Intravenous Infusion Of L-arginine Research Articles

L-arginine supplementation improved neonatal outcomes in pregnancies with hypertensive disorder or intrauterine growth restriction: A systematic review and meta-analysis of randomized controlled trials

Previous research established that the availability of l-arginine affects placental vascular development and fetal growth. However, practical details associated with the effects of l-arginine supplementation on the neonatal outcomes of hypertensive disorder (HD) and intrauterine growth restriction (IUGR) pregnancies are limited. The PubMed, ScienceDirect, and Web of Science databases were searched for peer-reviewed literature published by September 30, 2021 to investigate the operational details of l-arginine supplementation in improving neonatal outcomes in complicated pregnancies. Standardized mean difference (SMD) and weighted mean difference (WMD) of continuous variables, as well as the risk ratio (RR) for categorical variables were pooled by random-effects models. The results indicated that l-arginine supplementation increased the plasma nitric oxide (NO) concentrations in IUGR pregnancies (SMD: 0.71; 95% CI: 0.45, 0.97; I2=0%), but decreased the risk of preeclampsia in HD mothers (RR: 0.49; 95% CI: 0.31, 0.76; I2=0%). Administration with l-arginine elevated birth weights both in hypertensive and IUGR pregnant women, with WMDs of 194.70g (95% CI: 58.21, 331.20; I2=44.2%) and 134.00g (95% CI: 43.53, 224.46; I2=42.4%), respectively. However, the intervention had no effect on gestational age except in HD pregnancies (WMD: 7.05d; 95% CI: 3.16, 10.95; I2=36.5%). l-arginine administration during pregnancy significantly reduced the small for gestational age (SGA) risk of fetus both in HD (RR: 0.51; 95% CI: 0.31, 0.83; I2=0.0%) and IUGR mothers (RR: 0.46; 95% CI: 0.25, 0.88; I2=0.0%). Subgroup analyses revealed that l-arginine supplementation at <4g/d dosage or for ≥1-month duration or in the third trimester had a greater effect on birth weights in HD women without proteinuria, but a higher l-arginine dosage was more beneficial for extending gestational age and reducing the risk of SGA in older pregnancies. Additionally, intravenous infusion of l-arginine, but not oral administration, significantly increased birth weight in IUGR pregnancies with elevated NO concentrations, although the recommended amount should be confined to <4g/d. These findings provide practical guidelines for l-arginine supplementation to improve the birth outcomes of complicated pregnancies. CRD42021246290 (https://www.crd.york.ac.uk/PROSPERO).

P.69 - The evaluation of new biomarkers in a case of MELAS

The aim of our study is to evaluate the utility of new biomarkers, FGF-21 and GDF-15, as well as to confirm the efficacy of L-arginine and sodium pyruvate administration in a patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). The patient was 60 years old women with mtT3271C mutation who developed abrupt onset of aphasia and stroke-like episodes. Muscle pathology and laboratory findings were compatible with MELAS. She was treated with L-arginine and sodium pyruvates, but her condition got worsen and died in 2 years. During the clinical course of the patient, we examined FGF-21 and GDF-15 which were reported to be sensitive and specific new biomarkers of mitochondrial diseases. Traditional biomarkers, lactate and pyruvate, were also measured and the relationship between serum levels of biomarkers and clinical severity scale were evaluated. We also performed autopsy and examined pathology. New biomarkers showed consistently high values along with the course and increased with disease progression. Of note, serum degree showed temporal fall when her consciousness was improved with sodium pyruvate therapy. In contrast, traditional biomarkers were increased in early stage and got decreased in advanced period. The intravenous infusion of L-arginine immediately recovered the stroke-like episodes attacks, but oral intake of L-arginine could not prevent the disease progression. Sodium pyruvate administration seemed to be effective, but was discontinued because of digestive dysfunction. In the pathological findings, most of stroke like lesions were on chronic stage, including cortical laminar necrosis and massive spongy change of gray and white matter. In this case, the utility of new biomarkers was demonstrated. Also, the positive effect of L-arginine and sodium pyruvate therapy on the disease progression was suggested.

Exogenous L‐Arginine Restores Spontaneous Cardiac Baroreflex Sensitivity in Never‐Treated Hypertensive Men

Depressed cardiac baroreflex sensitivity (cBRS) is associated with an increased risk of mortality in patients with hypertension. A candidate mechanism for the centrally mediated impairment in cBRS is reduced synthesis of the neuromodulator nitric oxide. Therefore, we investigated the effect of intravenous L‐arginine, a precursor of nitric oxide, on the cBRS in human hypertension. Beat‐to‐beat blood pressure (Finometer) and heart rate (ECG) were measured in both normotensive (n=8, 44±4 yrs., Norm) and never‐treated hypertensive men (n=8, 47±2 yrs., Hyper) before and during intravenous infusion of L‐arginine (1 g/min; total, 30 g) or saline. Linear regression analysis between RR interval and systolic blood pressure was used to determine the gain (i.e. sensitivity) of the arterial baroreflex control of the heart. Compared to Norm group, patients with hypertension had lower spontaneous cBRS (Norm: 13±1 vs. Hyper: 7.9±1 ms.mmHg‐1; P&lt;0.01). On administration of L‐arginine, cBRS increased in both groups (Norm: 17±3 vs. Hyper: 15±3 ms.mmHg‐1; P&lt;0.01 vs. before infusion) and returned to near resting values after infusion. Increases in cBRS during infusion of L‐arginine were greater in Hyper (P&lt;0.05) and differences between groups disappeared. Importantly, during saline infusion, the spontaneous cBRS remained unchanged in both groups. In conclusion, these data demonstrate that short‐term L‐arginine infusion restores the arterial baroreflex control of heart rate in never‐treated hypertensive men, probably via increased nitric oxide synthesis.

Effects of l-arginine on anatomical and electrophysiological deterioration of the eye in a rodent model of nonarteritic ischemic optic neuropathy

The aims of this study were to clarify the effectiveness of L-arginine (1) for reducing the severity of anatomical changes in the eye and improving visual function in the acute stage of a rodent model of nonarteritic ischemic optic neuropathy (rNAION) and (2) in preventing those changes in anatomy and visual function. For the first aim, L-arginine was intravenously injected into rats 3 h after rNAION induction; for the second aim, rNAION was induced after the oral administration of L-arginine for 7 days. The inner retinal thickness was determined over time by optical coherence tomography, and the amplitude of the scotopic threshold response (STR) and the number of surviving retinal ganglion cells (RGCs) were measured. These data were compared with the baseline data from the control group. Both intravenous infusion of L-arginine after rNAION induction and oral pretreatment with L-arginine significantly decreased optic disc edema in the acute stage and thinning of the inner retina, reduced the decrease in STR amplitude, and reduced the decrease in the number of RGCs during rNAION. Based on these results, we conclude that L-arginine treatment is effective for reducing anatomical changes in the eye and improving visual function in the acute stage of rNAION and that pretreatment with L-arginine is an effective therapy to reduce the severity of the condition during recurrence in the other eye.

Pulmonary hemodynamic disorder in pediatric sepsis and their correction with L-arginine infusion

The acute respiratory distress syndrome and pulmonary hypertension (PH) is one of the factors of septic mortality. Some data demonstrate arginine deficiency as an important pathogenic factor of septic PH. We suppose that intravenous L-arginine infusion improves NO production and reduce PH.

Differences between Cerebrovascular Reactivity to L-Arginine in the Anterior and Posterior Cerebral Circulation

Background: Cerebral endothelial function might be different in distinct cerebrovascular territory, thereby making these areas more susceptible to ischemia and stroke. Higher incidence and prevalence of stroke in males suggest that gender could have a strong influence on this difference. In order to evaluate cerebral endothelial function, we compared cerebrovascular reactivity (CVR) to L-arginine in the anterior and posterior cerebral circulation in healthy young males and females. Methods: Thirty healthy subjects, 15 females (32.1 ± 7.1 years) and 15 males (32.2 ± 6.3 years), were included. The mean arterial velocity in the middle cerebral artery (MCA) and the posterior cerebral artery (PCA) was measured by transcranial Doppler sonography before and after intravenous infusion of L-arginine, and CVR to L-arginine was then calculated. Results: CVR to L-arginine was significantly higher in PCA than in MCA in all subjects (19.2 ± 8.2 vs. 13.6 ± 7.1%, p ≤ 0.01). In addition, CVR to L-arginine was significantly more pronounced in females compared to males in PCA (22.7 ± 8.3 vs. 15.8 ± 6.7%, p ≤ 0.01) and MCA (16.8 ± 6.4 vs. 10.4 ± 6.4%, p < 0.05). Conclusions: Lower CVR to L-arginine and therefore lower cerebral endothelial function in the anterior cerebral circulation and in males might be related to the higher incidence of ischemia and stroke in the anterior cerebral circulation, particularly in males.

Role of the nitric oxide metabolic pathway and prostanoids in the pathogenesis of endothelial dysfunction and essential hypertension in young men

The aim of this study was to explore the role of selected prostanoids and the nitric oxide (NO) metabolic pathway in the pathogenesis of endothelial dysfunction (ED) in young men with and without essential hypertension (HTN). A total of 70 men aged 18-40 years old (23 hypertensive and 47 normotensive) were investigated. Initial metabolite concentrations of the NO pathway (asymmetric dimethylarginine, L-arginine and symmetric dimethylarginine), selected cardiovascular risk markers (serum lipids, creatinine, glucose and high-sensitivity C-reactive protein), oxidative stress markers (malonylodialdehyde, thiol index and nitrotyrosine) and prostanoids (thromboxane B2 (TxB(2)) and 6-keto-prostaglandin F (PGF)-1-α) were measured. Ultrasound assessment of endothelial function (flow-mediated vasodilation (FMD)) of the brachial artery was studied before and after intravenous infusion of L-arginine (16.0 g). All measurements were repeated after oral administration of indomethacin (75 mg per day) for 2 days. The prevalence of ED was similar in both hypertensive and normotensive groups. A lower baseline plasma level of 6-keto-PGF-1-α and a higher baseline of TxB(2) were observed in the hypertensive group. A different response to indomethacin assessed by prostanoid levels was observed and was dependent on the presence of HTN. No significant differences in metabolites of the NO pathway were observed at either baseline or following indomethacin treatment. In hypertensive patients, L-arginine and indomethacin had a synergistic positive effect on FMD. ED in young normotensive men primarily depends on NO deficiency. In young hypertensive men, disorders in prostanoid metabolism have important roles in decreasing NO bioavailability. The high prevalence of ED in potentially healthy subjects suggests that the ultrasound FMD measurement is an important tool in the stratification of cardiovascular risk.

Statin Treatment Improves Cerebral More Than Systemic Endothelial Dysfunction in Patients With Arterial Hypertension

The pleiotropic effects of statins on the endothelial function are well recognized. However, the effect of statins might not be equally pronounced in the cerebral and systemic circulation. We compared cerebral and systemic endothelial function by L-arginine cerebrovascular reactivity and flow-mediated dilatation (FMD), respectively, in patients with arterial hypertension (AH) and healthy controls before and after atorvastatin treatment. L-arginine reactivity and FMD were measured in patients with AH (29 patients, aged 61.1 +/- 6.2 years) and 21 healthy controls. The mean arterial velocity (v(m)) in both middle cerebral arteries was measured by transcranial Doppler sonography before, during, and after a 30-min intravenous infusion of L-arginine. FMD of the brachial artery after hyperemia was determined. The measurements were repeated after 3 months of treatment with atorvastatin. L-arginine reactivity and FMD were decreased in patients with AH (12.5 +/- 8.7%; 2.7 +/- 5.0 %) compared with controls (21.3 +/- 10.9%; 8.5 +/- 5.9%) (P < 0.01). After atorvastatin treatment, L-arginine reactivity and FMD improved in patients with AH (19.5 +/- 10.6%; 4.6 +/- 4.1%) compared with the controls (20.2 +/- 10.2%; 9.7 +/- 3.9%). The use of statin restored the cerebral circulation reactivity, while there was little change in the systemic circulation measured by FMD. The decreased L-arginine reactivity and FMD were found to improve after atorvastatin treatment in patients with AH, but the results suggest that statin therapy improved cerebral more than systemic endothelial function.

Adaptation of the hypothalamic blood flow to chronic nitric oxide deficiency is independent of vasodilator prostanoids

The aim of our study was to investigate the adaptation of the hypothalamic circulation to chronic nitric oxide (NO) deficiency in rats. Hypothalamic blood flow (HBF) remained unaltered during chronic oral administration of the NO synthase (NOS) inhibitor N G-nitro- l-arginine methyl ester ( l-NAME, 1 mg/ml drinking water) although acute NOS blockade by intravenous l-NAME injection (50 mg/kg) induced a dramatic HBF decrease. In chronically NOS blocked animals, however, acute l-NAME administration failed to influence the HBF. Reversal of chronic NOS blockade by intravenous l-arginine infusion evoked significant hypothalamic hyperemia suggesting the appearance of a compensatory vasodilator mechanism in the absence of NO. In order to clarify the potential involvement of vasodilator prostanoids in this adaptation, cyclooxygenase (COX) mRNA and protein levels were determined in the hypothalamus, but none of the known isoenzymes (COX-1, COX-2, COX-3) showed upregulation after chronic NOS blockade. Furthermore, levels of vasodilator prostanoid (PGI 2, PGE 2 and PGD 2) metabolites were also not elevated. Interestingly, however, hypothalamic levels of vasoconstrictor prostanoids (TXA 2 and PGF 2α) decreased after chronic NOS blockade. COX inhibition by indomethacin but not by diclofenac decreased the HBF in control animals. However, neither indomethacin nor diclofenac induced an altered HBF-response after chronic l-NAME treatment. Although urinary excretion of PGI 2 and PGE 2 metabolites markedly increased during chronic NOS blockade, indicating COX activation in the systemic circulation, we conclude that the adaptation of the hypothalamic circulation to the reduction of NO synthesis is independent of vasodilator prostanoids. Reduced release of vasoconstrictor prostanoids, however, may contribute to the normalization of HBF after chronic loss of NO.

Statins and Cerebral Vasomotor Reactivity

See related article, pages 2540-2545. Animal models have shown that cholesterol-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (commonly called statins) may augment absolute cerebral blood flow (CBF) by enhancing nitric oxide synthase (eNOS).1 Statins upregulate type III endothelial eNOS in thrombocytes, decrease platelet activation, and protect from cerebral ischemia in normocholesterolemic mice.2 Statins may also provide additional beneficial effects by upregulating endogenous tissue plasminogen activator and enhancing clot lysis in a mouse model of embolic focal ischemia.3 Statins given 24 hours after experimental ischemia can enhance CBF, angiogenesis, neurogenesis and sinaptogenesis.4 How can these findings be applied in the clinical setting? A meta-analysis of published clinical trials showed that low-density lipoprotein–lowering with statins may decrease the risk of stroke in diabetic or hypertensive patients with normal low-density lipoprotein cholesterol at baseline, and in patients with coronary artery disease, with respectively 48%, 27% and 25% reduction in stroke incidence.5 Does any relationship exist among statins and cerebral vasomotor reactivity? Functional transcranial Doppler (TCD) ultrasonography permits the assessment of cognitively induced CBF velocity changes6 and the evaluation of cerebral vasomotor reactivity.7 TCD can be used to reliably evaluate age-related changes in the physiological response of the human cerebral circulation. A diminished nitric oxide–mediated cerebral vasomotor response may exist in aging subjects and in patients with vascular risk factors.8 Because there are no reliable markers for the functional status of the cerebral small vessels in elderly patients at risk of stroke, TCD studies may be useful. Although some parameters …

Influence of Atorvastatin Treatment on l -Arginine Cerebrovascular Reactivity and Flow-Mediated Dilatation in Patients With Lacunar Infarctions

In our study we hypothesized that statins improve endothelial function in patients with lacunar infarctions (LI). Cerebral and systemic endothelial function was determined before and after 3-months treatment with atorvastatin. Cerebral endothelial function was determined by L-arginine reactivity and systemic endothelial function by flow-mediated dilatation (FMD) in patients with LI (18 patients, aged 61.1+/-7.6 years), 20 age- and gender-matched patients with similar risk factors (SR) and 19 age- and gender-matched healthy controls. The mean arterial velocity (v(m)) in both middle cerebral arteries was measured by transcranial Doppler sonography before, during and after a 30-minute intravenous infusion of L-arginine. FMD of the brachial artery after hyperaemia was determined. The measurements were repeated after 3-months treatment with 40 mg of atorvastatin per day. L-arginine reactivity was decreased in LI patients (13.1+/-8.4%) and in patients with SR compared with healthy controls (P < or = 0.01). FMD was more impaired in patients with LI (0.06+/-4.9%) compared with patients with SR and healthy controls (P < or = 0.01). After atorvastatin treatment, L-arginine reactivity and FMD improved in both patients with LI (17.1+/-7.6%; 7.0+/-5.7%) and patients with SR (P < or = 0.01). Previously mildly increased cholesterol values normalized. The decreased L-arginine reactivity and FMD improve after atorvastatin treatment in both patients with LI and patients with SR.

Cerebrovascular Reactivity to L-Arginine in Patients with Lacunar Infarctions

Background: It is well known that endothelial dysfunction plays an important role in the pathogenesis of many cardiovascular disorders. The aim of this study was to test the hypothesis that specific, marked endothelial dysfunction of cerebral arteries is present in patients with lacunar cerebral infarctions. Methods: Cerebrovascular reactivity to L-arginine, which reveals the function of the cerebral endothelium, was investigated in patients with lacunar infarctions (20 patients, 11 male and 9 female, aged 60.9 ± 7.3 years), 21 age- and gender-matched asymptomatic patients with similar cardiovascular risk factors (all patients had arterial hypertension) and 21 age- and gender-matched healthy controls. The mean arterial velocity (v_m) in both middle cerebral arteries was measured by transcranial Doppler sonography during a 15-min baseline period, a 30-min intravenous infusion of L-arginine and a 15-min interval after L-arginine infusion. Arterial blood pressure, heart rate and CO₂ were measured continuously. Results: The measured v_m increase during L-arginine infusion in the patients with lacunar infarctions (13.4 ± 9.1%) was significantly lower compared to the healthy controls (20.5 ± 9.9%) but similar to that obtained in the patients with cardiovascular risk factors (11.5 ± 8.9%). Conclusions: Our results showed that cerebrovascular reactivity to L-arginine, which demonstrates cerebral endothelial function, is significantly impaired in patients with cardiovascular risk factors. Importantly, we found that patients with lacunar infarctions do not show any additional impairment of cerebral endothelial function.

Glutamine-dependent inhibition of pial arteriolar dilation to acetylcholine with and without hyperammonemia in the rat

Glutamine has been shown to influence endothelial-dependent relaxation and nitric oxide production in vitro, possibly by limiting arginine availability, but its effects in vivo have not been well studied. Hyperammonemia is a pathophysiological condition in which glutamine is elevated and contributes to depressed CO(2) reactivity of cerebral arterioles. We tested the hypothesis that acute hyperammonemia decreases pial arteriolar dilation to acetylcholine in vivo and that this decrease could be prevented by inhibiting glutamine synthetase with L-methionine-S-sulfoximine (MSO) or by intravenous infusion of L-arginine. Pial arteriolar diameter responses to topical superfusion of acetylcholine were measured in anesthetized rats before and at 6 h of infusion of either sodium or ammonium acetate. Ammonium acetate infusion increased plasma ammonia concentration from approximately 30 to approximately 600 microM and increased cerebral glutamine concentration fourfold. Arteriolar dilation to acetylcholine was intact after infusion of sodium acetate in groups pretreated with vehicle or with MSO plus methionine, which was coadministered to prevent MSO-induced seizures. In contrast, dilation in response to acetylcholine was completely blocked in hyperammonemic groups pretreated with vehicle or methionine alone. However, MSO plus methionine administration before hyperammonemia, which maintained cerebral glutamine concentration at control values, preserved acetylcholine dilation. Intravenous infusion of L-arginine during the last 2 h of the ammonium acetate infusion partially restored dilation to acetylcholine without reducing cerebral glutamine accumulation. Superfusion of 1 or 2 mM L-glutamine through the cranial window for 1 h in the absence of hyperammonemia attenuated acetylcholine dilation but had no effect on endothelial-independent dilation to nitroprusside. We conclude that 1) hyperammonemia reduces acetylcholine-evoked dilation in cerebral arterioles, 2) this reduction depends on increased glutamine rather than ammonium ions, and 3) increasing arginine partially overcomes the inhibitory effect of glutamine.

L-arginine supplementation does not inhibit neointimal formation after coronary stenting in human beings: an intravascular ultrasound study

Background In-stent restenosis results from neointimal tissue proliferation. L-arginine supplementation improves endothelial function and reduces neointimal formation after arterial injury in animals. The aim of the study was to assess the influence of L-arginine administration on neointimal proliferation after coronary stenting in human beings. Methods We performed a prospective, randomized, double-blinded, placebo-controlled study in 60 men without diabetes. L-arginine/placebo was administered intravenously 12 hours before percutaneous coronary intervention (200 mg/kg for 240 minutes), during the procedure (200 mg/kg for 240 minutes), and intracoronarily immediately before stent implantation (500 mg for 10 minutes), and it was followed by oral treatment for next 2 weeks (6.0 g/d). By quantitative coronary angiography, late lumen loss, and intravascular ultrasound, neointimal volume and percent neointimal volume were calculated after 7 months of follow-up to assess neointimal formation. Results There were no differences in baseline clinical or angiographic characteristics between the two groups. Intravenous infusion of L-arginine increased plasma L-arginine concentrations 6-fold compared with placebo (661 ± 264 vs 107 ± 71 mmol/L, P < .001). During the 2-week period of oral treatment with L-arginine there was a sustained, significant increase of plasma L-arginine level (150 ± 50 vs 100 ± 17, P < .001, 135 ± 42 vs 89 ± 27, P < .001, respectively, on days 7 and 14 in the L-arginine group vs placebo). However, at 7-month follow-up, there was no difference in neointimal formation measured both by quantitative coronary angiography and intravascular ultrasound between the study groups. Conclusions Chronic systemic L-arginine administration has no effect on neointimal formation after coronary stenting in human beings.

Asymmetrical dimethylarginine: the Uber marker?

The traditional risk factors of hypercholesterolemia, hypertension, diabetes mellitus, and tobacco exposure identify a subset of patients at greater cardiovascular risk. A variety of clinical phenotypes, biochemical markers, and genetic polymorphisms have been proposed to explain the variance in risk not explained by the traditional factors. Notably, all of the traditional risk factors, as well as the great majority of new risk markers, are associated with endothelial vasodilator dysfunction. Because the end points (endothelial dysfunction leading to plaque formation, progression, and rupture) are the same, it follows that diverse risk factors ultimately share common pathways(s) of pathobiology. We and others have provided evidence for a ubiquitous mechanism of endothelial pathobiology shared by all risk factors and markers examined to date. This mechanism of endothelial derangement is mediated by an endogenous inhibitor of nitric oxide synthase (NOS), a molecule known as asymmetrical dimethylarginine (ADMA). Risk factors impair endothelial vasodilator function by causing the accumulation of ADMA. Furthermore, by blocking NO generation, ADMA initiates and promotes processes involved in atherogenesis, plaque progression. and plaque rupture. This review examines the burgeoning body of literature that supports ADMA as an “Uber marker,” a biochemical factor mediating the adverse vascular effects of many other risk factors and markers. Endothelial NOS converts the amino acid l-arginine into l-citrulline and NO. The importance of NO in vascular homeostasis has been discussed elsewhere.1 In addition to its vasodilator activity, NO inhibits key processes involved in vascular disease, including leukocyte adhesion, platelet aggregation, and vascular smooth muscle cell proliferation. In animal models, alterations in vascular NO synthesis profoundly influence the progression of atherosclerosis and restenosis.2–6 These experimental observations have gained greater significance with recent reports that impairment of the NOS pathway independently predicts cardiovascular events.7–11 Major causes of impairment of the NOS pathway are …

Renal medullary nitric oxide deficit of Dahl S rats enhances hypertensive actions of angiotensin II.

Studies were designed to examine the hypothesis that the renal medulla of Dahl salt-sensitive (Dahl S) rats has a reduced capacity to generate nitric oxide (NO), which diminishes the ability to buffer against the chronic hypertensive effects of small elevations of circulating ANG II. NO synthase (NOS) activity in the outer medulla of Dahl S rats (arginine-citrulline conversion assay) was significantly reduced. This decrease in NOS activity was associated with the downregulation of protein expression of NOS I, NOS II, and NOS III isoforms in this region as determined by Western blot analysis. In anesthetized Dahl S rats, we observed that a low subpressor intravenous infusion of ANG II (5 ng. kg(-1). min(-1)) did not increase the concentration of NO in the renal medulla as measured by a microdialysis with oxyhemoglobin trapping technique. In contrast, ANG II produced a 38% increase in the concentration of NO (87 +/- 8 to 117 +/- 8 nmol/l) in the outer medulla of Brown-Norway (BN) rats. The same intravenous dose of ANG II reduced renal medullary blood flow as determined by laser-Doppler flowmetry in Dahl S, but not in BN rats. A 7-day intravenous ANG II infusion at a dose of 3 ng. kg(-1). min(-1) did not change mean arterial pressure (MAP) in the BN rats but increased MAP in Dahl S rats from 120 +/- 2 to 138 +/- 2 mmHg (P < 0.05). ANG II failed to increase MAP after NO substrate was provided by infusion of L-arginine (300 microg. kg(-1). min(-1)) into the renal medulla of Dahl S rats. Intravenous infusion of L-arginine at the same dose had no effect on the ANG II-induced hypertension. These results indicate that an impaired NO counterregulatory system in the outer medulla of Dahl S rats makes them more susceptible to the hypertensive actions of small elevations of ANG II.

Effects of L-Arginine and L-NAME on the Renal Function in Hypertensive and Normotensive Subjects

Background/Aim: Renal vasodilation in response to L-arginine has been reported to be diminished in hypertensive (HT) subjects. If this diminished renal vasodilator response indicates disturbance of the renal NO pathway, a diminished renal vasoconstrictor response to NO synthase inhibition may be present in HT subjects as well. The present study was conducted to compare the effects of L-arginine and N^G-nitro-L-arginine methyl ester (L-NAME) on renal and systemic hemodynamics between HT and normotensive (NT) subjects. Methods: The responses of renal and systemic vascular resistances (RVR and SVR) and plasma noradrenaline and renin (NOR and PRA) to systemic NO stimulation and inhibition were studied in patients with grade 1 essential HT and age- and sex-matched NT subjects. On separate occasions, after baseline values were obtained, 40-min randomly administered intravenous infusions of L-arginine (12.5 mg·kg^–1·min^–1) or L-NAME (0.0125 mg·kg^–1·min^–1) were given. Results: Baseline values of RVR (129 ± 21 and 162 ± 10 resistance units) and SVR (15.1 ± 4.3 and 21.6 ± 5.1 resistance units) were higher (p < 0.01) in HT than in NT subjects, whereas the baseline values of NOR and PRA were similar. Infusion of L-arginine caused similar decrements in SVR (29 ± 10 and 31 ± 11%), but the decrease in RVR was smaller (22 ± 8 and 35 ± 12%, respectively; p < 0.05) in HT than in NT subjects. In response to L-NAME, the increments in RVR (66 ± 10 and 61 ± 25%) and SVR (36 ± 21 and 34 ± 18%) were similar in HT and NT subjects. In both groups, infusion of L-arginine was associated with similar increments, whereas infusion of L-NAME was associated with similar decrements in NOR and PRA. Conclusions: This study confirms the smaller renal vasodilator response to L-arginine in HT than in NT subjects. Whether this is caused by a disturbance of the renal NO pathway remains doubtful considering the observed similar L-NAME-induced increments in RVR and SVR in the two groups of subjects

L-Arginine supplementation in pigs decreases liver protein turnover and increases hindquarter protein turnover both during and after endotoxemia

Accumulating evidence suggests that L-arginine, under conditions of septicemia, not only enhances immune function but also improves protein metabolism. Because the effect of L-arginine administration on the protein metabolism of different organs is unknown, the aim of the study was to elucidate the effects of exogenous supplementation of L-arginine during endotoxemia on the in vivo protein metabolism of individual organs and at the whole-body level. Female pigs were cannulated with catheters in the aorta and the splenic, caval, portal, hepatic, and renal veins, enabling measurements across the hindquarter, portal-drained viscera, liver, and kidneys. Endotoxemia was induced by a 24-h continuous intravenous infusion of endotoxin (3 microg x kg body wt(-1) x h(-1)). At 8 h, an intravenous infusion of L-arginine was started (n = 8). Control pigs (n = 6) received L-alanine. At 24 h, blood was sampled. After cessation of the endotoxin infusion, L-arginine and L-alanine infusions were continued as a supplement in the enterally infused diet. At 48 h, blood samples were obtained during the postendotoxemic and nutritionally supported conditions. Stable isotopes were used to assess protein metabolism and phenylalanine hydroxylation. Both during and after the endotoxin challenge, L-arginine administration enhanced protein synthesis and degradation across the hindquarter and simultaneously reduced protein synthesis and degradation in the liver at equal rates. Protein turnover across the kidneys and portal-drained viscera remained unaffected. After endotoxemia, L-arginine infusion decreased whole-body protein turnover without affecting the net protein balance. L-Arginine administration affects protein turnover of the muscle area and the liver oppositely.

Role of abnormal nitric oxide systems in salt-sensitive hypertension

A large percentage of human hypertensive patients are salt sensitive, referring to the dependence of hypertension on sodium intake, but the cause of the salt sensitivity is not known. Although several mechanisms may contribute to salt-sensitive hypertension, the nitric oxide (NO) system appears to play a major role. Studies in humans and Dahl salt-sensitive (S) rats indicate that NO production is decreased during hypertension. Intravenous l-arginine infusion in Dahl S rats increases NO production and prevents salt-sensitive hypertension. In the Dahl salt-resistant (R) rat, NO production by both inducible NO synthase (iNOS) and neuronal NOS (nNOS) help to prevent salt-sensitive hypertension. Experimental evidence is summarized, indicating that the Dahl S rat has a deficient production of NO by nNOS, although NO production by iNOS appears to moderately decrease salt sensitivity. Other evidence about the importance of NO in salt-sensitive hypertension is reviewed, including the role of the renal NO system.

L-arginine improves post-ischemic vasodilation in coronary heart disease patients taking vasodilating drugs.

The hypothesis that intravenous L-arginine infusion improves the vasodilatory response to ischemia in the resistance vessels of human lower limbs in relatively young coronary heart disease patients taking vasodilating drugs was tested. Twenty patients with onset of symptoms of coronary artery disease before age 50, operated for aortocoronary bypass and taking vasodilating drugs, were compared with 20 control subjects of comparable age and gender; neither group included heavy smokers (>10 cigarettes/day). Blood flow in the lower limbs was measured noninvasively with strain-gauge plethysmography, both at rest and during a reactive hyperemia test. Intravenous infusion of L-arginine was performed in nine coronary heart disease patients and in nine control subjects. Resting blood flow to the lower limbs was 2.3 mL/min/100 mL in control subjects vs 3.4 mL/min/100 mL in patients (difference not statistically significant). Peak blood flow measured after a 3-minute arterial occlusion was 24.0 mL/min/100 mL in control subjects vs 20.3 mL/min/100 mL in coronary heart disease patients (P<0.05). Peripheral minimal vascular resistances were 4.28 and 5.46 peripheral resistances units (p.r.u.) in control subjects and patients, respectively (P<0.05). Intravenous infusion of L-arginine was followed by increased resting blood flow in cases and controls (P=0.009), with a parallel reduction in peripheral resting vascular resistances (P=0.009). Coronary heart disease patients showed increased peak blood flow (P=0.04) and reduced minimal vascular resistances (P=0.02), whereas no statistically significant changes in these parameters were detectable in control subjects. Intravenous glucose infusion, leading to increased serum insulin concentration, did not modify any hemodynamic parameter. Hemodynamic responses in the skeletal muscle are impaired during a reactive hyperemia test in relatively young coronary heart disease patients taking vasodilating drugs. Intravenous L-arginine infusion corrects the impaired vasodilatory response of the lower limbs to an acute increase in flow following a cuff thigh occlusion.