (l-NAME), an inhibitor of nitric oxide (NO) synthesis, was investigated in patients with septic shock. Methods: Blood was sampled at intervals before, during and after 12-h infusion of l-NAME 1 mg · kg⁻¹ · h⁻¹ in nine septic shock patients for determination of plasma concentrations by high-performance liquid chromatography (HPLC). In three patients the renal clearance of the drug was determined. Results: Incubation of l-NAME with plasma and blood in vitro revealed hydrolysis to N ^G-nitro-l-arginine (l-NOARG), the active inhibitor of NO synthesis. l-NOARG did not undergo further degradation. Continuous intravenous infusion of 1 mg · kg⁻¹ · h⁻¹ of l-NAME for 12 h in patients with septic shock increased blood pressure and resulted in increasing plasma concentrations of l-NOARG (C_max 6.2 μg · ml⁻¹ at 12 h) whereas l-NAME concentrations reached a plateau within 1.5 h (C_max 1.0 μg · ml⁻¹). After the infusion was stopped l-NAME disappeared from the plasma rapidly (half-life 19.2 min) whereas l-NOARG concentration declined slowly (half-life 22.9 h). The calculated volume of distribution for l-NAME was 0.45 l · kg⁻¹ body weight and 1.96 l · kg⁻¹ for l-NOARG. The renal clearance for l-NOARG was 3.5% of total body clearance for l-NOARG, whereas l-NAME could not be detected in urine. Conclusion: We conclude that vasoconstriction with l-NAME in septic patients may result from hydrolysis to l-NOARG, the active inhibitor of NO synthesis. The long plasma half-life and large volume of distribution for l-NOARG suggests extensive distribution to extravascular tissues. Since renal excretion is minimal, elimination of the metabolite l-NOARG follows other pathways. Received: 13 March 1998 / Accepted in revised form: 30 June 1998     

Involvement of NO/cGMP pathway in toluene-induced locomotor hyperactivity in female rats

Rationale Nitric oxide (NO) is implicated in the acute locomotor activating effects of some addictive drugs such as amphetamine, caffeine, and PCP, but has not been investigated in the case of toluene.Objectives This study determined the contribution of the NO-cyclic GMP (cGMP) pathway to locomotor stimulant effects of toluene.Methods Locomotor activity was measured for 90 min immediately following toluene (500–1,000 mg/kg, IP) or corn oil treatments in Sprague-Dawley female rats. A NO generator, sodium nitroprusside (SNP) (3 and 6 mg/kg), a NO precursor, l-arginine (l-Arg) (250 mg/kg), a NO synthase inhibitor,N^G-nitro-l-arginine methyl ester (l-NAME) (5–20 mg/kg, IP), and a soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 mg/kg) were injected 5 min before toluene (750 mg/kg, IP) treatment. The combination effects of SNP with l-NAME, l-arginine with l-NAME, SNP with ODQ and l-arginine with ODQ on toluene-induced locomotor hyperactivity were also determined.Results The locomotor hyperactivity induced by toluene was significantly inhibited by SNP and l-arginine, but enhanced by l-NAME and ODQ. SNP and l-arginine completely reversed the combined effects of l-NAME and toluene to a basal level and abolished the enhancing effects of ODQ.Conclusions The results suggested that NO/cGMP-dependent mechanism might be involved in toluene-induced locomotor activity in rats.     

Anti-nociceptive activity of nitric oxide synthase inhibitors in the mouse: dissociation between the effect of l-NAME and l-NMMA

Abstract— The anti-nociceptive effect of selective inhibitors of nitric oxide synthase has been assessed in a formalin-induced paw-licking model in mice. l -N^G-Nitro arginine methyl ester (l -NAME) but not l -N^G-monomethyl arginine (l -NMMA) exhibited anti-nociceptive activity in both the early and late phases of paw licking following intraperitoneal administration. The effect on the late phase response was more pronounced. l -NAME (0·1–100 μg) and l -N^G-nitro arginine base (l -NOARG; 10 μg) but not d -NAME (10 μg) were also anti-nociceptive following intracerebroventricular administration. l -NAME (10 μg) administered by this route did not influence locomotor activity. l -NMMA was inactive at doses up to 40 μg by this route. At higher doses (75–200 μg) l -NMMA produced a similar and non-dose related reduction in early/late phase paw-licking time. d -NMMA (100 μg) was inactive. The greater anti-nociceptive effect of l -NAME in this model accords with recently published biochemical data indicating that l -NAME is several orders of magnitude more potent than l -NMMA as an inhibitor of brain nitric oxide synthase. These data support the use of l -NAME as a selective tool to investigate the central pharmacological effects of nitric oxide.     

Nitric oxide synthase inhibition blocks phencyclidine-induced behavioural effects on prepulse inhibition and locomotor activity in the rat

The ability of the nitric oxide synthase inhibitor, N ^G-nitro-L-arginine methyl ester (L-NAME), to block the behavioural effects of the potent psychotomimetic, phencyclidine, was tested in rats using two different behavioural models. L-NAME was found to block both phencyclidine-induced disruption of prepulse inhibition of acoustic startle and phencyclidine-induced stimulation of locomotor activity. A selective action of L-NAME on the effects of phencyclidine was indicated, since L-NAME did not alter the effects of amphetamine, another potent psychotomimetic, in these behavioural models. These observations suggest that a nitric oxide-dependent mechanism may be involved in the effects of phencyclidine in the central nervous system. Received: 2 September 1996/Final version: 21 December 1996     

Exogenous L‐arginine attenuates the effects of angiotensin II on renal hemodynamics and the pressure natriuresis–diuresis relationship

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Negative modulation of nitric oxide production by neurotensin as a putative mechanism of the diuretic action of SR 48692 in rats

1. We investigated the effect of the non-peptide neurotensin (NT) antagonist SR 48692 on renal function in rats and the involvement of nitric oxide (NO) in the diuretic action of this compound.
2. In fed animals, SR 48692 dose-dependently (0.5 to 12.5 mg kg⁻¹, p.o., 0.03 to 1 mg kg⁻¹, i.p. and 0.1 to 1 μg/rat, i.c.v.) increased urine output and urinary excretion of Na⁺, K⁺ and Cl⁻ and reduced urine osmolality. The diuretic activity was also evident in water-deprived, fasted animals and in fasted, water-loaded rats.
3. NT (0.1 μg/rat, i.c.v.) had no effect on urine output in fed rats, but reduced the diuretic action of SR 48692 (1 μg/rat, i.c.v.). The opposite result was obtained in fasted, water-loaded animals: NT dose-dependently (0.01 and 0.1 μg/rat, i.c.v.) inhibited diuresis and this effect was significantly inhibited by i.c.v. SR 48692. In this experimental condition, SR 48692 did not further increase the on-going diuresis.
4. The NO synthesis inhibitor N^ω-nitro-L-arginine methyl ester (L-NAME; 30 mg kg⁻¹, i.p.) alone had no effect on urine output in fed rats but prevented the diuretic action of i.c.v. or i.p. SR 48692; L-arginine (1 g kg⁻¹, i.p.) but not D-arginine (1 g kg⁻¹, i.p.) restored the SR 48692-dependent increase in diuresis. L-NAME had no effect on furosemide-stimulated diuresis.
5. Systemically administered L-NAME or i.c.v. NT in fasted, water-loaded rats significantly reduced water diuresis but this effect was no longer seen in animals given i.p. L-arginine. Rats receiving i.c.v. NT, whose diuresis was significantly reduced, also excreted less nitrates and nitrites in urine.
6. Increased diuresis after central or systemic administration of SR 48692 to fed rats was paralleled by increased urinary excretion of nitrates and nitrites, this being consistent with peripheral enhancement of NO production after NT-receptor blockade by SR 48692. The increase in diuresis after furosemide also involved an increase of nitrates and nitrites in urine, but this effect was about half that attained with an equipotent diuretic dose of SR 48692.
7. In fed rats, the NO donor isosorbide-dinitrate, reduced systolic blood pressure (unlike SR 48692 which did not affect blood pressure) but also dose-dependently (1 and 5 mg kg⁻¹, i.p.) stimulated urine output.
8. The overall effects of SR 48692 strongly support a link between the actions of endogenous NT, AVP and peripheral NO production in the modulation of renal excretion of water, Na⁺, K⁺ and Cl⁻.

     

Involvement of the renal kallikrein-kinin system in K(+)-induced diuresis and natriuresis in anesthetized rats

Intravenous infusion of a high-K(+) solution (67.5 mM KCl, 67.5 mM NaCl) to anesthetized rats increased urine volume by 47.6% after 60 min, compared with infusion of a Na(+) solution (135 mM NaCl). This treatment also increased urinary excretion of Na(+) by 32.2%, in parallel with an increase in excretion of K(+) or Cl(-). Urinary excretion of kallikrein increased within 60 min after the start of K(+) infusion. A bradykinin B(2) receptor antagonist, 8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-me thylamino ]-2,6-dichlorobenzyloxy]-2-methylquinoline (FR173657; 1.0 mg/kg, i.v. ), inhibited the K(+)-induced diuresis and natriuresis by 41.0% and 26.7%, respectively. These results indicate that K(+) load induces diuresis and natriuresis through the renal kallikrein-kinin system in rats.     

Renal alpha 2-adrenoceptor blockade decreases sodium and water excretion in the anesthetized rat

The reported effects of renal alpha 2-adrenoceptor blockade on sodium and water excretion have been inconsistent. We therefore studied the effect of an intrarenal infusion of an alpha 2-adrenoceptor antagonist in rats undergoing two distinct levels of diuresis and natriuresis. Renal excretion of sodium and water was studied in anesthetized rats that had been unilaterally nephrectomized (right kidney) 10 days prior to the experimental day. In the presence of the lower rate of saline infusion an intrarenal infusion of the alpha 2-adrenoceptor antagonist, yohimbine, (25.6 nmol/kg per min) resulted in no change in urine volume or sodium and potassium excretion. In the presence of the modest diuresis, due to the higher level of saline infusion, intrarenal yohimbine resulted in a decrease in urine volume, sodium excretion and free water clearance. These effects of yohimbine were not found in adrenalectomized rats. The ability to demonstrate an effect of renal alpha 2-adrenoceptor blockade was dependent on the baseline level of sodium and water excretion. These results suggest that renal alpha 2-adrenoceptors may mediate the inhibition of the renal action of vasopressin by adrenal catecholamines.     

EFFECTS OF CHRONIC NICOTINE INGESTION ON PRESSOR RESPONSE TON-NE2RO- -ARGININE METHYL ESTER ANDEX VIVOCONTRACTION AND RELAXATION RESPONSE OF AORTA TO -ARGININE

Effects of nitric oxide synthase inhibition on blood vessels were studied in nicotine-treated rats. Male Sprague–Dawley rats drank a nicotine solution with a concentration of 25 or 50 μg/ml for 15 days. The blood pressure and heart rate of chloralose-anaesthetized rats and isolated aortic strip contractions were measured.N^ωNitro- -arginine methyl ester ( -NAME)-induced hypertension was significantly reduced after chronic nicotine treatment. TheE_maxof contractions of isolated aortic strips to noradrenaline were dose-dependently enhanced by nicotine and the potentiation was abolished by -arginine. The relaxation of aortic strips to acetylcholine was significantly decreased in nicotine-treated rats, whereas -arginine, but not -arginine, reversed this action. Neither nicotine nor -NAME affected the heart rate. The results show that chronic nicotine treatment reduced the pressor response of -NAME.     

EFFECTS OF SARAFOTOXIN S6c ON RENAL HAEMODYNAMICS AND URINE FORMATION IN ANAESTHETIZED DOGS

1. The effects of sarafotoxin S6c (S6c), a selective endothelin ETB receptor agonist, on renal haemodynamics and urine formation were examined in anaesthetized dogs. 2. Intrarenal arterial infusion of S6c at a rate of 1 or 5 ng/kg per min produced a transient increase in renal blood flow (RBF), with no change in systemic blood pressure and heart rate; RBF then decreased gradually to below the basal value. There were significant and dose-dependent increases in urine flow and free water clearance and decreases in urine osmolality during S6c infusion, whereas urinary excretion of sodium and glomerular filtration rate (GFR) remained unchanged. Simultaneously, S6c administration elicited a marked increase in urinary excretion of nitric oxide (NO) metabolites, N0₂^? and N0₃^? (UNO*V). 3. In dogs simultaneously administered S6c (5 ng/kg per min) and iV^G-nitro-L-arginine (NOARG; 40 (jig/kg per min), a NO synthase inhibitor, the renal vasodilator effect of S6c was abolished and marked reductions in RBF and GFR were observed. The S6c-induced diuretic action was not affected by NOARG. In the presence of NOARG, there was a small amount of UNO_xV at the basal level and the administration of S6c did not increase UNOxV. 4. These results suggest that an intrarenal arterial infusion of S6c enhances the production of NO in the kidney and that this enhancement contributes to the peptide-induced renal vasodilation. In contrast, it is unlikely that S6c-induced water diuresis is related to NO production stimulated by this peptide.     

Nitric oxide is involved in the memory facilitation induced by spermidine in rats

Rationale Spermidine (SPD) is an endogenous polyamine that modulates N-methyl-d-aspartate receptor functions, which has been reported to facilitate memory formation.Objectives In the current study, we investigated the involvement of nitric oxide in the facilitatory effect of SPD on the memory of adult male Wistar rats in the inhibitory avoidance task.Results The coadministration of the nonspecific NOS inhibitor N ^G nitro-l-arginine methyl ester (l-NAME) (0.1 nmol, intrahippocampus) with spermidine (0.2 nmol), immediately after training, prevented the memory improvement caused by spermidine in the avoidance inhibitory task. Spermidine increased nitrite and nitrate levels (NO_X) in the hippocampus 30 min after its administration, and l-NAME coinjection prevented the stimulatory effect of spermidine on NO_X levels. The systemic injection of 7-nitroindazole (30 mg/kg, i.p.), 30 min before training, impaired memory and did not prevent spermidine-induced increase of NO_X levels in the hippocampus.Conclusions These results suggest that memory enhancement by spermidine is prevented by the nonspecific nitric oxide synthase inhibitor l-NAME.     

The Role of Nitric Oxide and Sulphydryls in Gastric Mucosal Protection Induced by Sodium Cromoglycate in Rats

The role of endogenous nitric oxide and sulphydryls in gastric protection afforded by sodium cromoglycate against ethanol-induced gastric lesions was studied in rats. Drugs were administered either intraperitoneally (i.p.) or subcutaneously (s.c.) 30, 45 or 60 min before oral administration of ethanol. Administration of cromoglycate before ethanol dose-dependently inhibited ethanol-induced gastric lesions. Pretreatment with N^G-nitro-l -arginine methyl ester (L-NAME), an inhibitor of nitric oxide biosynthesis, dose-dependently aggravated gastric lesions and reduced cromoglycate-induced gastric protection. The attenuating effect of L-NAME on gastric protection elicited by cromoglycate was reversible by pretreatment with l -arginine but not by d -arginine. On the other hand, ethanol-induced gastric lesions were found to be associated with a reduction of nonprotein sulphydryl content of glandular stomachs. Pretreatment with cromoglycate prevented non protein sulphydryl depletion and afforded protection. Pretreatment with N-ethylmaleimide, a sulphydryl blocker, caused dose-dependent enhancement of ethanol-induced gastric lesions and further depletion of non protein-sulphydryl. Treatment with N-ethylmaleimide before cromoglycate reduced the gastric protection that was associated with depletion of nonprotein sulphydryls. Furthermore, combined N-ethylmaleimide and L-NAME pretreatment caused a greater aggravation of ethanol-induced gastric lesions and significantly produced a higher reduction of the protective effects of cromoglycate. However, pretreatment with l -arginine only partially restored the protective effects of cromoglycate. These results suggest that the protective effects of cromoglycate may be dependent on the maintenance of a critical level of both endogenous nitric oxide and nonprotein sulphydryls in the gastric mucosa.