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ARGININE



Table of Contents
image Differential regulation of macrophage arginine metabolism: a proposed role in wound healing.
image Human dermal fibroblasts produce nitric oxide and express both constitutive and inducible nitric oxide synthase isoforms.
image Role of lactose, arginine and lysine combination in fracture healing (an experimental study)
image Sepsis impairs anastomotic collagen gene expression and synthesis: A possible role for nitric oxide
image Regionally different vascular response to vasoactive substances in the remodelled infarcted rat heart; Aberrant vasculature in the infarct scar
image Modulation of tendon healing by nitric oxide
image Acute protein-calorie malnutrition impairs wound healing: A possible role of decreased wound nitric oxide synthesis
image Dietary L-arginine in renal disease
image Arginine-enriched diets: Rationale for use and experimental data
image Effects of an arginine-glycine-aspartic acid peptide-containing artificial matrix on epithelial migration in vitro and experimental second-degree burn wound healing in vivo
image Spontaneously increased production of nitric oxide and aberrant expression of the inducible nitric oxide synthase in vivo in the transforming growth factor beta1 null mouse
image Nitric oxide is necessary for a switch from stationary to locomoting phenotype in epithelial cells
image The effect of an arginine-glycine-aspartic acid peptide and hyaluronate synthetic matrix on epithelialization of meshed skin graft interstices
image Clinical application of basic arginine amidase in human male urine.
image Arginine needs, physiological state and usual diets. A reevaluation.
image Modulation of immune function and weight loss by L-arginine in obstructive jaundice in the rat.
image Can the length of hospital stay be influenced by enteral immunonutrition?
image L-arginine restores dilator responses of the basilar artery to acetylcholine during chronic hypertension.
image Dietary L-arginine attenuates blood pressure in mineralocorticoid-salt hypertensive rats.
image Role of exogenous L-arginine in hepatic ischemia-reperfusion injury
image Can the kidney prevent cardiovascular diseases?
image L-arginine prevents corticotropin-induced increases in blood pressure in the rat.
image Improvement of cardiac output and liver blood flow and reduction of pulmonary vascular resistance by intravenous infusion of L-arginine during the early reperfusion period in pig liver transplantation.
image Renal response to L-arginine in salt-sensitive patients with essential hypertension.
image Contrasting effect of antihypertensive treatment on the renal response to L-arginine.
image Endothelial dysfunction: Clinical implications.
image L-Arginine reduces lipid peroxidation in patients with diabetes mellitus.
image Short-term oral administration of L-arginine reverses defective endothelium-dependent relaxation and cGMP generation in diabetes.
image Metformin improves hemodynamic and rheological responses to L-arginine in NIDDM patients.
image Impairment of coronary blood flow regulation by endothelium-derived nitric oxide in dogs with alloxan-induced diabetes.
image Involvement of the L-arginine-nitric oxide pathway in hyperglycaemia-induced coronary artery dysfunction of isolated guinea pig hearts.
image Deficient nitric oxide responsible for reduced nerve blood flow in diabetic rats: effects of L-NAME, L-arginine, sodium nitroprusside and evening primrose oil.
image Agmatine and spermidine reduce collagen accumulation in kidneys of diabetic db/db mice.
image L-arginine reduces heart collagen accumulation in the diabetic db/db mouse.
image L-Arginine does not restore dilatation of the basilar artery during diabetes mellitus.
image Evaluation of the mechanism of endothelial dysfunction in the genetically-diabetic BB rat.
image Elevation of D-glucose impairs coronary artery autoregulation after slight reduction of coronary flow.
image Impaired arginine metabolism and NO synthesis in coronary endothelial cells of the spontaneously diabetic BB rat.
image Directions in antihypertensive treatment--our future from the past.
image Human and rat macrophages mediate fungistatic activity against Rhizopus species differently: in vitro and ex vivo studies.
image Vascular and hormonal responses to arginine: provision of substrate for nitric oxide or non-specific effect?
image Glutamine and arginine metabolism in tumor-bearing rats receiving total parenteral nutrition
image Dietary modulation of amino acid transport in rat and human liver
image Muscle wasting and dedifferentiation induced by oxidative stress in a murine model of cachexia is prevented by inhibitors of nitric oxide synthesis and antioxidants
image Modulation of immune function and weight loss by L-arginine in obstructive jaundice in the rat
image Evaluation of the effect of arginine-enriched amino acid solution on tumor growth
image Regulation of macrophage physiology by L-arginine: Role of the oxidative L-arginine deiminase pathway
image Growth hormone secretion in Alzheimer's disease: Studies with growth hormone-releasing hormone alone and combined with pyridostigmine or arginine
image Prevention of preeclampsia with calcium supplementation and its relation with the L-arginine:nitric oxide pathway.
image Dietary supplementation of nucleotides and arginine promotes healing of small bowel ulcers in experimental ulcerative ileitis
image Effect of arginine on toxin production by clostridium difficile in defined medium
image Stress-induced enhancement of colitis in rats: CRF and arginine vasopressin are not involved
image Manipulation of the L-arginine-nitric oxide pathway in experimental colitis
image Experimental colitis is ameliorated by inhibition of nitric oxide synthase activity
image Growth inhibition of subcutaneously transplanted hepatomas by alterations of the dietary arginine-methionine balance

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Agmatine and spermidine reduce collagen accumulation in kidneys of diabetic db/db mice.

Nephron (SWITZERLAND) 1995, 69 (2) p155-8

In the present study, we tested the hypothesis whether agmatine and spermidine, metabolites of arginine metabolism, share the pharmacological activities of arginine reducing collagen accumulation in the diabetic kidney. Eleven db/db mice were administered agmatine and 12 db/db mice spermidine (50 mg/kg body weight). Ten db/db mice received no treatment as negative controls and 10 db/db mice were treated with aminoguanidine (50mg/kg body weight) as positive controls. Mean kidney OH-proline content reflecting kidney collagen content and mean CML concentration were significantly higher but acid solubility of collagen significantly lower in the untreated group than in the treated groups. Agmatine, although missing the alpha-amino group and the carboxyl group, and spermidine, although missing the guanidino group, thus still revealed the arginine activity. We hypothesize that the strongly nucleophilic structure of polyamines common to all active compounds is able to block reactive carbonyls.



L-arginine reduces heart collagen accumulation in the diabetic db/db mouse

Circulation (UNITED STATES) Jul 1994, 90 (1) p479-83

BACKGROUND: Diabetic cardiomyopathy presents with significant collagen accumulation; decreased solubility, increased glucose-mediated abnormal cross-linking, free radical cross-linking, or glucose-induced increased transcription of collagen is incriminated. In a previous study, we reducedcollagen accumulation in the kidneys of diabetic mice by treatment with oral arginine. This observation led us to examine the effect of arginine oncardial fibrosis. METHODS AND RESULTS: Twenty-nine db/db spontaneouslydiabetic mice were used in the experiments. Sixteen were given L-arginine(free base, in tap water, 50 mg/kg body wt per day) for 4 months. At theend of the experiment, we determined total collagen content of total ventricular tissue, acid solubility, carboxymethyllysine, O-tyrosine, glutathione, blood glucose, and fructosamine as parameters for glycemic control. Heart collagen level was significantly (P = .0001) reduced in the experimental group (mean, 0.24 +/- 0.05) compared with the control group (mean, 0.49 +/- 0.10 mumol hydroxyproline per 100 mg heart tissue). Significantly more collagen could be eluted from heart samples of the experimental group (P = .02). Carboxymethyllysine and O-tyrosine did not differ when related to heart weight. Glutathione level was significantly higher in the untreated group (P = .003). Parameters of glycemic control did not differ between the groups. CONCLUSIONS: Our findings clearly indicate that L-arginine reduced total heart collagen and increased acid solubility of heart collagen. Both findings are compatible with the cross-linking hypothesis. The data for carboxymethyllysine, O-tyrosine, and glutathione would rule out the glycoxidation hypothesis and, therefore, free radical cross-linking. The postulated mechanism of action is most likely the blocking of reactive carbonyl functions by L-arginine in analogyto amino guanidine activity. Correlations of collagen with glycemic control, however, point to an association of glucose with collagen metabolism, a phenomenon documented in cel cultures at the transcriptional level.



L-Arginine does not restore dilatation of the basilar artery during diabetes mellitus.

J Cereb Blood Flow Metab (UNITED STATES) May 1996, 16 (3) p500-6

The goal of this study was to test the hypothesis that administration of L-arginine, a substrate for the synthesis of nitric oxide, restores endothelium-dependent dilatation of the basilar artery during diabetes mellitus. We measured the diameter, of the basilar artery in vivo in nondiabetic and diabetic (streptozotocin; 50-60 mg/kg i.p.) rats in response to endothelium-dependent agonists (acetylcholine and bradykinin) and an endothelium-independent agonist (nitroglycerin) before and during application of L-arginine. Topical application of acetylcholine (1.0 and 10 muM) and bradykinin (1.0 and 10 microM) produced dilatation in nondiabetic rats of the basilar artery which was impaired in diabetic rats. Topical application of nitroglycerin (0.1 and 1.0 microM) produced similar dilatation of the basilar artery in nondiabetic and diabetic rats. Topical application of L-arginine (0.1 and 3 mM) did not enhance dilatation of the basilar artery in response to acetylcholine and bradykinin in diabetic rats. Thus, impairment of dilatation of the basilar artery in diabetic rats in response to acetylcholine and bradykinin appears to be related to a mechanism unrelated to the availability of L-arginine for nitric oxide synthase.



Evaluation of the mechanism of endothelial dysfunction in the genetically-diabetic BB rat.

Life Sci (ENGLAND) 1996, 58 (9) pPL147-52

Endothelial dysfunction is known to occur in chemically-induced animal models of diabetes. The BB diabetic rat is a genetic diabetes-prone model which more closely resembles Type I diabetes mellitus. In this study, we examined the role of superoxide anion radical and cyclooxygenase activity on endothelial dysfunction in aorta of the spontaneous diabetic BB rat. Vascular endothelial function was studied in vitro in aortic rings from 8-wk diabetic rats and age-matched nondiabetic littermates. There was no alteration in reactivity to norepinephrine as a result of diabetes. Relaxation to acetylcholine (but not nitroglycerin) was impaired in diabetic rings. Relaxation to acetylcholine was abolished by 100 microM L-nitroarginine but unaltered by an equimolar concentration of aminoguanidine (an inducible nitric oxide synthase inhibitor) in both control and diabetic rings. Incubation with 10 microM indomethacin did not alter relaxation to acetylcholine in either control or diabetic rings. In contrast, addition of 20 U/ml superoxide dismutase enhanced relaxation to acetylcholine in diabetic rings but had no effect on relaxation to acetylcholine in control rings. Thus, nitric oxide-mediated, endothelium-dependent relaxation is diminished in aortic rings of the genetic diabetic BB rat. Furthermore, superoxide anion radicals but not cyclooxygenase products play an important role in endothelial dysfunction in this genetic diabetic model.



Elevation of D-glucose impairs coronary artery autoregulation after slight reduction of coronary flow.

Eur J Clin Invest (ENGLAND) Aug 1995, 25 (8) p590-4

Diabetes mellitus is thought to increase the susceptibility of tissue to hypoxic injury through D-glucose-induced alterations of intracellular metabolism. Therefore the effects of hyperglycaemia on coronary artery autoregulation under slight reduction of coronary flow were investigated in isolated perfused guinea-pig hearts. Under normal (10 mM) D-glucose concentrations coronary autoregulation was intact in response to a slight reduction of coronary flow (from 6 to 4.5 mL min-1) when L-arginine as a precursor of the endothelium-derived relaxing factor (EDRF/NO) was available and formation of prostaglandines was intact. Under high (44 mM) D-glucose concentrations on the other hand, a sustained vasodilatation dependent on the availability of L-arginine was observed, when formation of prostaglandins was blocked. This effect was partially reduced in the presence of prostaglandin synthesis. Furthermore, the effect of L-arginine under both conditions could be antagonized by the L-arginine-analogue NG-nitro-L-arginine-methyl-ester (100 microM). Our results suggest that hyperglycaemia impairs coronary artery autoregulation by reducing the threshold for hypoxic vasodilatation in an EDRF/NO-dependent manner. Concomitantly a shift from the formation of vasodilatatory to vasoconstrictive prostaglandines was observed. These results might be of particular interest in patients with diabetes mellitus and ischaemic heart disease.



Impaired arginine metabolism and NO synthesis in coronary endothelial cells of the spontaneously diabetic BB rat.

Am J Physiol (UNITED STATES) Oct 1995, 269 (4 Pt 2) pH1312-8

Arginine metabolism via nitric oxide (NO) synthase and other pathways was studied in coronary endothelial cells (EC) from the spontaneously diabetic BB rat, an animal model of human type I diabetes mellitus (IDDM). EC were prepared from insulin-treated diabetic BB (BBd) and non-diabetes-prone BB (BBn) rats. Basal NO synthesis was studied in EC cultured for 48 h in medium containing 0.4 mM L-arginine. At the end of the culture period, the medium was analyzed for nitrite and nitrate (two major end stable oxidation products of NO), and the cells were used to determine arginine uptake and metabolism and the activities of some arginine-degrading enzymes. For studies of arginine metabolism, cells were incubated at 37 degrees C for 1 h in Krebs-Henseleit bicarbonate buffer (pH 7.4) containing 1 mM L(-)[1-14C]arginine or L(-)[1-14C]ornithine. The rates of production of nitrite plus nitrate by BBd EC were only 15% of those of BBn cells. This impaired NO synthesis in BBd EC was not due to alterations in arginine uptake, NO synthase activity, or intracellular arginine concentrations but might have resulted from a limited intracellular availability of cofactors of NO synthase. In addition to the arginine-NO pathway, arginine was found to be metabolized to urea, ornithine, and, to a much lesser extent, CO2 via arginase and ornithine aminotransferase. The activities of arginase and the formation of ornithine and urea from arginine were decreased by 90% in BBd compared with BBn cells. These results, coupled with the reduced NO synthesis, indicate metabolic defects in arginine metabolism in BBd EC.



Directions in antihypertensive treatment--our future from the past.

Eur Heart J (ENGLAND) May 1995, 16 Suppl C p74-83

Future directions in antihypertensive treatment will rely on our present experience with antihypertensive drugs, on new concepts of cardiovascular regulation and on novel antihypertensive agents. At present, we seek early detection of hypertension; treatment should focus on normalization of blood pressure, the reversal or prevention of left ventricular hypertrophy, associated coronary artery disease and on the prevention of, or reparation of, myocardial fibrosis and microangiopathy. Therefore, combination therapy is advisable in severe cases, and any monotherapy should focus on the pharmacological principles compatible with these goals. ACE inhibitors and calcium antagonists appear to meet these requirements. There are, in addition, novel drugs i.e. angiotensin II receptor antagonists and renin inhibitors, as well as therapeutic stimulation of endothelial nitric oxide by L-arginine, the inhibition of endothelin-1 mediated vasoconstriction, and potassium-channel openers. All are examined in this contribution to delineate the perspectives in antihypertensive therapy. (75 Refs.)



Human and rat macrophages mediate fungistatic activity against Rhizopus species differently: in vitro and ex vivo studies.

Infect Immun (UNITED STATES) Nov 1995, 63 (11) p4489-94

Both rat alveolar macrophages and a human macrophages cell line with characteristics of human tissue (e.g., alveolar) macrophages (THP-1) were found to inhibit the germination of Rhizopus spores. However, the conditions under which fungistatic activity occurs are different for these two cell types. The inhibition of Rhizopus spore germination by rat alveolar macrophages requires the activation of macrophages and the presence of serum and L-arginine. During rat alveolar macrophage-mediated fungistatic activity, L-arginine is oxidized to nitric. Human macrophage-mediated fungistatic activity is similar to that mediated by rat macrophages in terms of the serum requirement, but it does not require L-arginine. Human macrophages did not produce any nitrite detectable by the colorimetric assay. Their ability to inhibit germination was enhanced by the combination of endotoxin and gamma interferon. The inhibition of Rhizopus spore germination by rat alveolar macrophages is thus mediated by the generation of nitric oxide, whereas the mechanism of similar inhibition by human macrophages remains poorly understood. Serum samples from diabetic rats as well as from patients with diabetes or uremia decreased the inhibitory effect of macrophages on spore germination. Dialysis of the serum samples against a buffered salt solution antagonized this phenomenon, indicating that a low-molecular-weight factor in the sera of patients with diabetes or uremia may modulate local antifungal defense mechanisms. The absence of L-arginine-dependent nitrogen oxidation in human macrophages, compared with its presence in rat alveolar macrophages, under conditions during which fungistatic activity occurs suggests that this phenomenon is species specific.



Vascular and hormonal responses to arginine: provision of substrate for nitric oxide or non-specific effect?

Clin Sci (Colch) (ENGLAND) Aug 1995, 89 (2) p183-90

1. The vascular and hormonal effects of L- and D-arginine were compared in healthy subjects and in patients with insulin-dependent diabetes mellitus or untreated essential hypertension.

2. Infusion of L- or D-arginine (40 mumol/l) in the forearm vascular bed, sufficient to increase the local concentration approximately 20-fold, had no effect on blood flow or the vasodilator response to acetylcholine (30 and 100 nmol/min) in patients with insulin-dependent diabetes (n = 7) or essential hypertension (n = 7), or in age- and sex-matched control subjects (n = 7 in both groups).

3. Systemic infusion of 10 g of L-arginine (n = 5) or D-arginine (n = 3) increased plasma concentration of arginine approximately 20-fold without altering supine or erect haemodynamics. Increases in plasma insulin, prolactin and glucagon were seen with both enantiomers. The stereopurity of arginine was confirmed in a cell-culture assay system.

4. We conclude that, in healthy subjects and patients with essential hypertension or insulin-dependent diabetes, synthesis of nitric oxide within the vasculature is not limited by substrate availability. At high concentrations of arginine, non-stereospecific effects, including alterations in hormone concentration, occur. It remains to be determined whether these non-stereospecific hormonal changes might contribute to certain haemodynamic effects of arginine.



Glutamine and arginine metabolism in tumor-bearing rats receiving total parenteral nutrition

Metabolism: Clinical and Experimental (USA), 1997, 46/4 (370-373)

Arginine supplementation increases glutamine levels in muscle and plasma. Since glutamine production is increased in catabolic states, these observations prompted us to investigate whether the flux of arginine to glutamine was increased in tumor-bearing (TB) rats, and we measured the synthesis rate of glutamine from arginine in control versus TB rats receiving standard total parenteral nutrition (TPN) solution. Male Donryu rats (N = 36; body weight, 200 to 225 g) were divided into two groups, control and TB rats. Yoshida sarcoma cells (1 x 106) were inoculated into the back of the rats (n = 18) subcutaneously on day 0. The rats were given free access to water and rat chow. On day 5, all animals, including non-TB rats (n = 18), were catheterized at the jugular vein and TPN was begun. On day 10, TPN solution containing either U-14C-glutamine (2.0 microCi/h) or U-14C-arginine (2.0 microCi/h) was infused as a 6-hour constant infusion. At the end of the isotope infusion, plasma was collected to determine the glutamine production rate in rats receiving U-14C-glutamine, and the ratio of specific activity of glutamine to specific activity of arginine was measured in rats receiving U- 14C-arginine. Only 2 g tumor caused a decrease in glutamine levels and an increase in glutamine and arginine production. The low flux rate of arginine to glutamine was observed in control rats (Arg to Gln, 41.0 plus or minus 11.9 micromol/kg/h). On the other hand, TB caused a significant increase in Arg to Gln compared with the control (213.3 plus or minus 66.1 micromol/kg/h, P < .01 v control). An increase in the flux rate of Arg to Gln was associated with an enhancement in the ratio of specific activity of ornithine to specific activity of arginine in TB rats (control 51.5% plus or minus 10.9% v 77.4% plus or minus 8.9%, P < .05). We conclude that (1) glutamine and arginine metabolism is altered with very small tumors, (2) although the flux of Arg to Gln was increased in TB and rats, the small increase in Arg to Gln cannot explain the obseved large increase in Gln production.



Dietary modulation of amino acid transport in rat and human liver

Journal of Surgical Research (USA), 1996, 63/1 (263-268)

Specialized diets enriched in the amino acids glutamine and arginine have been shown to benefit surgical patients. In the liver, glutamine supports glutathione biosynthesis, arginine regulates nitric oxide synthesis, and both of these amino acids serve as precursors for ureagenesis, gluconeogenesis, and acute phase protein synthesis. The effects of a diet enriched with glutamine and arginine on hepatic plasma membrane transport activity have not been studied in humans. We hypothesized that feeding supradietary amounts of these nutrients would enhance the activities of the specific carriers which mediate their transmembrane transport in the liver. We fed surgical patients (n = 8) and rats (n = 6) one of three diets: a) a regular diet, b) an enteral liquid diet containing arginine and glutamine, or c) an enteral diet supplemented with pharmacologic amounts of glutamine and arginine. Diets were isocaloric and were administered for 3 days. Hepatic plasma membrane vesicles were prepared from rat liver and from human wedge biopsies obtained at laparotomy. The transport of glutamine and arginine by rat and human vesicles was assayed. Vesicle integrity and functionality were verified by osmolarity plots, enzyme marker enrichments, and time courses. Provision of both a standard enteral liquid diet and one enriched with glutamine and arginine increased the activities of Systems N (glutamine) and y' (arginine) in rat and human liver compared to a control diet. The diet supplemented with glutamine and arginine was the most effective in increasing transport activity. We conclude that the liver responds to diets enriched with specific amino acids by increasing membrane transport activity. This adaptive response provides essential precursors for hepatocytes which may enhance hepatic synthetic functions during catabolic states. This study provides insights into the mechanisms by which enteral nutrition regulates nutrient transport at the cellular level and may provide a biochemical rationale for the use of formulas which are enrched with conditionally essential nutrients.



Muscle wasting and dedifferentiation induced by oxidative stress in a murine model of cachexia is prevented by inhibitors of nitric oxide synthesis and antioxidants

EMBO Journal (United Kingdom), 1996, 15/8 (1753-1765)

Muscle wasting is a critical feature of patients afflicted by AIDS or cancer. In a murine model of muscle wasting, tumor necrosis factor alpha (TNFalpha) induces oxidative stress and nitric oxide synthase (NOS) in skeletal muscle, leading to decreased myosin creatinine phosphokinase (MCK) expression and binding activities. The impaired MCK-E box binding activities resulted from abnormal myogenin-Jun-D complexes, and were normalized by the addition of Jun-D, dithiothreitol or Ref-1, a nuclear redox protein. Treatment of skeletal muscle cells with a phorbol ester, a superoxide-generating system, an NO donor or a Jun-D antisense oligonucleotide decreased Jun-D activity and transcription from the MCK-E box, which were prevented by antioxidants, a scavenger of reducing equivalents, a NOS inhibitor and/or overexpression of Jun-D. The decreased body weight, muscle wasting and skeletal muscle molecular abnormalities of cachexia were prevented by treatment of TNFalpha mice with the antioxidants D-alpha-tocopherol or BW755c, or the NOS inhibitor nitro-L-arginine.



Modulation of immune function and weight loss by L-arginine in obstructive jaundice in the rat

BR. J. SURG. (United Kingdom), 1994, 81/8 (1199-1201)

Jaundiced surgical patients have a high incidence of postoperative complications. Many causative factors have been identified including cachexia and immune suppression. The amino acid L-arginine has anabolic and immunostimulatory properties. It was hypothesized that dietary supplementation with L-arginine would diminish the weight loss and immune suppression of obstructive jaundice. Sixteen male Wistar rats rendered jaundiced by bile duct ligation were allocated to two groups. The test group (n = 8) received drinking water supplemented with 1.8 per cent L-arginine ad libitum and the control group (n = 8) received a solution of isonitrogenous glycine. Both groups had free access to standard chow. Body-weight, and fluid and food intake were recorded. After 21 days, delayed-type hypersensitivity to 2,4-dinitrofluorobenzene was assessed. Animals receiving L-arginine consumed more food than controls (mean(s.e.m.) 414(16) versus 360(13) g, P < 0.05) and lost less weight (mean(s.e.m.) proportion of initial body-weight lost 7.8(1.2) versus 14.8(1.4) per cent, P < 0.05). The delayed-type hypersensitivity response was significantly greater in rats receiving L-arginine (mean(s.e.m.) increase in ear thickness 23.9(2.7) versus 9.4(2.1) per cent, P < 0.05). In this animal model of obstructive jaundice dietary supplementation with L-arginine diminished both weight loss and immune suppression.



Evaluation of the effect of arginine-enriched amino acid solution on tumor growth

J. PARENTER. ENTER. NUTR. (USA), 1985, 9/4 (428-434)

To investigate the effect of arginine-enriched solution on tumor growth and metastasis, rats were infused with solutions containing 5.5 and 0.66% arginine for 8 days. Infusions were started at the same time of subcutaneous transplant of Yoshida sarcoma. Arginine-rich solution suppressed tumor growth at an early stage and prevented metastases to the liver and kidney. In addition, arginine supplements enhanced the phagocytic activity of alveolar macrophages. It also resulted in maintenance of a positive nitrogen balance and prevented the increases in the levels of several amino acids observed in the control group. The suppressive effect of arginine-enriched solution on tumor growth may be due to its activation of the immunologic system, in which the phagocytic activity of macrophages probably participates.



Regulation of macrophage physiology by L-arginine: Role of the oxidative L-arginine deiminase pathway

J. IMMUNOL. (USA), 1989, 143/11 (3641-3646)

The L-arginine content of the extracellular fluid in sites of predominant macrophage infiltration is reduced below plasma levels due to the activity of macrophage-derived arginase. Investigation of the effects of altered L-arginine availability on macrophage physiology reveals that culture of rat peritoneal macrophages in media containing L-arginine in the concentrations present in inflammatory lesions (<0.1 mM) enhances activation-associated functions. In contrast, culture in the higher L-arginine concentrations found in standard tissue culture media (0.4 to 1.2 mM) suppresses most macrophage functions (superoxide production, phagocytosis, and protein synthesis). An exception is the tumor cytotoxicity of Corynebacterium parvum-elicited macrophages which is enhanced by culture in supraphysiologic concentrations of L-arginine. Work reported here investigated the mechanisms for these L-arginine-dependent effects and, more specifically, the role of the recently described oxidative L-arginine deiminase pathway in the regulation of macrophage physiology. Overnight culture of resident or C. parvum-elicited peritoneal macrophages in media containing increasing concentrations of L-arginine (6 microM to 1 mM) resulted in: inhibition of electron transport chain activity (resident and C. parvum-elicited macrophages), increased lactate production (resident macrophages), and decreased ATP content (resident and C. parvum-elicited macrophages). In line with these findings, viability was markedly decreased after 2 days of culture when the initial L-arginine concentration was greater than or equal to0.1 mM. As shown before, increasing media concentrations of L-arginine were associated with suppression of superoxide production and cytotoxicity in resident macrophages and with reduced superoxide prodution and increased cytotoxicity in C. parvum-elicited macrophages. All L-arginine-dependent metabolic and functional alterations, as well as the loss of viability, were prevented by N(G)-monomethyl-L-arginine, a specific inhibitor of the oxidative L-arginine deiminase pathway. These results demonstrate that flux of L-arginine through the oxidative L-arginine deiminase pathway results in the inhibition of oxidative metabolism in rat macrophages. This metabolic inhibition may, through alterations in the macrophage high energy phosphate stores, mediate the suppression of cell functions and result ultimately in cell death.



Growth hormone secretion in Alzheimer's disease: Studies with growth hormone-releasing hormone alone and combined with pyridostigmine or arginine

DEMENTIA (Switzerland), 1993, 4/6 (315-320)

There is evidence that GH secretion is reduced in normal elderly subjects as well as in patients with Alzheimer's disease (AD). To clarify the mechanisms underlying this GH hyposecretory state in 14 elderly subjects (age 65-75 years) and 15 AD patients (age 61-78 years), we studied the effects of both pyridostigmine (PD, 120 mg orally), a cholinesterase inhibitor, and arginine (ARG, 0.5 g/kg i.v.), two substances likely acting via inhibition of hypothalamic somatostatin, on GH response to GHRH (1 microg/kg i.v.). The GH response to PD alone was also studied. Twenty-two young healthy volunteers were studied as control group. Basal GH levels were similar in young, elderly and AD subjects (0.7 plus or minus 0.2, 0.8 plus or minus 0.2 and 0.9 plus or minus 0.2 microg/l). IGF-I levels were lower (p < 0.005) in elderly (73.9 plus or minus 8.2 microg/l) and in AD subjects (108.0 plus or minus 5.9 microg/l) than in young subjects (288.7 plus or minus 22.1 microg/l); however, they were higher (p < 0.01) in AD patients than in the elderly subjects. The PD-induced GH release did not significantly differ in young, elderly and AD subjects while the GH responses to GHRH in the elderly (AUC: 297.9 plus or minus 49.2 microg/l/h) and in AD subjects (437.6 plus or minus 93.5 microg/l/h) were lower (p < 0.01) than in young subjects (658.6 plus or minus 100.1 microg/l/h). PD potentiated the GH response to GHRH both in elderly and in AD subjects (901.7 plus or minus 222.4 and 1,070.3 plus or minus 207.2 microg/l/h, p < 0.005) but these responses were lower (p < 0.0001) than those recorded in young subjects (2,041.1 plus or minus 245.6 microg/l/h). ARG potentiated the GHRH-induced GH rise both in elderly and in AD subjects (1,545.2 plus or minus 246.0 and 1,659.3 plus or minus 196.8 microg/l/h, p < 0.001) but in this case, the GH response to GHRH + ARG overlapped with that in young subjects (2,140.2 plus or minus 229.5 microg/l/h). In contrast to young subjects, in elderly and in AD subjects, the potentiating effect of ARG on GHRH-induced GH rise was higher (p < 0.01) than that of PD. These results show that testing neural controls of GH secretion with different neuroactive substances does not allow to differentiate normal aging from AD. In both groups, somatotroph responsiveness to GHRH is potentiated by the enhancement of the cholinergic activity but much more by ARG, which is compatible with the presence of a cholinergic impairment.



Prevention of preeclampsia with calcium supplementation and its relation with the L-arginine:nitric oxide pathway

Braz J Med Biol Res (BRAZIL) Jun 1996, 29 (6) p731-41

Pregnancy-induced hypertension (PIH) remains a common cause of maternal and fetal morbidity and mortality. During the past 7 years, some progress has been made in the prevention of PIH. Specifically, clinical studies have shown that supplementation with calcium can significantly reduce the frequency of PIH, especially in populations with a low calcium intake. We have suggested that, in such a population, calcium supplementation is a safe and effective measure for reducing the incidence of PIH. Calcium supplementation reduces the risk of PIH by maintaining the serum ionized calcium level which is crucial for the production of endothelial nitric oxide, the increased generation of which maintains the vasodilatation that is characteristic of normal pregnancy. In PIH there is an impaired nitric oxide synthesis and cyclic GMP production. (99 Refs.)



Dietary supplementation of nucleotides and arginine promotes healing of small bowel ulcers in experimental ulcerative ileitis

Sukumar P.; Loo A.; Magur E.; Nandi J.; Oler A.; Levine R.A.
Dr. R.A. Levine, Division of Gastroenterology, University Hospital, 750
East Adams Street, Syracuse, NY 13210 USA
Digestive Diseases and Sciences (USA) , 1997, 42/7 (1530-1536)

We previously showed that intravenous total parenteral nutrition supplemented with nucleosides and nucleotides (NS/NT) promoted ulcer healing in rats with indomethacin-induced ileitis. The present study evaluated whether dietary NT supplementation would similarly affect ulcer healing in this model. Female Lewis rats were randomized into either control or experimental groups receiving yeast RNA containing NT or arginine, glutamine, fish oil, guar gum, or a combination of yeast RNA + arginine diets. Ileitis was induced by two doses of indomethacin (7.5 mg/kg) administered subcutaneously 24 hr apart. Ulcer number and length were determined at 4, 8, and 14 days after induction of ileitis. Ileal villous and crypt length, crypt-villous ratio, and bromodeoxyuridine (BrdU) labeling were studied in the control and yeast RNA-supplemented diet groups. Ileal ulceration was present in all groups at 4 and 8 days and was almost healed by 14 days. Rats receiving yeast RNA, arginine, and yeast RNA + arginine diets showed a significant decrease in ulcer number (56%, 28%, and 34%, respectively) and length (67%, 41%, and 48%, respectively) compared to controls at 8 but not at 4 days.Glutamine, fish oil, and guar gum had no effect on ulcer healing at 4, 8, or 14 days. Among the histological parameters, a significant decrease in crypt length in the yeast RNA-supplemented group at 8 days suggested an acceleration of the healing process and restoration to a near-normal crypt- villous architecture. We conclude that the yeast RNA, arginine, and yeast RNA + arginine diets accelerated ulcer healing, as indicated by decreased ulcer number and length. We postulate that the underlying mechanism(s) contributing to ulcer healing may be related, in part, to increased cell proliferation.



Effect of arginine on toxin production by clostridium difficile in defined medium
Karasawa T.; Maegawa T.; Nojiri T.; Yamakawa K.; Nakamura S.
Dr. S. Nakamura, Department of Bacteriology, School of Medicine, Kanazawa
University, 13-1 Takara-machi, Kanazawa, Ishikawa 920 Japan
Microbiology and Immunology (Japan) , 1997, 41/8 (581-585)

Twenty strains of Clostridium difficile were examined for the effect of arginine on toxin production in a defined medium. In three strains, the production of toxins A and B was greatly enhanced in the absence of arginine. These strains showed distinctively poorer growth in the absence of arginine in com-parison with the remaining 17 strains, indicating that the presence of arginine is required for good growth among the three strains. From the present results, test strains were divided into two groups: a group in which arginine insufficiency caused distinctly poor growth and enhanced toxin production, and another group in which there was neither distinctly poor growth nor enhanced toxin production.The phenomenon is discussed in relation to the biosynthesis and catabolism of arginine.



Stress-induced enhancement of colitis in rats: CRF and arginine vasopressin are not involved
Gue M.; Bonbonne C.; Fioramonti J.; More J.; Del Rio-Lacheze C.; Comera
C.; Bueno L.
American Journal of Physiology - Gastrointestinal and Liver Physiology (USA) , 1997, 272/1 35-1 (G84-G91)

Because exacerbation of colitis seems to be associated with stress, we proposed evaluating the influence of stress and the involvement of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) on experimental colitis in rats. Partial restraint stress was applied during 4 consecutive days, before or after intracolonic 2,4,6-trinitrobenzenesulfoni c acid (TNB) instillation (15 mg) in rats. Finally, two groups of rats were centrally injected with alpha-helical CRF-(9-41) (5 microg) or AVP antagonist (5 microg) before each session of stress. Stress was applied before or right after TNB enhanced colitis, with an increase in macroscopic and histological scores and myeloperoxidase activity. alpha-Helical CRF-(9-41) or AVP antagonist had no effect on TNB-induced colitis but enhanced the effects of stress on colitis. These results show that stress may exacerbate experimental colitis in rats and that CRF and AVP are not responsible for this effect.



Manipulation of the L-arginine-nitric oxide pathway in experimental colitis

Neilly P.J.D.; Kirk S.J.; Gardiner K.R.; Anderson N.H.; Rowlands B.J. Department of Pathology, Queen's University of Belfast, Belfast United Kingdom British Journal of Surgery (United Kingdom) , 1995, 82/9 (1188-1191)

The role of the L-arginine-nitric oxide pathway in the pathogenesis of colonic inflammation was assessed using L-arginine and its competitive analogue N(omega)-nitro-Larginine methyl ester (L-NAME) in a rat model of colitis. In the first study oral L-arginine 2 per cent (control: 3.4 per cent L-glycine) was administered with and without L-NAME 100 mg/l. Orally administered L-arginine increased colonic inflammation (P = 0.004) and decreased thymic weight (P = 0.0007). Addition of L-NAME reduced the colonic inflammation and prevented loss of body-weight (P < 0.04). In thesecond study L-NAME was administered orally in concentrations of 100, 200 and 500 mg/l (control: no L-NAME). L-NAME 500 mg/l reduced colonic inflammation and increased thymic weight and body-weight (P < 0.01). Thymic weight and body-weight correlated positively with the concentration of L-NAME administered orally (r(s) 0.3, P = 0.04). L-NAME 1 g/l was administered topically as an enema (control: suspension agent). Topical L-NAME reduced colonic inflammation and increased thymic weight (P < 0.05). These results suggest that the L-arginine-nitric oxide pathway mediates colonic inflammation in this model.



Experimental colitis is ameliorated by inhibition of nitric oxide synthase activity

Rachmilewitz D.; Karmeli F.; Okon E.; Bursztyn M.Department of Medicine, Hadassah University Hospital, Mount Scopus, PO Box 24035, Jerusalem 91240 Israel Gut (United Kingdom) , 1995, 37/2 (247-255)

Enhanced nitric oxide (NO) generation by stimulated NO synthase (NOS) activity may, through its oxidative metabolism contribute to tissue injury in experimental colitis. In this study the possible amelioration of experimental colitis by N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS activity, was evaluated. Colitis was induced in rats by intracolonic administration of 30 mg trinitrobenzene sulphonic acid (TNB) dissolved in 0.25 ml 50% ethanol or by flushing the colon of capsaicin pretreated rats with 2 ml of 5% acetic acid. In several experiments, L-NAME 0.1 mg/ml was added to the drinking water at the time of colitis induction with TNB or seven days before acetic acid treatment. Rats were killed at various time intervals after induction of colitis. A 10 cm distal colonic segment was isolated, weighed, lesion area measured, and explants organ cultured for 24 hours for determination of NO generation by the Greiss reaction. The rest of the mucosa was scraped for determination of myeloperoxidase and NOS activities and leukotriene generation. In TNB treated rats mean arterial pressure was also determined up to 72 hours after damage induction, with or without cotreatment with nitroprusside. L-NAME significantly decreased the extent of tissue injury in TNB treated rats. Seven days after TNB treatment lesion area was reduced by 55%, colonic weight by 37%, and myeloperoxidase and NOS activity by 59% and 42%, respectively. Acetic acid induced colitis in capsaicin pretreated rats was also significantly decreased by L-NAME. Twenty four hours after acetic acid treatment lesion area was reduced by 61%, colonic weight by 21%, and NOS activity by 39%. Mean (SEM) arterial blood pressure in TNB + L-NAME treated rats was 37.6 (8.1) mm Hg higher than in TNB treated rats, an effect that was only partially abolished by nitroprusside. These results show that inhibition of NO synthesis by an L-arginine analogue significantly ameliorates the extent of tissue injury in two models of experimental colitis, an effect that is not due only to its vasoconstrictor properties.Modulation of NO generation may be a novel therapeutic approach in inflammatory bowel disease.



Growth inhibition of subcutaneously transplanted hepatomas by alterations of the dietary arginine-methionine balance

Nutrition and Cancer (USA) , 1996, 25/3 (317-327)

We hypothesized that alteration of the dietary arginine-methionine balance might inhibit tumor growth and suggest nutritional strategies for cancer therapy. The Morris hepatoma 3924A was subcutaneously transplanted in ACI rats. Control diets containing normal levels of arginine, ates (59%), fat (10%), and fiber, vitamins, and minerals (7%) weren (24%), fed for 28 days. Six experimental diets were adjusted to maintain amino acids at 23-25% and carbohydrates at 58-60%; these diets were 1%-2% deficient in arginine or supplemented with 1-2% arginine (expressed as percent amino acid content of diet) in combination with normal, deficient, and supplementary levels of methionine. Daily food intake was unaffected by the experimental diets. The control groups gained 26.4 plus or minus 2.8 g body weight, and small body weight decrements ranged from 3.5% to 8.4% in the groups fed the experimental diets. Tumor weight of controls was 8.5 plus or minus 1.5% of body weight. The experimental diets that produced significant tumor growth inhibition (TGI) were 1) the arginine-methionine-deficient diet, 2) the arginine-excess-methionine-deficient diet. 3) the arginine-deficient diet, and 4) the excess-arginine diet. Diets containing excess methionine failed to produce TGI. TGI resulted in tumor weights 41-46% of control values. TGI was associated with significantly lower blood urea nitrogen, plasma protein, and tumor spermidine-to-spermine ratio than in tumor-bearing controls. It is concluded that dietary alteration of a single amino acid, arginine, might be a potentially useful nutritional strategy for controlling tumor growth.