Cationic amino acids inhibit the effects of L-arginine in rat aorta exposed to lipopolysaccharide

Schott, Christa; Vetrovsky, Petr; Stoclet, Jean‐Claude

doi:10.1016/0014-2999(93)90240-i

Cited by 12 publications

(5 citation statements)

References 7 publications

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“…Such an apparent discrepancy between the K, or Ki values of L-arginine for its transporter (about 100 PM) and the concentration producing halfmaximal relaxation (8 ,uM) in rat aortic rings exposed to LPS, has also been described previously [11,21]. K, values of L-arginine and OH-L-Arg are respectively about 100 and 200 PM for the transporter [l 1 and this study] and about 1 to 10,~M for NO-synthase [2,3].…”

Section: Discussionsupporting

confidence: 61%

Exogenous N^G‐hydroxy‐l‐arginine causes nitrite production in vascular smooth muscle cells in the absence of nitric oxide synthase activity

et al. 1994

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Nitric oxide (NO) production from exogenous NG-hydroxy-L-arginine (OH-L-Arg) was investigated in rat aortic smooth muscle cells in culture by measuring nitrite accumulation in the culture medium. As well, the interaction between OH-L-Arg and L-arginine uptake via the y+ cationic amino acid transporter was studied. In cells without NO-synthase activity, OH-L-Arg (l-1000 ,uM) induced a dose-dependent nitrite production with a half-maximal effective concentration (EC,,) of 18.0 f 1.5 PM (n = 4-7). This nitrite accumulation was not inhibited by the NO-synthase inhibitor No-nitro+arginine methyl ester, L-NAME (300 PM). In contrast, it was abolished by miconaxole (100 pM), an inhibitor of cytochrome PJ5@ Incubation of vascular smooth muscle cells with LPS (10 &ml) induced an L-NAME inhibited nitrite accumulation, but did not enhance the OH-L-Arg induced nitrite production. OH-L-Arg and other cationic amino acids, L-lysine and L-ornithine, competitively inhibited [3H]-L-arginine uptake in rat aortic smooth muscle cells, with inhibition constants of 195 f 23 ,uM (a = 12), 260 & 4OpM (n = 5) and 330 f 10pM (n = 5), respectively. These results show that OH-L-Arg is recognized by the cationic ~-amino acid carrier present in vascular smooth muscle cells and can be oxidized to NO and nitrite in these cells in the absence of NO-synthase, probably by cytochrome P4M or by a reaction involving a cytochrome P4r,, byproduct.

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Section: Discussionsupporting

confidence: 61%

Exogenous N^G‐hydroxy‐l‐arginine causes nitrite production in vascular smooth muscle cells in the absence of nitric oxide synthase activity

et al. 1994

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“…As expected, classical inhibitors of NOS such as SEITU, AG, and NMMA strongly decreased the level of NO 2 - accumulation in the supernatants of activated cells incubated in the presence of 1 mM l -Arg, whereas l -NAME was less efficient (Figure A). Furthermore, the addition of l -lysine, a known competitor for the y + -amino acid transport system ( , ), also strongly inhibited NO 2 - formation in these supernatants. In control experiments, it was observed that supernatants of activated macrophages incubated in l -Arg-free RPMI medium contained low levels of NO 2 - in comparison to supernatants of cells incubated in RPMI medium containing 1 mM l -Arg (4 ± 2 and 70 ± 10 μM after 30 h, respectively).…”

Section: Resultsmentioning

confidence: 97%

First Non-α-Amino Acid Guanidines Acting as Efficient NO Precursors upon Oxidation by NO-Synthase II or Activated Mouse Macrophages

et al. 2002

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A study of the oxidation of a series of guanidines related to L-arginine (L-Arg) and of various alkyl- and arylguanidines, by recombinant NO-synthase II (NOS II), led us to the discovery of the first non-alpha-amino acid guanidine substrate of NOS, acting as an efficient NO precursor. This compound, 3-(trifluoromethyl)propylguanidine, 4, led to a rate of NO formation (k(cat) = 220 +/- 50 min(-1)) only 2 times lower than that of L-Arg. Formation of 1 mol of NO upon NOS II-catalyzed oxidation of 4 occurred with consumption of 2.9 mol of NADPH, which corresponds to a 52% coupling between electron transfer and oxygenation of its guanidine function. Its oxidation by activated mouse macrophages in an L-Arg-free medium resulted in NO(2)(-) formation that was inhibited by classical NOS inhibitors with a rate only 2-3 times lower than that observed with L-Arg itself. These results open the way toward the research of selective, stable guanidine substrates of NOS that could be interesting, new NO donors after in situ oxidation by a given NOS isoform.

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“…l ‐Lys is an alternate substrate for system y + , which competitively inhibits l ‐Arg transport (White, 1985; Bogle et al , 1992) and may thus limit iNOS‐dependent NO production. In vitro , l ‐Lys blocks interleukin‐1β (IL‐1β) stimulated NO production by vascular cells (Durante et al , 1995) and partially reverses the NO‐mediated hyporeactivity of rat aortic rings exposed to endotoxin (Schott et al , 1993b). Our results provide evidence that such effects of l ‐Lys also occur in vivo .…”

Section: Discussionmentioning

confidence: 99%

Effect of L‐lysine on nitric oxide overproduction in endotoxic shock

Liaudet¹,

Gnaegi²,

Rosselet³

et al. 1997

British J Pharmacology

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1 An enhanced production of nitric oxide (NO) from L-arginine, related to the di use expression of an inducible NO synthase (iNOS), contributes to the pathogenesis of endotoxic shock. Since iNOS activity depends on extracellular L-arginine, we hypothesized that limiting cellular L-arginine uptake would reduce NO production in endotoxic shock. We investigated the e ects of L-lysine, an inhibitor of Larginine uptake through system y + , on NO production, multiple organ dysfunction and lactate levels, in normal and endotoxaemic rats. 2 Anaesthetized rats challenged with intravenous lipopolysaccharide (LPS, 10 mg kg 71 ) received a 5 h infusion of either L-lysine (500 mmol kg 71 h 71 , n=12) or isotonic saline (2 ml kg 71 h 71 , n=11). In rats treated with saline, LPS produced a large increase in plasma nitrate and L-citrulline concentrations at 5 h, both markers of enhanced NO production. LPS also caused severe hypotension, low cardiac output and marked hyperlactataemia. All these changes were signi®cantly reduced by L-lysine administration.3 Endotoxaemia also caused a signi®cant rise in the plasma levels of alanine aminotransferase (ALAT), lipase, urea and creatinine, and hence, liver, pancreatic and renal dysfunction. These changes tended to be less pronounced in rats treated with L-lysine, although the di erences did not reach statistical signi®cance. 4 Similar experiments were conducted in 10 rats challenged with LPS vehicle in place of LPS and then treated with L-lysine (500 mmol kg 71 h 71 , n=5) or saline (2 ml kg 71 h 71 , n=5) for 5 h. In these animals, all the haemodynamic and metabolic variables remained stable and not statistically di erent between both treatment groups, except for a slight rise in ALAT, which was comparable in L-lysine and saline-treated rats. 5 In conclusion, L-lysine, an inhibitor of cellular L-arginine uptake, reduces NO production and exerts bene®cial haemodynamic e ects in endotoxaemic rats. L-lysine also reduces hyperlactataemia and tends to blunt the development of organ injury in these animals. Contrastingly, L-lysine has no e ects in the absence of endotoxin and thus appears to act as a selective modulator of iNOS activity.

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Cationic amino acids inhibit the effects of L-arginine in rat aorta exposed to lipopolysaccharide

Cited by 12 publications

References 7 publications

Exogenous N^G‐hydroxy‐l‐arginine causes nitrite production in vascular smooth muscle cells in the absence of nitric oxide synthase activity

Exogenous N^G‐hydroxy‐l‐arginine causes nitrite production in vascular smooth muscle cells in the absence of nitric oxide synthase activity

First Non-α-Amino Acid Guanidines Acting as Efficient NO Precursors upon Oxidation by NO-Synthase II or Activated Mouse Macrophages

Effect of L‐lysine on nitric oxide overproduction in endotoxic shock

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Cationic amino acids inhibit the effects of L-arginine in rat aorta exposed to lipopolysaccharide

Cited by 12 publications

References 7 publications

Exogenous NG‐hydroxy‐l‐arginine causes nitrite production in vascular smooth muscle cells in the absence of nitric oxide synthase activity

Exogenous NG‐hydroxy‐l‐arginine causes nitrite production in vascular smooth muscle cells in the absence of nitric oxide synthase activity

First Non-α-Amino Acid Guanidines Acting as Efficient NO Precursors upon Oxidation by NO-Synthase II or Activated Mouse Macrophages

Effect of L‐lysine on nitric oxide overproduction in endotoxic shock

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Exogenous N^G‐hydroxy‐l‐arginine causes nitrite production in vascular smooth muscle cells in the absence of nitric oxide synthase activity

Exogenous N^G‐hydroxy‐l‐arginine causes nitrite production in vascular smooth muscle cells in the absence of nitric oxide synthase activity