scholarly journals The Citrulline Recycling Pathway Sustains Cardiovascular Function in Arginine-Depleted Healthy Mice, but Cannot Sustain Nitric Oxide Production during Endotoxin Challenge

2018 ◽  
Vol 148 (6) ◽  
pp. 844-850 ◽  
Author(s):  
Yang Yuan ◽  
Mahmoud A Mohammad ◽  
Ancizar Betancourt ◽  
Inka C Didelija ◽  
Chandrasekar Yallampalli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nitric Oxide ◽  
Blood Pressure ◽  
Ex Vivo ◽  
Arginine Deiminase ◽  
Mesenteric Arteries ◽  
Saline Control ◽  
No Production ◽  
Endotoxin Challenge ◽  
Recycling Pathway

Abstract Background The recycling of citrulline by argininosuccinate synthase 1 (ASS1) and argininosuccinate lyase (ASL) is crucial to maintain arginine availability and nitric oxide (NO) production. Pegylated arginine deiminase (ADI-PEG20) is a bacterial enzyme used to deplete circulating arginine. Objective The goal of this research was to test the hypothesis that citrulline is able to sustain intracellular arginine availability for NO production in ADI-PEG20 arginine–depleted mice. Methods Six- to 8-wk-old male C57BL/6J mice injected with ADI-PEG20 (5 IU) or saline (control) were used in 4 different studies. Arginine, citrulline, and NO kinetics were determined by using stable isotopes in unchallenged (study 1) and endotoxin-challenged (study 2) mice. Blood pressure was determined by telemetry for 6 d after ADI-PEG20 administration (study 3), and vasomotor activity and ASS1 and ASL gene expression were determined in mesenteric arteries collected from additional mice (study 4). Results ADI-PEG20 administration resulted in arginine depletion (<1 compared with 111 ± 37 µmol/L) but in greater plasma citrulline concentrations (900 ± 123 compared with 76 ± 8 µmol/L; P < 0.001) and fluxes (402 ± 17 compared with 126 ± 4 µmol ⋅ kg−1 ⋅ h−1; P < 0.001) compared with controls. Endotoxin-challenged ADI-PEG20–treated mice produced less NO than controls (13 ± 1 compared with 27 ± 2 µmol ⋅ kg−1 ⋅ h−1; P < 0.001). No differences (P > 0.50) were observed for cardiovascular variables (heart rate, blood pressure) between ADI-PEG20–treated and control mice. Furthermore, no ex vivo vasomotor differences were observed between the 2 treatments. ADI-PEG20 administration resulted in greater gene expression of ASS1 (∼3-fold) but lower expression of ASL (–30%). Conclusion ADI-PEG20 successfully depleted circulating arginine without any effect on cardiovascular endpoints in healthy mice but limited NO production after endotoxin challenge. Therefore, the citrulline recycling pathway can sustain local arginine availability independently from circulating arginine, satisfying the demand of arginine for endothelial NO production; however, it is unable to do so when a high demand for arginine is elicited by endotoxin.

Abstract 167: A Cell-Autonomous Role for Endothelial GTP Cyclohydrolase 1 and Tetrahydrobiopterin in Blood Pressure Regulation

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Surawee Chuaiphichai ◽  
Eileen McNeill ◽  
Gillian Douglas ◽  
Mark J Crabtree ◽  
Jennifer K Bendall ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Endothelial Cell ◽  
De Novo ◽  
Soluble Guanylate Cyclase ◽  
Ex Vivo ◽  
Mesenteric Arteries ◽  
Gtp Cyclohydrolase ◽  
Enos Uncoupling

Tetrahydrobiopterin (BH4) is an essential cofactor for endothelial nitric oxide synthase (eNOS) function and nitric oxide (NO) generation. Augmentation of BH4 levels can prevent eNOS uncoupling and improve endothelial dysfunction in vascular disease states. However, the physiological requirement for de-novo endothelial cell BH4 biosynthesis in eNOS function remains unclear. We generated a novel mouse model with endothelial cell-specific deletion of GCH1, encoding GTP cyclohydrolase 1, an essential enzyme for BH4 biosynthesis, to test the cell-autonomous requirement for endothelial BH4 biosynthesis in vivo. Mice with a floxed GCH1 allele ( GCH1 fl/fl ) were crossed with Tie2cre mice to delete GCH1 in endothelial cells. GCH1 fl/fl Tie2cre mice demonstrated virtually absent NO bioactivity and significantly greater O 2 • - production. GCH1 fl/fl Tie2cre aortas and mesenteric arteries had enhanced vasoconstriction to phenylephrine and impaired endothelium-dependent vasodilatations to acetylcholine and SLIGRL. Endothelium-dependent vasodilatations in GCH1 fl/fl Tie2cre aortas were in part mediated by NOS-derived hydrogen peroxide (H 2 O 2 ), which mediated vasodilatation through soluble guanylate cyclase. Ex vivo supplementation of aortic rings with the BH4 analogue sepiapterin restored normal endothelial function and abolished eNOS-derived H 2 O 2 production in GCH1 fl/fl Tie2cre aortas. GCH1 fl/fl Tie2cre mice had higher systemic blood pressure than wild-type littermates, which was normalised by NOS inhibitor, L-NAME. Taken together, these studies reveal an endothelial cell-autonomous requirement for GCH1 and BH4 in regulation of vascular tone and blood pressure, and identify endothelial cell BH4 as a pivotal regulator of NO vs. H 2 O 2 as alternative eNOS-derived endothelial derived relaxing factors.

Abstract 15: Novel Functions of Small GTPase Rap1 in Regulating Endothelial Homeostasis: Control of Nitric Oxide Release, Vascular Function and Blood Pressure

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Sribalaji Lakshmikanthan ◽  
Xiaodong Zheng ◽  
Yoshinori Nishijima ◽  
Jeannette Vasquez-Vivar ◽  
David X Zhang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Shear Flow ◽  
Knockout Mice ◽  
Ex Vivo ◽  
Left Ventricular ◽  
Small Gtpase ◽  
No Production ◽  
Endothelial Homeostasis

Endothelial dysfunction, resulting from decreased nitric oxide (NO) bioavailability is a pathology linked to endothelial vasomotor dysfunction and hypertension, inflammation and atherosclerosis, perturbed endothelial barrier and progression of diabetes. In blood vessels, NO is produced by the endothelial NO synthase (eNOS), the activity of which is regulated by Ca2+/calmodulin, binding of regulatory cofactors, and posttranslational modifications, including phosphorylation events on Ser1177, which stimulate NO production. Rap1 is a ubiquitously expressed small GTPase implicated in promoting vascular barrier. We have shown that endothelial cell (EC)-specific Rap1 deletion leads to defective angiogenesis in vivo due to faulty VEGFR2 activation and signaling. Importantly, EC-specific Rap1 knockout mice developed hypertension and pathological left ventricular hypertrophy. The objective of the study was to determine the role of small G protein Rap1 in regulating endothelial NO production and endothelial-dependent vasorelaxation in vivo and ex vivo. Using ex vivo myography and tamoxifen-inducible, endothelial-specific Rap1-knockout mice (Cadh5-CreERT2+/0;Rap1f/f), we demonstrate that Rap1 deficiency completely abrogates NO-dependent vasodilation and attenuates NO production. Mechanistically, we show that Rap1 is rapidly activated in response to receptor agonists that activate eNOS via Ca2+/calmodulin- dependent pathway and in response to shear flow, which modules eNOS activity by its phosphorylation. Rap1 deletion in human ECs, in vitro, leads to deficient NO release in response to both these stimuli, and interferes with PI3K/Akt pathway and eNOS Ser1177 phosphorylation. Further, we demonstrate Rap1 is required for transducing signals from the endothelial mechanosensing complex comprising PECAM-1, VE-cadherin and VEGFR2 in response to shear flow, leading to ligand-independent VEGFR2 activation and signaling to stimulate NO production. We conclude that Rap1 in endothelium is critically required for endothelial homeostasis and NO production, thereby affecting vascular tone and regulation of blood pressure. Furthermore, this study establishes Rap1 as a novel regulator of mechanotransduction in response to shear flow.

Loss of α2B-adrenoceptors increases magnitude of hypertension following nitric oxide synthase inhibition

2006 ◽  
Vol 291 (5) ◽  
pp. H2403-H2408 ◽  
Author(s):  
Laura C. Duling ◽  
Tom W. Cherng ◽  
Jason R. Griego ◽  
Michael F. Perrine ◽  
Nancy L. Kanagy
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Arterial Pressure ◽  
Mesenteric Arteries ◽  
No Production ◽  
Vascular Endothelial ◽  
Wild Type ◽  
Inner Diameter ◽  
Oxide Synthase ◽  
Arterial Tone

Vascular α2B-adrenoceptors (α2B-AR) may mediate vasoconstriction and contribute to the development of hypertension. Therefore, we hypothesized that blood pressure would not increase as much in mice with mutated α2B-AR as in wild-type (WT) mice following nitric oxide (NO) synthase (NOS) inhibition with Nω-nitro-l-arginine (l-NNA, 250 mg/l in drinking water). Mean arterial pressure (MAP) was recorded in heterozygous (HET) α2B-AR knockout mice and WT littermates using telemetry devices for 7 control and 14 l-NNA treatment days. MAP in HET mice was increased significantly on treatment days 1 and 4 to 14, whereas MAP did not change in WT mice ( days 0 and 14 = 113 ± 3 and 114 ± 4 mmHg in WT, 108 ± 0.3 and 135 ± 13 mmHg in HET, P < 0.05). MAP was significantly higher in HET than in WT mice days 10 through 14 ( P < 0.05). Thus blood pressure increased more rather than less in mice with decreased α2B-AR expression. We therefore examined constrictor responses to phenylephrine (PE, 10−9 to 10−4 M) with and without NOS inhibition to determine basal NO contributions to arterial tone. In small pressurized mesenteric arteries (inner diameter = 177 ± 5 μm), PE constriction was decreased in untreated HET arteries compared with WT ( P < 0.05). l-NNA (100 μM) augmented PE constriction more in HET arteries than in WT arteries, and responses were not different between groups in the presence of l-NNA. Acetylcholine dilated preconstricted arteries from HET mice more than arteries from WT mice. Endothelial NOS expression was increased in HET compared with WT mesenteric arteries by Western analysis. Griess assay showed increased NOx concentrations in HET plasma compared with those in WT plasma. These data demonstrate that diminished α2B-AR expression increases the dependence of arterial pressure and vascular tone on NO production and that vascular α2B-AR either directly or indirectly regulates vascular endothelial NOS function.

Endothelial dysfunction and arterial pressure regulation during early diabetes in mice: roles for nitric oxide and endothelium-derived hyperpolarizing factor

2007 ◽  
Vol 293 (2) ◽  
pp. R707-R713 ◽  
Author(s):  
Sharyn M. Fitzgerald ◽  
Barbara K. Kemp-Harper ◽  
Helena C. Parkington ◽  
Geoffrey A. Head ◽  
Roger G. Evans
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Arterial Pressure ◽  
Early Stage ◽  
Mesenteric Arteries ◽  
No Production ◽  
Wild Type ◽  
Early Diabetes ◽  
Diabetes In Mice ◽  
Vehicle Treatment

We determined whether nitric oxide (NO) counters the development of hypertension at the onset of diabetes in mice, whether this is dependent on endothelial NO synthase (eNOS), and whether non-NO endothelium-dependent vasodilator mechanisms are altered in diabetes in mice. Male mice were instrumented for chronic measurement of mean arterial pressure (MAP). In wild-type mice, MAP was greater after 5 wk of Nω-nitro-l-arginine methyl ester (l-NAME; 100 mg·kg−1·day−1 in drinking water; 97 ± 3 mmHg) than after vehicle treatment (88 ± 3 mmHg). MAP was also elevated in eNOS null mice (113 ± 4 mmHg). Seven days after streptozotocin treatment (200 mg/kg iv) MAP was further increased in l-NAME-treated mice (108 ± 5 mmHg) but not in vehicle-treated mice (88 ± 3 mmHg) nor eNOS null mice (104 ± 3 mmHg). In wild-type mice, maximal vasorelaxation of mesenteric arteries to acetylcholine was not altered by chronic l-NAME or induction of diabetes but was reduced by 42 ± 6% in l-NAME-treated diabetic mice. Furthermore, the relative roles of NO and endothelium-derived hyperpolarizing factor (EDHF) in acetylcholine-induced vasorelaxation were altered; the EDHF component was enhanced by l-NAME and blunted by diabetes. These data suggest that NO protects against the development of hypertension during early-stage diabetes in mice, even in the absence of eNOS. Furthermore, in mesenteric arteries, diabetes is associated with reduced EDHF function, with an apparent compensatory increase in NO function. Thus, prior inhibition of NOS results in endothelial dysfunction in early diabetes, since the diabetes-induced reduction in EDHF function cannot be compensated by increases in NO production.

scholarly journals Decreased endothelial nitric oxide, systemic oxidative stress, and increased sympathetic modulation contribute to hypertension in obese rats

2014 ◽  
Vol 306 (10) ◽  
pp. H1472-H1480 ◽  
Author(s):  
Natalia Veronez da Cunha ◽  
Phileno Pinge-Filho ◽  
Carolina Panis ◽  
Bruno Rodrigues Silva ◽  
Laena Pernomian ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lipid Peroxidation ◽  
Endothelial Cells ◽  
Arterial Pressure ◽  
Vascular Reactivity ◽  
Monosodium Glutamate ◽  
Saline Control ◽  
Pulse Interval ◽  
No Production ◽  
Obese Rats

We investigated the involvement of nitric oxide (NO) and reactive oxygen species (ROS) on autonomic cardiovascular parameters, vascular reactivity, and endothelial cells isolated from aorta of monosodium glutamate (MSG) obese rats. Obesity was induced by administration of 4 mg/g body wt of MSG or equimolar saline [control (CTR)] to newborn rats. At the 60th day, the treatment was started with NG-nitro-l-arginine methyl ester (l-NAME, 20 mg/kg) or 0.9% saline. At the 90th day, after artery catheterization, mean arterial pressure (MAP) and heart rate were recorded. Plasma was collected to assess lipid peroxidation. Endothelial cells isolated from aorta were evaluated by flow cytometry and fluorescence intensity (FI) emitted by NO-sensitive dye [4,5-diaminofluoresceindiacetate (DAF-2DA)] and by ROS-sensitive dye [dihydroethidium (DHE)]. Vascular reactivity was made by concentration-response curves of acetylcholine. MSG showed hypertension compared with CTR. Treatment with l-NAME increased MAP only in CTR. The MSG induced an increase in the low-frequency (LF) band and a decrease in the high-frequency band of pulse interval. l-NAME treatment increased the LF band of systolic arterial pressure only in CTR without changes in MSG. Lipid peroxidation levels were higher in MSG and were attenuated after l-NAME. In endothelial cells, basal FI to DAF was higher in CTR than in MSG. In both groups, acetylcholine increased FI for DAF from basal. The FI baseline to DHE was higher in MSG than in CTR. Acetylcholine increased FI to DHE in the CTR group, but decreased in MSG animals. We suggest that reduced NO production and increased production of ROS may contribute to hypertension in obese MSG animals.

scholarly journals Nitric oxide synthase-mediated blood pressure regulation in obese melanocortin-4 receptor-deficient pregnant rats

2016 ◽  
Vol 311 (5) ◽  
pp. R851-R857 ◽  
Author(s):  
Frank T. Spradley ◽  
Jennifer M. Sasser ◽  
Jacqueline B. Musall ◽  
Jennifer C. Sullivan ◽  
Joey P. Granger
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Mesenteric Arteries ◽  
Elevated Blood Pressure ◽  
Pressure Regulation ◽  
Elevated Blood ◽  
Pregnant Rats ◽  
Melanocortin 4 Receptor ◽  
Regulation Of Blood Pressure

Although obesity increases the risk for hypertension in pregnancy, the mechanisms responsible are unknown. Increased nitric oxide (NO) production results in vasodilation and reduced blood pressure during normal pregnancy in lean rats; however, the role of NO is less clear during obese pregnancies. We examined the impact of obesity on NO synthase (NOS)-mediated regulation of blood pressure during pregnancy by testing the hypothesis that NOS activity, expression, and regulation of vascular tone and blood pressure are reduced in obese pregnant rats. At gestational day 19, melanocortin-4 receptor (MC4R)-deficient obese rats (MC4R) had greater body weight and fat mass with elevated blood pressure and circulating sFlt-1 levels compared with MC4R pregnant rats. MC4R pregnant rats also had less circulating cGMP levels and reduced total NOS enzymatic activity and expression in mesenteric arteries. Despite decreased biochemical measures of NO/NOS in MC4R rats, NOS inhibition enhanced vasoconstriction only in mesenteric arteries from MC4R rats, suggesting greater NOS-mediated tone. To examine the role of NOS on blood pressure regulation in obese pregnant rats, MC4R and MC4R pregnant rats were administered the nonselective NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME, 100 mg/l) from gestational day 14 to 19 in drinking water. The degree by which l-NAME raised blood pressure was similar between obese and lean pregnant rats. Although MC4R obese pregnant rats had elevated blood pressure associated with reduced total NOS activity and expression, they had enhanced NOS-mediated attenuation of vasoconstriction, with no evidence of alterations in NOS-mediated regulation of blood pressure.

Renal and pressor effects of aminoguanidine in cirrhotic rats with ascites.

1996 ◽  
Vol 7 (12) ◽  
pp. 2694-2699
Author(s):  
M C Ortíz ◽  
L A Fortepiani ◽  
C Martínez ◽  
N M Atucha ◽  
J García-Estañ
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Liver Cirrhosis ◽  
Experimental Model ◽  
Systemic Blood Pressure ◽  
Arterial Hypotension ◽  
Control Group ◽  
No Production ◽  
Water Excretion ◽  
Excretory Function

Recent work indicates that nitric oxide (NO) plays an important role in the systemic and renal alterations of liver cirrhosis. This study used aminoguanidine (AG), a preferential inhibitor of inducible nitric oxide synthase (iNOS), to evaluate the role of this NOS isoform in the systemic and renal alterations of an experimental model of liver cirrhosis with ascites (carbon tetrachloride/ phenobarbital). Experiments have been performed in anesthetized cirrhotic rats and their respective control rats prepared for clearance studies. Administration of AG (10 to 100 mg/kg, iv) elevated dose-dependent mean arterial pressure (MAP, in mm Hg) in the cirrhotic rats from a basal level of 79.3 +/- 3.6 to 115.0 +/- 4.7, whereas in the control animals, MAP increased only with the highest dose of the inhibitor (from 121.8 +/- 3.6 to 133.3 +/- 1.4). In the cirrhotic group, AG also significantly increased sodium and water excretion, whereas these effects were very modest in the control group. Plasma concentration of nitrates+nitrites, measured as an index of NO production, were significantly increased in the cirrhotic animals in the basal period and decreased with AG to levels not significantly different from the control animals. Similar experiments performed with the nonspecific NOS inhibitor N omega-nitro-L-arginine (NNA) also demonstrated an increased pressor sensitivity of the cirrhotic rats, but the arterial hypotension was completely corrected. These results, in an experimental model of liver cirrhosis with ascites, show that AG exerts a beneficial effect as a result of inhibition of NO production, increasing blood pressure and improving the reduced excretory function. Because NNA, but not AG, completely normalized the arterial hypotension, it is suggested that the constitutive NOS isoform is also contributing in an important degree. It is concluded that the activation of both inducible and constitutive NOS isoforms plays an important role in the lower systemic blood pressure and associated abnormalities that characterize liver cirrhosis.

Abstract 111: Xanthine Oxidoreductase Plays a Key Role in Nitrate, Nitrite and Nitric Oxide Homeostasis When the Endothelial Nitric Oxide Synthase is Compromised

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Maria Peleli ◽  
Christa Zollbrecht ◽  
Marcelo Montenegro ◽  
Michael Hezel ◽  
Eddie Weitzberg ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Primary Source ◽  
No Production ◽  
Xanthine Oxidoreductase ◽  
Physiological Conditions ◽  
Inorganic Nitrate ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Xanthine oxidoreductase (XOR) is generally known as a source of superoxide production, but this enzyme has also been suggested to mediate NO production via reduction of inorganic nitrate (NO 3 - ) and nitrite(NO 2 - ). This pathway for NO generation is of particular importance during certain pathologies, whereas endothelial NO synthase (eNOS) is the primary source of vascular NO generation under normal physiological conditions. The exact interplay between the NOS and XOR-derived NO is not yet fully elucidated. The aim of the present study was to investigate if eNOS deficiency is partly compensated by XOR upregulation and sensitization of the NO 3 - - NO 2 - - NO pathway. NO 3 - and NO 2 - were similar between naïve eNOS KO and wildtype (wt) mice, but reduced upon chronic treatment with the non-selective NOS inhibitor L-NAME (wt: 25.0±5.2, eNOS KO: 39.2±6.4, L-NAME: 8.2±1.6 μ NO 3 - -, wt: 0.38±0.07, eNOS KO: 0.42±0.04, L-NAME: 0.12±0.02 μ NO 2 - ). XOR function was upregulated in eNOS KO compared with wt mice [(mRNA: wt 1±0.07, eNOS KO 1.38±0.17), (activity: wt 825±54, eNOS KO 1327±280 CLU/mg/min), (uric acid: wt 32.87±1.53, eNOS KO 43.23±3.54 μ)]. None of these markers of XOR activity was increased in nNOS KO and iNOS KO mice. Following acute dose of NO 3 - (10 mg/kg bw, i.p.), the increase of plasma NO 2 - was more pronounced in eNOS KO (+0.51±0.13 μ) compared with wt (+0.22±0.09 μ), and this augmented response in the eNOS KO was abolished by treatment with the highly selective XOR inhibitor febuxostat (FEB). Liver from eNOS KO had higher reducing capacity of NO 2 - to NO compared with wt, and this effect was attenuated by FEB (Δppb of NO: wt +8.7±4.2, eNOS KO +44.2±15.0, wt+FEB +22.2±9.6, eNOS KO+FEB +26.8±10.2). Treatment with FEB increased blood pressure in eNOS KO (ΔMAP:+10.2±5.6 mmHg), but had no effect in wt (ΔMAP:-0.6±3.3 mmHg). Supplementation with NO 3 - (10 mM, drinking water) reduced blood pressure in eNOS KO (ΔMAP: -6.3±2.2 mmHg), and this effect was abolished by FEB (ΔMAP: +1.1±1.9 mmHg). In conclusion, upregulated and altered XOR function in conditions with eNOS deficiency can facilitate the NO 3 - - NO 2 - - NO pathway and hence play a significant role in vascular NO homeostasis.

scholarly journals The Effects of Oral l-Arginine and l-Citrulline Supplementation on Blood Pressure

Nutrients ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1679 ◽  
Author(s):  
David Khalaf ◽  
Marcus Krüger ◽  
Markus Wehland ◽  
Manfred Infanger ◽  
Daniela Grimm
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Animal Studies ◽  
Current Data ◽  
No Production ◽  
First Pass Metabolism ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Antihypertensive Properties ◽  
Pass Metabolism

Nitric oxide (NO) is a well-known vasodilator produced by the vascular endothelium via the enzyme endothelial nitric oxide synthase (eNOS). The inadequate production of NO has been linked to elevated blood pressure (BP) in both human and animal studies, and might be due to substrate inaccessibility. This review aimed to investigate whether oral administration of the amino acids l-arginine (Arg) and l-citrulline (Cit), which are potential substrates for eNOS, could effectively reduce BP by increasing NO production. Both Arg and Cit are effective at increasing plasma Arg. Cit is approximately twice as potent, which is most likely due to a lower first-pass metabolism. The current data suggest that oral Arg supplementation can lower BP by 5.39/2.66 mmHg, which is an effect that is comparable with diet changes and exercise implementation. The antihypertensive properties of Cit are more questionable, but are likely in the range of 4.1/2.08 to 7.54/3.77 mmHg. The exact mechanism by which Cit and Arg exert their effect is not fully understood, as normal plasma Arg concentration greatly exceeds the Michaelis constant (Km) of eNOS. Thus, elevated plasma Arg concentrations would not be expected to increase endogenous NO production significantly, but have nonetheless been observed in other studies. This phenomenon is known as the “l-arginine paradox”.

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