Protective Effect Of L-arginine Research Articles

The Protective Effect of L-Arginine against Aspartame-Induced Toxicity on Adrenal Cortex of Adult Male Albino Rats: Histological, Immunohistochemical, and Biochemical Study

The Protective Effect of L-Arginine against Aspartame-Induced Toxicity on Adrenal Cortex of Adult Male Albino Rats: Histological, Immunohistochemical, and Biochemical Study

Long lasting protective effects of early l-arginine treatment on endothelium in an in vitro study

Excess nutrient supply, such as high fat and high glucose intake, promotes oxidative stress and advanced glycation end products accumulation. Oxidative stress and AGE accumulation cause pathological elevation of arginase activity and pro-inflammatory signaling implicated in endothelial dysfunction. Several studies showed positive effects of l-arginine supplementation in endothelial function but little is currently known about the role of l-arginine as prevention of endothelial dysfunction caused by excessive nutrient supply (overfeeding). Our aim was to evaluate a possible protective effect of l-arginine on endothelial dysfunction caused by excessive nutrient supply (overfeeding), using human endothelial cells line in an invitro study. Endothelial EA.hy926cells were pre-treated with 1.72mM of l-arginine for 24h and afterwards subjected to nutritional stress (high lipid, high insulin and high glucose concentrations) for further 24h. After treatment discontinuation, the cells were kept in culture for 48h, in physiological condition, to evaluate the effects of treatments after normalization. Excess nutrient supply in EA.hy926cell line showed an increase of oxidative and nitrosative stress, a rise of AGEs production, high arginase activity, leading the cells to acidosis and to cell death. l-arginine pretreatment protects the cells by reducing apoptosis, acidosis, oxidative and nitrosative stress, arginase activity and AGE accumulation. l-arginine pretreatment reduces AGEs generation and accumulation by regulating STAB1 and RAGE gene expression levels. STAB1, acting as receptor scavenger of AGEs, interferes with AGE-RAGE binding and thus prevents activation of intracellular signaling pathways leading to cell damage. Moreover the reduction of oxidative stress promotes a decrease of excessive activation of arginase involved in endothelial dysfunction. The effects of pretreatment with l-arginine last even in the absence of stimuli and despite after treatment discontinuation. An early l-arginine treatment is able to prevent oxidative stress and AGEs accumulation caused by overfeeding in human endothelial cell line by regulating STAB1/RAGE gene expression and by reducing excess arginase activity. The positive effects of l-arginine pretreatment continue even after treatment discontinuation in normal conditions.

Protective effect of L-arginine against renal damage induced by cadmium and lead intoxication in rats

Objective: This study was conducted to investigate the protective effect of L-arginine (L-Arg) on renal damage induced by cadmium (Cd) and lead (Pb) toxicities in rats. Methods: Thirty-six healthy mature male albino rats were allocated into six experimental groups (n=6/group): control group, L-arginine group (L-Arg) administered 200 mg/kg b.wt L-Arg, cadmium chloride group (Cd) received 5 mg/kg b.wt Cd chloride, lead acetate group (Pb) received 25 mg/kg b.wt Pb acetate, L-Arg + Cd chloride group (L-Arg + Cd) received L-Arg 30 minutes prior to Cd chloride, and L-Arg + Pb acetate group (L-Arg + Pb) received L-Arg 30 minutes prior to Pb acetate. All treatments were given orally once daily for 15 days. Results: The results revealed that exposure of rats to Cd chloride and Pb acetate resulted in a significant (p < 0.05) increase in serum creatinine, urea, uric acid, and renal malondialdehyde (MDA) levels and a significant (p < 0.05) decrease in superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) activities in kidney and induced histopathological alterations in kidney tissue. However, pretreatment with L-Arg attenuated all deleterious effects induced by Pb and Cd. Conclusion: The present results support the hypothesis that the amino acid, L-arginine, is an efficient antioxidant capable of minimizing the hazard effects of cadmium chloride and lead acetate on the kidney.

Apoptosis perturbations and expression of regulatory inflammatory factors in cisplatin-depleted rat livers under l-arginine protection.

Hepatic injury is one of the most common complications associated with cisplatin (CIS) use. Recently, liver protection lines are being discovered to stop the hepatic cell death due to inflammatory and apoptotic perturbations. l-arginine has protective effects in several models of liver injury. This study was designed to investigate the possible protective effect of l-arginine against CIS-induced acute hepatic injury in rats. Rats were divided into 4 groups: control, l-arginine, CIS, l-arginine + CIS. Liver function, oxidative stress, inflammatory cytokines, and apoptosis markers were assessed. l-arginine pretreatment protected the liver against CIS-induced toxicity as indicated by significantly alleviating the changes in liver function along with restoration of the antioxidant status. This finding was confirmed with the markedly improved pathological changes. l-arginine showed anti-inflammatory effect through the reduction of liver expression of iNOS, TNF-α, and NF-κβ, which were ameliorated to significant levels. Furthermore, l-arginine administration downregulated the liver expression of the apoptotic marker, caspase-3. The results recommend l-arginine as a hepatoprotective agent against CIS toxicity. Mostly, this hepatoprotective effect of l-arginine involved anti-inflammatory and anti-apoptotic activities.

The possible protective effect of L-arginine against 5-fluorouracil-induced nephrotoxicity in male albino rats.

5-fluorouracil (5-FU) is a potent antineoplastic agent used for the treatment of various malignancies. The L-arginine nitric oxide (NO) pathway involved in the pathogenesis of chemotherapy induced kidney damage. This work investigated the beneficial mechanism of L-arginine supplementation in 5-FU induced nephropathy. Eighty male Wistar rats were divided into four equal groups: control group; L-arginine group (378 mg/rat/day for 4 weeks); 5-FU group (189 mg/rat/week for 4 weeks) and L-arginine for 1 week before and 4 weeks concomitant with 5-FU group. At the end of experiment, the kidney functions were assessed and kidneys specimens were processed for paraffin sections and stained with haematoxylin and eosin (H&E), Masson's trichome (MT) and periodic acid-Schiff (PAS) stains. Other sections were processed for immunohistochemical demonstration of caspase-3 and inducible NO synthase (iNOS). Image analyser was used to analyse the results morphometrically and statistically. L-arginine administration to 5-FU treated animals elicited significant reduction in serum urea and creatinine levels, urine volume, urinary protein excretion and kidney/body weight ratio in comparison to fluorouracil treated group. L-arginine improved glomeruloscelerosis, degeneration of convoluted tubules and interstitial fibrosis in 5-FU treated animals. L-arginine attenuated effectively some biochemical and histological changes in 5-FU nephrotoxicity.

The protective effect of L-arginine, tadalafil, and their combination in rat testes after ischemia and reperfusion injury.

Nitric oxide (NO) plays an important role in the ischemia and reperfusion process. In this study, we aimed to examine the effect of L-arginine, tadalafil, and their combination for prevention of the ischemia reperfusion injury after testis torsion in rats. A total of 40 adult, male Sprague-Dawley rats were allocated into five groups. Three hours of left testicular torsion was performed in each group, excluding the control group. While the ischemia reperfusion (I/R) group had no treatment, I/R + Arg group received L-arginine, I/R + Td group received tadalafil and I/R + Arg + Td group received tadalafil and L-arginine 30 minutes before the detorsion. Then the left testis was untwisted for four hours of reperfusion. After bilateral orchiectomy, lipid peroxidation (LPx) and glutathione (GSH) activities were examined in testicular tissue. Spermatogenesis was evaluated with Johnsen's score. LPx levels of the I/R group were found to be significantly higher than for groups that received drugs for both testes (p<0.001). GSH levels of the combination group were higher than I/R group in ipsilateral testis (p<0.01) and it was significantly higher than other groups for contralateral testis (p<0.001 for I/R group, p<0.01 for I/R + Arg, p<0.05 for I/R + Td). Mean Johnsen's score of the I/R group was found to be significantly lower than treatment groups in ipsilateral testis (p<0.001 for I/R + Arg + Td group, p<0.01 for other treatment goups) and contralateral testis (p<0.001). The mean Johnsen score of the combination group was significantly higher than that of other treatment groups in ipsilateral testis (p<0.05) and it was significantly higher than in the I/R + Td group in the contralateral testis (p<0.05). L-arginine, tadalafil, and combination of these two molecules showed protective effect against ischemia/reperfusion injury for both testes after unilateral testis torsion.

The Protective Effect of L-arginine in Cisplatin-induced Nephrotoxicity in Streptozotocin-induced Diabetic Rats.

Background:Cisplatin (CP) is accompanied with a nephrotoxicity. L-arginine (LA) plays an important role in the regulation of renal function. The present study was designed to investigate the protective role of LA supplementation in CP-induced nephrotoxicity in a diabetic rat's model.Materials and Methods:Sixteen adult female and male Wistar rats were used and they received a single dose of streptozotocin (STZ) (60 mg/kg i.p.). Diabetic female and male rats were arranged as groups 1–5 and groups 6–10, respectively. Groups 1 and 6 (LA groups) received LA alone. Groups 2 and 7 (CP groups) received CP alone. Groups 3 and 8 (CP + LA [PT] groups) received LA as prophylaxis and then treated with LA and CP. Groups 4 and 9 (CP + LA [T] groups) were treated with LA and CP simultaneously. Groups 5 and 10 (CP + LA [P] groups) received LA as prophylaxis and then treated with CP.Results:The serum creatinine (Cr) level of males in Groups 8 and 9 was significantly increased when compared with LA and CP (P < 0.05), whereas no differences were observed in Cr level in female groups. Blood urea nitrogen/Cr ratio and kidney weight were reduced in all CP-receiving male rats. Such observation was not seen in female rats. Different results related to weight loss were obtained between male and female animals. The kidney tissue damage score in CP + LA (PT) male group was significantly greater than CP group (P < 0.05).Conclusion:Our findings indicate that administration of LA in female and male rats has no protective effect on the severity of nephrotoxicity induced by CP in diabetic rats.

Neuroprotective mechanism of ischemic postconditioning in mice: a possible relationship between protein kinase C and nitric oxide pathways

BackgroundThe present study was conducted to pharmacologically investigate the role of protein kinase C (PKC) pathway in neuroprotective mechanism of ischemic postconditioning (iPoCo) and determine the influence of nitric oxide (NO) signaling in PKC-mediated effects. Materials and methodsBilateral carotid artery occlusion of 12 min followed by reperfusion for 24 h was used to produce ischemia and reperfusion (I/R)–induced cerebral injury in male Swiss mice. Memory was assessed using Morris water maze test. Degree of motor incoordination was evaluated using inclined beam-walk test, rota-rod test, and lateral push test. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Brain acetylcholinesterase activity, thiobarbituric acid reactive species, nitrite/nitrate, and reduced glutathione levels were also estimated. ResultsBilateral carotid artery occlusion followed by reperfusion produced significant rise in cerebral infarct size, acetylcholinesterase activity, and thiobarbituric acid reactive species levels along with the fall in nitrite/nitrate and glutathione levels. A significant impairment of memory and motor coordination was also noted. iPoCo consisting of three episodes of 10 s carotid artery occlusion and reperfusion significantly attenuated infarct size, memory impairment, motor incoordination, and altered biochemicals. iPoCo-induced neuroprotective effects were significantly abolished by chelerythrine (a nonselective PKC inhibitor). l-Arginine, an NO precursor significantly attenuated I/R-induced injury and mimicked the neuroprotective effect of postconditioning. Furthermore, this protective effect of l-arginine on I/R injury and iPoCo was abolished when it was coadministered with chelerythrine. ConclusionsIt may be concluded that neuroprotective mechanism of iPoCo involves PKC mediated pathway with NO signaling as an essential step.

Protective effect of L-arginine on gentamicin-induced nephrotoxicity in rats.

Introduction:L-arginine has a protective effect on gentamicin-induced renal failure and it may decrease the tubular reabsorption of another cationic substance, gentamicin due to its cationic structure. The aim of this study is to compare the possible protective effects of L-arginine and its inactive isomer D-arginine on gentamicin-induced nephrotoxicity in rats.Materials and Methods:Wistar albino rats were housed in metabolic cages and assigned to six groups as: control group, gentamicin (100 mg/kg), gentamicin + L-arginine (2 g/l), gentamicin + D-arginine (2 g/l), gentamicin + L-arginine + Nv-nitro-L-arginine methyl ester (L-NAME) (100 mg/l) and gentamicin + D-arginine + L-NAME. Gentamicin was administered by subcutaneous injections and the other drugs were added in drinking water for seven consecutive days. The animals were killed by decapitation and intracardiac blood and urine samples were obtained on the seventh day. Blood urea nitrogen, serum creatinine, sodium, potassium, urine gamma glutamyl transferase, creatinine, sodium, potassium and gentamicin levels were measured using High Performance Liquid Chromatography (HPLC) technique.Results:Gentamicin treated group had significant increase in blood urea nitrogen, serum creatinine, fractional Na excretion and urine gamma glutamyl transferase levels, and significant decrease in creatinine clearance compared to the control group. L-arginine and D-arginine reversed these findings. L-NAME abolished the nephroprotective effect of L-arginine. The urinary levels of gentamicin were significantly increased in rats treated with L-arginine or D-arginine compared to those treated with gentamicin. L-arginine and D-arginine reversed the advanced degenerative changes due to gentamicin administration in histopathological examination.Conclusion:Our study revealed the protective effect of L-arginine on gentamicin-induced nephrotoxicity, the contribution of the cationic feature of L-arginine, and the major role of NO in this protective effect.

L-arginine protects against ethylene glycol-induced gastric mucosal damage in rats: immunohistochemical and electron microscopic study

Ethylene glycol is an alcohol widely used in industry as an antifreeze. It affects the normal gastric mucosal defense mechanisms, inducing surface ulcerations. L-arginine is a precursor of nitric oxide that exhibits multiple biological properties; among them is the acceleration of wound healing, especially in the stomach. Caspase-3 immunohistochemistry, and semithin and ultrathin section examinations were used to investigate the possible protective effect of L-arginine on ethylene glycol-induced gastric mucosal damage in rats. Three animal groups were used: group A (control group), group B (received 3.3 mL/kg ethylene glycol for 2 weeks), and group C (received 200 mg/kg of L-arginine and 3.3 mL/kg ethylene glycol for 2 weeks). By examination, group B showed significant increases in caspase-3 positive cells in comparison to the control, semithin sections revealed surface disruption and ulcerations, and ultrathin sections showed multiple pathological changes in cells lining the gastric mucosal glands. In group C significant decreases in caspase-3 positive cells were encountered and the other pathological findings in group B were found to be reversed. Therefore, we conclude that ethylene glycol-induced damage to the gastric mucosa could be prevented by L-arginine administration.

L-Arginine Supplementation Protects Against Hepatic Ischemia–Reperfusion Lesions in Rabbits

We evaluated the effects of a substrate in the biosynthesis of nitric oxide (NO)- l-arginine (LARG)-on hepatic lesions caused by ischemia/reperfusion (I/R) injury in rabbit livers. Rabbits were pretreated with LARG (150 mg/kg IV) or saline solution 0.9% (SS) before the hepatic I/R procedure. The effects of LARG on hepatic injury were evaluated before and after I/R. The warm hepatic I/R procedure produced profound acute liver injury, as indicated by elevated values of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactic dehydrogenase (LDH), as well as a high apoptotic cell count. All changes were attenuated by treatment with LARG before the hepatic I/R procedure. These results suggested that LARG produced protective effects on hepatic I/R lesions. This protective effect of LARG was probably associated with blocking generation of superoxide anions during the hepatic I/R procedure.

Protective effect of L-arginine against necrosis and apoptosis induced by experimental ischemic and reperfusion in rat liver

Background/Aim:To study the effect of L-arginine on apoptosis and necrosis induced by 1-h ischemia followed by 3-h reperfusion.Materials and Methods:Adult Wistar rats underwent 60 min of partial liver ischemia followed by 3-h reperfusion. Eighteen Wistar rats were divided into sham-operated control group (I) (n = 6), ischemia and reperfusion (I/R) group (0.9% saline (5 mL/kg, orally) for 7 days) (II) (n = 6), and L-arginine-treated group (10 mg/kg body weight daily orally for 7 days before inducing ischemia-reperfusion maneuver) (III) (n = 6). Apoptotic and necrotic hepatocytes, nitric oxide levels in hepatocytes, Bcl-2 mRNA, and Bcl-2 protein were measured. Liver injury was assessed by plasma alanine transaminases (ALT), aspartate transaminases (AST), liver histopathology, and electron microscopy.Results:An ischemic and reperfusion hepatocellular injury occurred as was indicated by increased serum ALT, AST, histopathology, and electron microscopy. Apoptosis and necrosis associated marker gene Bcl-2 mRNA and protein expression were decreased in I/R group. Pretreatment with L-arginine significantly decreased serum ALT and AST level and apoptotic and necrotic cells after 1 h ischemia followed by 3 h of reperfusion. Nitric oxide production in hepatocytes was increased twofold by L-arginine treatment when compared with I/R group. Histopathology and transmission electron microscopy (TEM) studies showed markedly diminished hepatocellular injury in L-arginine-pretreated rats during the hepatic I/R.Conclusion:Thus, it may be concluded that L-arginine afforded significant protection from necrosis and apoptosis in I/R injury by upregulated Bcl-2 gene and nitric oxide production.

L-arginine Attenuates Acute Pulmonary Embolism-Induced Increases in Lung Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9

To evaluate the effects of L-arginine on acute pulmonary embolism (APE)-induced pulmonary hypertension and increases in lung matrix metalloproteinase (MMP)-2 and MMP-9 activities. Prospective trial. University laboratory. Using an isolated lung perfusion rat model of APE, we examined whether L-arginine (0, 0.5, 3, and 10 mmol/L; five to seven rats per group) attenuates the pulmonary hypertension induced by the injection of 6.6 mg/kg of 300 microm microspheres into the pulmonary artery. In a second series of experiments (6 to 11 rats per group), we investigated whether nonselective inhibition of nitric oxide (NO) synthases with N(G)-nitro-L-arginine methyl ester (L-NAME; 4 mmol/L) decreases the effects produced by L-arginine. Lung MMP-2 and MMP-9 activities were determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis gelatin zymography. L-arginine at 0.5, 3, and 10 mmol/L attenuated APE-induced pulmonary hypertension by 25 to 42% (all p < 0.05). The protective effect of L-arginine was completely reversed by inhibition of NO synthesis with L-NAME. APE was associated with increased lung MMP-2 and MMP-9 activities (both p < 0.05). While L-arginine at 0.5 mmol/L produced no effect on MMPs, L-arginine 3 at mmol/L and 10 mmol/L attenuated the increases in MMP-2 and MMP-9 activities after APE (both p < 0.05). L-arginine attenuates APE-induced pulmonary hypertension through mechanisms involving increased NO synthesis and maybe attenuation of lung MMP-2 and MMP-9 activities.

L-Arginine prevents air embolism-induced acute lung injury in rats

Pulmonary air embolism, causing vessel obstruction and primary or secondary reactions of blood, can lead to acute lung injury. In addition, nitric oxide has been known to play a key role in various causes of lung injury. In this study we employed the isolated rat lung model to investigate the effects of l-arginine on air embolism-induced lung injury. Randomized, controlled study. Animal-care facility procedure room. Forty-two adult male Sprague-Dawley rats each weighing 250-350 g. Infusion of air at the rate of 0.25 mL/min for 1 min into the pulmonary artery in isolated and perfused rat lung resulted in pulmonary hypertension and lung edema. Air embolism elicited a significant increase in microvascular permeability as measured by the capillary filtration coefficient, lung weight gain, lung weight-to-body weight ratio, pulmonary arterial pressure, and protein concentration of bronchoalveolar lavage fluid. Pretreatment with L-arginine (4 mmol/L) significantly attenuated the acute lung injury induced by air embolism as shown by a significant decrease in all of the assessed variables but did not alter the pulmonary arterial pressure (p < .05). The protective effect of l-arginine was blocked when N(G)-nitro-L-arginine methyl ester (5 mmol/L) was added. Pretreatment with N(G)-nitro-L-arginine methyl ester exacerbated air embolism-induced lung injury. Our findings suggest that L-arginine can prevent air embolism-induced lung injury.

L-Arginine attenuates acute pulmonary embolism-induced oxidative stress and pulmonary hypertension

l-Arginine is substrate for nitric oxide (NO) synthesis and produces pulmonary vasodilatory effects in patients with pulmonary hypertension and in hypoxic animals. We hypothesized that l-arginine would attenuate the increase in oxidative stress and the pulmonary hypertension observed during acute pulmonary embolism (APE). Using an isolated lung perfusion rat model of APE, we examined whether l-arginine (0, 0.1, 0.5, 3, and 10 mmol/L) attenuates the pulmonary hypertension induced by the injection of 6.6 mg/kg of 300 microm Sephadex microspheres into the pulmonary artery. Thiobarbituric acid reactive species (TBA-RS) and nitrite/nitrate (NO(x)) concentrations were measured in lung perfusate to assess oxidative stress and NO production. l-Arginine (0.5, 3, and 10 mmol/L) attenuated (all P<0.05) APE-induced pulmonary hypertension by about 50%. The protective effect of l-arginine was completely reversed by inhibition of NO synthesis with l-NAME (4 mmol/L). In addition, l-arginine (0.5-10 mmol/L) blunted the increase in TBA-RS observed after APE. NO(x) tended to increase only when l-arginine (10 mmol/L) was added to the lung perfusate of non-embolized lungs. Taken together, these findings suggest that l-arginine attenuates APE-induced pulmonary hypertension through antioxidant mechanisms involving increased NO synthesis.

Effect of arginine and lysine on mitochondrial function during isoproterenol induced myocardial infarction in rats

Mitochondria are important subcellular organelles involved in the energy production that are susceptible to oxidative stress. Acute myocardial infarction has been shown to correlate with an increase in oxidative stress. The protective effect of L-arginine and L-lysine on mitochondrial enzymes, mitochondrial lipid peroxidation, Ca 2+ content, enzymes of respiratory chain and ATP production was examined during isoproterenol induced myocardial infarction. Rats administered isoproterenol (150 mg kg -1 daily, i.p.) for two days showed a significant increase in mitochondrial lipid peroxidation and Ca 2+ content while the activities of the cardiac marker enzymes, mitochondrial tricarboxylic acid cycle enzymes, enzymes of respiratory chain and ATP production were decreased. Prior oral treatment of L-arginine (250 mg kg −1 daily) along with L-lysine (5 mg kg −1 daily) in combination for 5 days significantly (p < 0.05) prevented these alterations and restored the mitochondrial function at near normal state. These results confirm the combined efficacy of L-arginine and L-lysine in alleviating isoproterenol induced mitochondrial damage.

Effect of arginine and lysine on mitochondrial function during isoproterenol induced myocardial infarction in rats

Mitochondria are important subcellular organelles involved in the energy production that are susceptible to oxidative stress. Acute myocardial infarction has been shown to correlate with an increase in oxidative stress. The protective effect of L-arginine and L-lysine on mitochondrial enzymes, mitochondrial lipid peroxidation, Ca 2+ content, enzymes of respiratory chain and ATP production was examined during isoproterenol induced myocardial infarction. Rats administered isoproterenol (150 mg kg -1 daily, i.p.) for two days showed a significant increase in mitochondrial lipid peroxidation and Ca 2+ content while the activities of the cardiac marker enzymes, mitochondrial tricarboxylic acid cycle enzymes, enzymes of respiratory chain and ATP production were decreased. Prior oral treatment of L-arginine (250 mg kg −1 daily) along with L-lysine (5 mg kg −1 daily) in combination for 5 days significantly (p < 0.05) prevented these alterations and restored the mitochondrial function at near normal state. These results confirm the combined efficacy of L-arginine and L-lysine in alleviating isoproterenol induced mitochondrial damage.

Blockade of the L-arginine/NO synthase pathway worsens hepatic apoptosis and liver transplant preservation injury

Organ graft preservation injury is a major problem complicating liver transplantation. The L-arginine/nitric oxide pathway has protective effects in several models of liver injury. The purpose of this study was to evaluate the role of the L-arginine/NO synthase (NOS) pathway on liver preservation injury and to characterize endogenous inducible NOS (iNOS) expression. Orthotopic liver transplantation was performed with 18-hour University of Wisconsin preservation solution in syngeneic rats. Recipient rats were either untreated or treated with L-arginine, D-arginine, nonspecific NOS inhibitor N G -nitro- L-arginine methyl ester ( L-NAME), or iNOS selective inhibitor L- N 6 -(1-imino-ethyl)lysine ( L-NIL) after revascularization. As early as 1 hour following reperfusion, circulating arginine levels decreased 10-fold and ornithine levels increased 4-fold. A corresponding increase in arginase I protein was detected in serum. To address the profound arginine deficiency, we supplemented recipients with arginine after transplantation. L-arginine (but not D-arginine) supplementation significantly reduced preservation injury 12 hours after reperfusion, suggesting that the protective effect of L-arginine was mediated through the generation of NO. iNOS protein expression peaked in the liver 6 to 12 hours following reperfusion. Blockade of the L-arginine/NO pathway with L-NAME significantly increased necrotic and apoptotic cell death in the transplanted graft. Addition of the iNOS selective inhibitor L-NIL mildly increased liver transaminase levels and also increased apoptosis in the liver graft. In conclusion, transplant recipients are profoundly arginine deficient postreperfusion due to arginase release. L-Arginine supplementation and NO synthesis decrease necrotic and apoptotic cell death and ameliorate liver transplant preservation injury. (H EPATOLOGY 2002;36:573-581.)

L-arginine protects against stress-induced gastric mucosal lesions by preserving gastric mucus.

1. We have shown that exogenously administered L-arginine protects against water immersion restraint (WIR) stress-induced gastric mucosal lesions in rats through preservation of nitric oxide (NO) generation via constitutive nitric oxide synthase (cNOS), but not inducible nitric oxide synthase (iNOS), in the gastric mucosa. We have also indicated that impaired gastric mucus synthesis and secretion occur through a decrease in gastric cNOS activity in WIR-stressed rats. Therefore, in the presesnt study, we examined whether exogenously administered L-arginine exerts a protective effect against WIR stress-induced gastric mucosal lesions in rats through preservation of gastric mucus synthesis and secretion by NO generated from the administered amino acid via cNOS in the gastric mucosa. 2. Rats were subjected to WIR stress for 3 and 6 h. Either L-arginine (150-600 mg/kg) or D-arginine (600 mg/kg) was injected intraperitoneally 0.5 h prior to WIR stress. Either N(G)-monomethyl L-arginine (L-NMMA; 100 mg/kg) or N(G)-monomethyl D-arginine (D-NMMA; 100 mg/kg) was injected subcutaneously 0.5 h prior to WIR stress. Total NOS, cNOS, iNOS, nitrite and nitrate (breakdown products of NO), hexosamine (an index of gastric mucin) and adherent mucus were assayed in the gastric mucosa. 3. Pretreatment with L-arginine, but not D-arginine, protected against gastric mucosal lesions in rats subjected to WIR stress for 3 and 6 h in a dose-dependent manner. Pretreatment with L-arginine, but not D-arginine, attenuated decreases in hexosamine and adherent mucus concentrations and cNOS activity and increases in total NOS and iNOS activities and nitrite/nitrate concentration in the gastric mucosal tissue of rats subjected to WIR stress for 3 and 6 h in a dose-dependent manner. Both the protective effect of L-arginine against gastric mucosal lesions and the attenuating effect of the amino acid on the decreases in gastric mucosal hexosamine and adherent mucus concentrations and cNOS activity in rats subjected to WIR stress for 6 h were counteracted by cotreatment with L-NMMA, a nitric oxide synthase inhibitor, but not D-NMMA. 4. These results suggest that exogenously administered L-arginine exerts a protective effect against stress-induced gastric mucosal lesions in rats at least partly through preservation of gastric mucus synthesis and secretion by NO produced from the administered amino acid via cNOS in gastric mucosal tissue.

Warm Hepatic Ischemia in Pigs: Effects of L-Arginine and Oligotide Treatment

Reperfusion injury represents a key event leading to graft nonfunction. Maintaining adequate nitric oxide levels and stimulating vasodilator synthesis can probably minimize endothelial damage. The aim of this study was to investigate the effect of L-arginine, a substrate of nitric oxide synthesis, and oligotide, a promoter of prostacyclin synthesis, on liver function and morphology after warm ischemia-reperfusion injury. After constructing a side-to-side portacaval shunt, ischemia was induced by clamping the hepatic hilum for 2 h above the shunt, in 19 female pigs divided into a control group ( n = 7), an L-arginine treatment group ( n = 6), and an oligotide treatment group ( n = 6). Liver function tests and measurements of serum and red blood cell malondialdehyde and plasma nitric oxide levels were performed before reperfusion and at 1, 10, 60, and 120 min after reperfusion. Liver biopsies, taken before reperfusion and at 30 min and 7 days after reperfusion, were analyzed for tissue malondialdehyde, histological-ultrastructural features, and apoptosis evaluation. Thirty minutes after reperfusion, liver malondialdehyde, sinusoidal congestion, necrosis, and apoptosis were significantly lower in the L-arginine group than in the controls ( p < .05). On postoperative day 7, tissue malondialdehyde decreased, while plasma nitric oxide and hepatocyte glycogen content were increased in the L-arginine group compared to controls ( p < .05). This study demonstrates the protective effect of L-arginine on hepatic lipoperoxidation and liver morphology in a pig model of warm ischemia-reperfusion injury. The increased plasma levels of nitric oxide a week after ischemia-reperfusion injury support the hypothesis that it has a role in preventing liver damage. The same beneficial effect was not confirmed for oligotide.