Hypoxia inhibits L-arginine uptake by pulmonary artery endothelial cells

Block, Edward R.; Herrera, Hector; Couch, Margaret W.

doi:10.1152/ajplung.1995.269.5.l574

Cited by 57 publications

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“…Hypoxia inhibits L-arginine transport with no significant effect on CAT-1 mRNA expression or membrane protein levels. 23,24 This effect is not reversible after a return to normoxia for 24 hours. 24 There is evidence that the placental bed in preeclampsia is hypoxic, 25 where inflammatory leukocytes in the hypoxic intervillous space may be exposed to damage of membrane CAT proteins that impairs function.…”

Section: Discussionmentioning

confidence: 96%

System y ⁺ Arginine Transport and NO Production in Peripheral Blood Mononuclear Cells in Pregnancy and Preeclampsia

et al. 2006

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Abstract-Systemic inflammation and oxidative stress are features of normal pregnancy and, in excess, contribute to the pathogenesis of preeclampsia. Inflammatory cell activation stimulates uptake of arginine (the precursor for nitric oxide) by transport system y ϩ , expression of one of its genes (CAT-2) together with inducible nitric oxide synthase, leading to nitric oxide production. We investigated whether these changes occur in peripheral blood mononuclear cells in normal pregnancy and are exaggerated in preeclampsia. Samples from matched trios of nonpregnant, normal pregnant, and preeclamptic women were studied. Arginine transport was characterized, and the expression of inducible nitric oxide synthase and cell-specific nitric oxide production were measured. Arginine uptake by system y ϩ was significantly increased (PϽ0.001) in peripheral blood mononuclear cells in normal pregnancy but not in preeclampsia. CAT-2 mRNA was not detected in cells from nonpregnant women but was detected in 3 of 10 normal pregnant and 8 of 10 of preeclamptic women (PϽ0.001). Inducible nitric oxide synthase protein expression was significantly increased in normal pregnant women (PϽ0.05) but not preeclamptic women. No significant differences in cell-specific nitric oxide production were observed. These changes confirm the predictions for normal pregnancy but not for preeclampsia in which, despite increases in CAT-2 expression, arginine uptake is not additionally increased. This may create a relative deficiency of arginine in PBMCs favoring superoxide and peroxynitrite production and contribute to oxidative and nitrosative stress in preeclampsia.

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Section: Discussionmentioning

confidence: 96%

System y ⁺ Arginine Transport and NO Production in Peripheral Blood Mononuclear Cells in Pregnancy and Preeclampsia

et al. 2006

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“…The Arg content of endothelial cells is derived primarily from plasma membranedependent transport of extracellular Arg, but can also be synthesized from L-cit [19]. BLOCK et al [20] showed that exposure to hypoxia causes significant reduction in the transport of Arg, only accompanied by a decrease in intracellular Arg content after long-term exposure to hypoxia. SU and BLOCK [21] demonstrated that hypoxia time dependently inhibits the synthesis of Arg from L-cit in pulmonary artery endothelial cells.…”

Section: L-arginine Availabilitymentioning

confidence: 99%

Response of nitric oxide pathway to l-arginine infusion at the altitude of 4,350 m

et al. 2001

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Response of nitric oxide pathway to L-arginine infusion at the altitude of 4,350 m. J-C. Schneider, I. Blazy, M. Déchaux, D. Rabier, N.P. Mason, J-P. Richalet. #ERS Journals Ltd 2001. ABSTRACT: It was hypothesized that hypoxia may inhibit nitric oxide (NO) production by reducing the availability of endothelial NO synthase (NOS III) substrate.To evaluate the effect of L-arginine on the NO release in high altitude, 11 subjects were infused with L-arginine (0.5 g?kg -1 ) during 30 min in normoxia and after 36 h at 4,350 m (hypoxia). The L-citrulline and cyclic guanosine monophosphate (cGMP) concentrations were measured to investigate NO synthesis and guanylyl cyclase activity respectively. L-citrulline concentration, arterial oxygen saturation (Sa,O 2 ), systemic blood pressure, heart rate and acute mountain sickness (AMS) score were measured at rest and 15, 30 and 45 min after starting infusion.The results showed that baseline L-citrulline was lower in hypoxia (pv0.05). L-arginine infusion increased L-citrulline concentration in both conditions. However, in hypoxia L-citrulline concentration remained lower than in normoxia (pv0.05). The concentration of cGMP was lower in hypoxia (pv0.05). In hypoxia, Sa,O 2 increased from 15 min after the start of the infusion to 45 min (pv0.05). Blood pressure and heart rate were not affected by L-arginine infusion.Subjects who experienced symptoms of AMS showed a slight decrease in AMS score with L-arginine.The decreased L-citrulline suggests a hypoxia-induced impairment of nitric oxide synthase III or a decrease in L-arginine availability. The improvement of arterial oxygen saturation by pretreatment with L-arginine could be ascribed to an enhancement of the ventilation/perfusion ratio. Collectively, these results are consistent with a decrease in nitric oxide production in hypoxia that could be antagonized by supplying nitric oxide synthase cosubstrate. Exposure to high altitude causes hypoxaemia, which is often accompanied by the clinical manifestations of acute mountain sickness (AMS) and may lead to the development of pulmonary hypertension and high altitude pulmonary oedema (HAPE). Several factors are incriminated: hypoxic pulmonary vasoconstriction (HPV), water retention, and permeability alterations [1]. Increased release of vasoconstrictors, such as endothelin or catecholamines, at high altitude may be partially responsible for HPV [2]. However, impairment of nitric oxide (NO) synthesis by pulmonary endothelial cells occurs in the pulmonary hypertensive process suggesting that the increase in pulmonary vascular tone could have its origin in a decline of endothelium-dependent relaxation [3]. NO is synthesized in pulmonary artery endothelial cells by the action of the endothelial constitutive NO synthase isoform (NOS III) on the cationic amino acid L-arginine (Arg). NO is produced from the terminal guanidino-nitrogen of Arg upon conversion to L-citrulline by NOS III in a reaction that requires molecular oxygen and cofactors. Direct measurement of NO release from vascular ...

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“…From Figures 1 and 2 it can be seen that the control curves fall approximately mid-way between those for 400 mM L-arginine and 10 mM Llysine, suggesting that the concentration of this endogenous Larginine is close to the EC 50 , or around 1 ± 7 mM (see Results and Figure 4). As the intracellular concentration of L-arginine is at least 100 fold greater than this (Gold et al, 1989;Baydoun et al, 1990;Block et al, 1995;Bogle et al, 1996), we can speculate that only a small amount of diusion and/or reverse Figure 7 Isoprenaline concentration-response curves in mesenteric arteries constricted with 50 mM PGF 2a , and in the presence of Larginine (400 mM) or L-arginine plus L-lysine (10 mM). Each point is the mean of 5 ± 7 experiments, and symbols are mean+s.e.mean.…”

Section: Concentration Dependence Of Response To L-argininementioning

confidence: 99%

“…It is generally assumed that under normal physiological conditions L-arginine is in excess, as the EC 50 for activation of eNOS is *1-10 mM (Palmer & Moncada, 1989;Su et al, 1997), yet the intracellular concentration of L-arginine in the endothelial cell is signi®cantly greater than 100 mM (Baydoun et al, 1990;Block et al, 1995), and sucient to maximally activate the enzyme (Su et al, 1997). Most studies on isolated preparations do not therefore include L-arginine in the extracellular medium.…”

Section: Introductionmentioning

confidence: 99%

Critical dependence of the NO‐mediated component of cyclic AMP‐induced vasorelaxation on extracellular L‐arginine in pulmonary arteries of the rat

Hucks

Ward

2000

British J Pharmacology

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1 A component of isoprenaline-mediated vasorelaxation in pulmonary arteries is mediated by nitric oxide (NO). We examined the eects of physiological concentrations (4400 mM) of L-arginine on isoprenaline-induced relaxation in rat pulmonary arteries, and following inhibition of L-arginine uptake with L-lysine. In addition, we examined the role of the endothelium, and whether L-arginine aected acetylcholine (ACh)-induced relaxation. 2 Isoprenaline-induced relaxation was potentiated by 400 mM L-arginine in pulmonary arteries; maximum relaxation was increased from 83+4% of initial tone to 94+4% (P50.05). L-lysine (10 mM) not only abolished the potentiation by L-arginine, but suppressed relaxation compared to control (70+4%, P50.05), even in the absence of L-arginine added to the bath. Blockade of NO synthase with 100 mM L-NMMA or removal of the endothelium inhibited isoprenaline-induced relaxation to the same extent as L-lysine, and under these conditions the presence or absence of 400 mM L-arginine made no dierence. L-lysine had no additional eect when applied in combination with L-NMMA. 3 The eect of extracellular L-arginine was concentration dependent, with an apparent EC 50 of *1±7 mM. 4 Relaxation to the membrane permeant cyclic AMP analogue CPT cyclic AMP was also potentiated by L-arginine and inhibited by L-lysine. There was however no dierence in relaxation induced by acetylcholine (ACh) in the presence of L-arginine or L-lysine, and isoprenaline-induced relaxation of mesenteric arteries was unaected by L-arginine or L-lysine. 5 These results strongly suggest that extracellular L-arginine is critically important for development of the NO-and endothelium-dependent component of cyclic AMP-induced vasorelaxation in rat pulmonary arteries, but is not required for ACh-induced relaxation. As the apparent EC 50 for this eect is in the low micromolar range it is likely to be fully activated in vivo, as plasma L-arginine is 4150 mM.

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Hypoxia inhibits L-arginine uptake by pulmonary artery endothelial cells

Cited by 57 publications

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System y ⁺ Arginine Transport and NO Production in Peripheral Blood Mononuclear Cells in Pregnancy and Preeclampsia

System y ⁺ Arginine Transport and NO Production in Peripheral Blood Mononuclear Cells in Pregnancy and Preeclampsia

Response of nitric oxide pathway to l-arginine infusion at the altitude of 4,350 m

Critical dependence of the NO‐mediated component of cyclic AMP‐induced vasorelaxation on extracellular L‐arginine in pulmonary arteries of the rat

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Hypoxia inhibits L-arginine uptake by pulmonary artery endothelial cells

Cited by 57 publications

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System y + Arginine Transport and NO Production in Peripheral Blood Mononuclear Cells in Pregnancy and Preeclampsia

System y + Arginine Transport and NO Production in Peripheral Blood Mononuclear Cells in Pregnancy and Preeclampsia

Response of nitric oxide pathway to l-arginine infusion at the altitude of 4,350 m

Critical dependence of the NO‐mediated component of cyclic AMP‐induced vasorelaxation on extracellular L‐arginine in pulmonary arteries of the rat

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System y ⁺ Arginine Transport and NO Production in Peripheral Blood Mononuclear Cells in Pregnancy and Preeclampsia

System y ⁺ Arginine Transport and NO Production in Peripheral Blood Mononuclear Cells in Pregnancy and Preeclampsia