Dietary l-Arginine Supplementation Protects Weanling Pigs from Deoxynivalenol-Induced Toxicity

This study was conducted to determine the positive effects of dietary supplementation with l-arginine (Arg) on piglets fed a deoxynivalenol (DON)-contaminated diet. A total of eighteen, 28-day-old healthy weanling pigs were randomly assigned into one of three groups: uncontaminated basal diet (control group), 6 mg/kg DON-contaminated diet (DON group) and 6 mg/kg DON + 1% l-arginine (DON + ARG group). After 21 days of Arg supplementation, piglets in the DON and DON + ARG groups were challenged by feeding 6 mg/kg DON-contaminated diet for seven days. The results showed that DON resulted in damage to piglets. However, clinical parameters, including jejunal morphology, amino acid concentrations in the serum, jejunum and ileum, were improved by Arg (p < 0.05). Furthermore, the mRNA levels for sodium-glucose transporter-1 (SGLT-1), glucose transporter type-2 (GLUT-2) and y⁺l-type amino acid transporter-1 (y⁺LAT-1) were downregulated in the DON group, but the values were increased in the DON + ARG group (p < 0.05). Collectively, these results indicate that dietary supplementation with Arg exerts a protective role in pigs fed DON-contaminated diets.     

Arginine therapy: a novel strategy to induce nitric oxide production in sickle cell disease

To determine the effects of L-arginine (L-Arg) supplementation on nitric oxide metabolite (NOx) production, oral L-Arg was given to normal controls, sickle cell disease (SCD) patients at steady state and SCD patients hospitalized with a vaso-occlusive crisis (VOC). L-Arg (0.1 g/kg) increased NOx formation by 18.8 +/- 68% in normal controls, whereas steady-state SCD patients demonstrated a paradoxical decrease in NOx of -16.7 +/- 4% (P = 0.004). In contrast, patients with VOC demonstrated a dramatic increase in NOx production by +77.7 +/- 103%, a response that was dose dependent. L-Arg appears to be the rate-limiting step in NOx production during VOC. Oral arginine may therefore benefit SCD patients by inducing an increase in NO production during VOC.     

ROLE OF l-ARGININE IN NITRIC OXIDE PRODUCTION IN HEALTH AND HYPERTENSION

• 1 l ‐Arginine is the substrate for vascular nitric oxide (NO) formation. Under normal physiological conditions, intracellular l ‐arginine levels far exceed the K_m of NO synthase for l ‐arginine. However, endogenous NO formation is dependent on extracellular l ‐arginine concentrations, giving rise to the concept of the ‘l ‐arginine paradox’.
• 2 Nitric oxide production in epithelial and endothelial cells is closely coupled to cellular l ‐arginine uptake, indicating that l ‐arginine transport mechanisms play a major role in the regulation of NO‐dependent function.
• 3 Consistent with the data in endothelial and epithelial cells are functional data indicating that exogenous l ‐arginine can increase renal vascular and tubular NO bioavailability and thereby influence kidney perfusion, function and arterial pressure. The integrated effect of increased cellular l ‐arginine transport is to lower arterial pressure. Therefore, the use of l ‐arginine in the treatment of hypertension warrants investigation.
• 4 Low NO bioavailability is central to the development and maintenance of hypertension and to related endothelial dysfunction and target organ damage. We propose that l ‐arginine can interrupt the vicious cycle that initiates and maintains low NO in hypertension by increasing the formation of NO.

     

L-精氨酸对大鼠脂多糖致急性肺损伤的影响及机理

目的:探讨L-精氨酸对大鼠急性肺损伤的影响及机理.方法:采用尾静脉注射脂多糖(lipopolysaccharide,LPS)制备大鼠急性肺损伤模型.将45只大鼠随机分为三组:生理盐水对照组(NS组)、急性肺损伤模型组(LPS组)和L-精氨酸预处理组(L-Arg组)(n=15),再各分为2、6、24 h三个时间点.LPS组尾静脉注射LPS(6 mg/kg)制备急性肺损伤模型,L-Arg组在造模前0.5 h腹腔注射L-Arg 500 mg/kg.测定各组大鼠不同时间点的动脉血气分析,肺组织湿/干重(W/D)比,肺组织HE病理切片,ELISA法测定血清TNF-α,硝酸还原酶法测定血清NO,Real Time-PCR法测定肺组织iNOSmRNA.结果:LPS组动脉血氧降低、W/D增高、血清TNF-α及NO增高、肺组织iNOSmRNA增高,且与对照组比较有显著差异(P<0.05),肺组织HE病理切片有肺损伤改变.L-Arg组肺损伤有改善,上述检测指标与LPS组有显著差异(P<0.05).结论:L-精氨酸预处理对LPS致大鼠急性肺损伤有保护作用.     

l-ARGININE INFUSION INDUCES HYPOTENSION AND DIURESIS/NATRIURESIS WITH CONCOMITANT INCREASED URINARY EXCRETION OF NITRITE/NITRATE AND CYCLIC GMP IN HUMANS

1. The vascular endothelium produces endothelium-derived relaxing factor (EDRF) or nitric oxide (NO), which exerts vasodilation through cyclic guanosine monophosphate (cGMP) as a second messenger. To determine whether EDRF has any vasodilating and natriuretic action in man, the present study examined the effects of L-arginine (L-Arg), a substrate for NO, on the responses of mean blood pressure (MBP) and heart rate (HR); plasma concentrations of cGMP, atrial natriuretic factor (ANF) and nitrite/nitrate (NOx); urinary excretion of sodium, cGMP and NOx; and urinary flow in eight normal male subjects. These parameters were compared with those following saline infusion in the same subjects. Clearance of para-aminohippuric acid (PAH) and inulin was studied in five normal subjects. 2. Infusion of L-Arg (30 g) caused a significant fall in MBP (-8 mmHg) with a concomitant rise in HR (10 beats/min), while saline infusion had no effects on these parameters. 3. Neither L-Arg nor saline infusion caused appreciable changes in plasma concentrations of ANF or NOx. Plasma cGMP concentrations increased significantly during (1.7-fold) and after (1.9-fold) L-Arg infusion, but only slightly (1.3-fold) during saline infusion. 4. Urine flow increased more remarkably following L-Arg infusion than that following saline infusion. Remarkable increases in urinary excretion of sodium and fractional excretion of sodium were observed after L-Arg infusion compared with those after saline infusion. Natriuresis was associated with enhanced urinary excretion of cGMP and Nox. Urinary Nox excretion showed positive correlations with urinary flow (r = 0.69, P less than 0.001) and with urinary cGMP excretion (r = 0.60, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of nitric oxide and renal nerves on renomedullary haemodynamics in SHR and Wistar rats,studied with laser Doppler technique

The threshold for activation of the humoral renal antihypertensive system, presumably residing in the renomedullary interstitial cells (RIC), is substantially reset upwards in the spontaneously hypertensive rat (SHR). Depressor reactions, normally elicited by an increased renal perfusion pressure, can be inhibited either by high frequency renal nerve stimulation or blockade of nitric oxide synthesis, i.e. manoeuvres decreasing renal blood flow at this high perfusion pressure. The present study was designed to explore the effects on regional renal haemodynamics of blocking NO synthesis with N-ω-nitro-l-arginine (l-NNA) in chloralose anaesthetized SHR and Wistar rats. Mean arterial blood pressure (MAP), heart rate (HR), renal blood flow (RBF), cortical blood perfusion (CBP) and papillary blood perfusion (PBP) were measured in renally innervated and denervated SHR (S_in=8, S_dn=8) and in Wistar rats (W_in=10, W_dn=10). An innervated non-treated Wistar group served as control (C_in=12). The laser Doppler technique was used to record CBP and PBP. MAP increased in all groups receiving l-NNA while HR, RBF and CBP simultaneously decreased. The relative decreases in RBF were more marked into the two SHR groups than in the corresponding Wistar groups. After l-NNA PBP also decreased in all four groups despite the increased MAP and more so in the S_i group; W_i -19±8 (P<0.05), W_d -17±6 (P=0.07), S_i -50±9 (P<0.01) and S_d-25±9% (P<0.05). We conclude that NO is important for maintaining PBP especially in SHR. The more marked decrease in PBP in the innervated SHR suggests a NO/renal nerve interaction in the control of renomedullary blood flow in SHR. This finding may be of importance for the regulation of the humoral renal depressor mechanism.     

The effect of <Emphasis Type="SmallCaps">l</Emphasis>-NAME and <Emphasis Type="SmallCaps">l</Emphasis>-arginine on impairment of memory formation and state-dependent learning induced by morphine in mice

Rationale. Morphine and nitric oxide (NO) have important functional interactions in different neural processes, and both modulate learning and memory although their interaction in cognitive performance has not been elucidated. Objective. To examine the effect of the NO synthase (NOS) inhibitor N^G-nitro-l-arginine methyl ester (l-NAME) and NOS substrate l-arginine on morphine-induced impairment of memory formation and the state-dependent retrieval of a passive avoidance task learned under morphine influence. Methods. All drugs were administered intraperitoneally, and a one-trial step-down paradigm was used for the assessment of memory in adult male NMRI mice. Morphine was administered 30 min before training to induce impairment of memory formation and 30 min before test to induce state-dependent retrieval of the memory acquired under pre-training morphine influence. l-NAME or l-arginine was administered either 5 min after training or 45 min before the test. Results. Pre-training morphine induced impairment of memory formation that was reversible by pre-test morphine but not saline. Post-training administration of l-arginine (200 mg/kg) and l-NAME (3, 10 and 30 mg/kg), respectively, facilitated and impaired the memory consolidation, but their pre-test injections did not affect retention. However, post-training l-arginine at per se non-effective doses of 20 mg/kg and 60 mg/kg reversed the morphine-induced impairment of memory formation. Pre-test administration of l-NAME (3 mg/kg and 10 mg/kg) could restore the memory impairment induced by pre-training morphine, and this effect was blocked by concomitant pre-test l-arginine (60 mg/kg). Concomitant administration of low doses of l-NAME (1 mg/kg) and morphine (0.5 mg/kg) pre-test also revealed an additive effect in restoring the morphine state of memory. Conclusion. These results suggest that the impairment of memory formation and the facilitation of retrieval induced by morphine involves decreased synthesis/release of NO and can be counteracted by NOS substrate. Electronic Publication     

Paradoxical increase in nitric oxide synthase activity in hypercholesterolaemic rats with impaired renal function and decreased activity of nitric oxide.

BACKGROUND: We have shown that acute exposure of oxidized low-density lipoprotein (OX-LDL) induces vasoconstriction in renal vessels and reduces glomerular filtration rate (GFR) in an isolated perfused rat kidney model by decreasing the activity of nitric oxide (NO). L-arginine has a protective role against OX-LDl-induced vasoconstriction. Micropuncture studies have demonstrated that short-term diet-induced hypercholesterolaemia is associated with decreased GFR and renal blood flow and increased glomerular capillary pressure. This may be mediated by decreased activity of NO. METHODS: Rats were made hypercholesterolaemic by supplementing the standard chow with 4% cholesterol and 1% sodium cholate. A group of rats on hypercholesterolaemic diet also received L-arginine in the drinking water. After 4 and 6 weeks, blood samples and 24-h urine samples were collected for the measurement of biochemical parameters. After 6 weeks, all rats were subjected to isolated perfusion of kidneys at a constant pressure of 100 mmHg. During isolated perfusion, the unused contralateral kidney was taken for morphological studies and for assessing the activity of nitric oxide synthase enzyme by beta-NADPH diaphorase histochemistry. RESULTS: Rats fed a high-cholesterol diet had LDL levels 3-6 times greater than the rats fed standard chow. Rats that received L-arginine in the drinking water had serum L-arginine levels 5-6 times greater than control rats. At 6 weeks, creatinine clearance was significantly lower in the rats on the high-cholesterol diet compared to the rats on standard chow and rats on high-cholesterol diet plus L-arginine. Twenty-four-hour urinary total nitrate and nitrite excretion in the hypercholesterolaemic rats was 1.5-2 times greater than that of control rats. Twenty-four-hour urinary cGMP excretion was significantly lower in the rats on a high-cholesterol diet, but in the rats on high-cholesterol diet and L-arginine, 24-h urinary cGMP excretion was not significantly different from that of control rats. During isolated perfusion of kidneys, renal perfusate flow was found to be significantly reduced in the kidneys taken from the rats on a high-fat diet compared to controls. L-arginine supplementation in the drinking water almost completely reversed the effect of a high-fat diet. Inulin clearance was also significantly reduced in kidneys on a high-fat diet in contrast to controls but not in kidneys on high fat-diet and L-arginine. Basal cGMP excretion in urine was significantly lower in the kidneys taken from the rats on a high-fat diet compared to controls. L-arginine supplementation restored the basal cGMP excretion in these kidneys. NO synthase (NOS) enzyme activity as assessed by NADPH diaphorase activity showed that kidney sections taken from the rats on a high-fat diet showed more intense staining, indicating increased activity compared to the kidney sections taken from the rats on a normal diet. CONCLUSION: Though activity of NO is diminished in hypercholesterolaemic rats with impaired renal function, there is a paradoxical increase in NO production and NOS activity. L-arginine reverses the effects of a high-fat diet.     

L-arginine metabolism in early-onset and late-onset pre-eclamptic pregnancies

Abstract

Objective. The present case-control study was undertaken to investigate l-arginine metabolism in pregnant women with early-onset and late-onset pre-eclampsia. Attempts were made to differentiate these two distinct diseases entities by using measured and derived parameters of l-arginine metabolism. Study design. Thirty-six patients with early-onset, 17 patients with late-onset pre-eclampsia and 15 healthy pregnant women at term were studied. Patients were categorized according to the weeks of gestation (< 34 vs. ≥ 34) at the appearance of clinical symptoms (hypertension + proteinuria). Venous samples were taken at gestational age of 29.8 ± 2.5, 36.1 ± 2.2 and 39.2 ± 1.2 weeks, respectively. L-arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), monomethylarginine (MMA) and l-ornithine were measured by LC-MS/MS method. L-arginine/ADMA, l-ornithine/l-arginine, ADMA/SDMA ratios and the arginine methylation index (arg-MI) were calculated. Results. Plasma levels of ADMA and MMA were significantly higher (p < 0.002) in pre-eclamptic patients than in healthy women. No significant differences could be detected between patients with early-onset and late-onset pre-eclampsia in either parameter studied. L-ornithine correlated positively with ADMA (r = 0.526, p < 0.001) and MMA (r = 0.533, p < 0.001) in the whole study population, and inversely with l-arginine (r = ? 0.277, p < 0.044) in the pre-eclamptic group. When compared with maternal plasma in venous cord blood l-arginine was markedly reduced (p < 0.05) and there was a significant elevation in ADMA, SDMA, MMA and l-ornithine (p < 0.001, for each) without discernible differences between the study groups. Conclusions. Parameters of l-arginine metabolism do not discriminate the early-onset from late-onset pre-eclampsia. Our study provided indirect evidences for the redirection of l-arginine-NOS to the l-arginine-arginase pathway.     

L-精氨酸对慢性阻塞性肺病大鼠模型的肺功能保护

目的探讨L-精氨酸对被动吸烟致肺损伤大鼠的肺功能保护作用。方法采用香烟熏吸加气道内注入脂多糖法建立慢性阻塞性肺病（COPD）大鼠模型，并应用L-精氨酸干预，检测各组大鼠的肺功能、动脉血气，检测肺组织匀浆的NO及一氧化氮合酶（NOS）含量，观察肺组织病理学改变并进行形态学定量检测，检测肺组织内皮型NOS（eNOS）和诱生型NOS（iNOS）的表达情况。结果大鼠模型基本符合人类COPD组织病理学改变特点，应用L-精氨酸干预后，大鼠的肺组织损伤减轻，肺功能改善。结论应用L-精氨酸干预，对于COPD的形成有预防保护作用。