A Rosselet

University Hospital of Lausanne, Lausanne, Vaud, Switzerland

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Publications (6)35.36 Total impact

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    ABSTRACT: The present study was aimed at examining the role of nitric oxide (NO) in the hypoxic contraction of isolated small pulmonary arteries (SPA) in the rat. Animals were treated with either saline (sham experiments) or Escherichia coli lipolysaccharide [LPS, to obtain expression of the inducible NO synthase (iNOS) in the lung] and killed 4 h later. SPA (300- to 600-micrometer outer diameter) were mounted as rings in organ chambers for the recording of isometric tension, precontracted with PGF2alpha, and exposed to either severe (bath PO2 8 +/- 3 mmHg) or milder (21 +/- 3 mmHg) hypoxia. In SPA from sham-treated rats, contractions elicited by severe hypoxia were completely suppressed by either endothelium removal or preincubation with an NOS inhibitor [NG-nitro-L-arginine methyl ester (L-NAME), 10(-3) M]. In SPA from LPS-treated rats, contractions elicited by severe hypoxia occurred irrespective of the presence or absence of endothelium and were largely suppressed by L-NAME. The milder hypoxia elicited no increase in vascular tone. These results indicate an essential role of NO in the hypoxic contractions of precontracted rat SPA. The endothelium independence of HPV in arteries from LPS-treated animals appears related to the extraendothelial expression of iNOS. The severe degree of hypoxia required to elicit any contraction is consistent with a mechanism of reduced NO production caused by a limited availability of O2 as a substrate for NOS.
    The American journal of physiology 05/1999; 276(4 Pt 2):H1207-14. · 3.28 Impact Factor
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    ABSTRACT: The effects of two nitric oxide synthase (NOS) inhibitors with different isoform selectivity were compared in a murine model of endotoxemia. Mice challenged with 70 mg/kg intraperitoneal (ip) lipopolysaccharide (LPS) were treated 6 h after LPS with either NG-gamma-L-arginine methyl ester (L-NAME, nonselective NOS inhibitor, 10-60 mg/kg), L-canavanine (selective inhibitor of inducible NOS, 50-300 mg/kg), or saline (0.2 mL) given ip. In a subset of mice, plasma concentrations of nitrate (NO breakdown product), lipase (pancreas injury), lactate dehydrogenase, and transaminases (liver injury) were measured 16 h after LPS. Although both inhibitors reduced plasma nitrate, they produced contrasting effects on survival and organ injury. L-NAME enhanced liver damage and tended to accelerate the time of death, while L-canavanine significantly reduced mortality and had no deleterious effects in terms of organ damage. These results indicate that nonselective NOS inhibitors are detrimental in endotoxic shock and support the potential usefulness of selective inducible NOS inhibitors in this setting.
    The Journal of Infectious Diseases 02/1998; 177(1):127-32. · 5.85 Impact Factor
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    ABSTRACT: S-methyl-isothiourea (SMT) is a potent inhibitor of NO synthase (NOS) with relative selectivity towards the inducible isoform (iNOS). We compared SMT and norepinephrine for the treatment of experimental endotoxic shock. Anesthetized rats challenged intravenously with lipopolysaccharide (LPS), 10 mg/kg, were treated after 1 h with a 4-h infusion of norepinephrine (titrated to maintain blood pressure within baseline values), SMT at low dose (0.1 mg x kg-1 x h-1), or at high dose (1 mg x kg-1 x h-1), or an equivalent volume of saline (2 ml x kg-1 x h-1). In saline-treated animals, LPS increased plasma nitrate and produced hypotension, low cardiac output (CO), lactic acidosis, and signs of liver and kidney dysfunction. Norepinephrine maintained blood pressure (BP) and reduced the fall in CO, without affecting lactic acidosis, organ dysfunction, and nitrate accumulation. The latter was dose-dependently blunted by SMT. Treatment with this agent prevented hypotension, through systemic vasoconstriction with the high dose and a maintained CO with the low dose. Low, but not high, dose SMT blunted lactic acidosis. Both doses reduced the signs of renal, but not liver, dysfunction. In additional studies, we obtained evidence that, in contrast with the high dose, SMT at low dose did not interfere with the function of constitutive NOS. These findings suggest a potential advantage of selective iNOS inhibition over standard adrenergic support in the therapy of septic shock.
    American Journal of Respiratory and Critical Care Medicine 02/1998; 157(1):162-70. · 11.04 Impact Factor
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    ABSTRACT: 1An enhanced production of nitric oxide (NO) from L-arginine, related to the diffuse 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 effects of L-lysine, an inhibitor of L-arginine uptake through system y+, on NO production, multiple organ dysfunction and lactate levels, in normal and endotoxaemic rats.2Anaesthetized rats challenged with intravenous lipopolysaccharide (LPS, 10 mg kg−1) received a 5 h infusion of either L-lysine (500 μmol kg−1 h−1, n=12) or isotonic saline (2 ml kg−1 h−1, 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 significantly reduced byL-lysine administration.3Endotoxaemia also caused a significant 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 differences did not reach statistical significance.4Similar experiments were conducted in 10 rats challenged with LPS vehicle in place of LPS and then treated with L-lysine (500 μmol kg−1 h−1, n=5) or saline (2 ml kg−1 h−1, n=5) for 5 h. In these animals, all the haemodynamic and metabolic variables remained stable and not statistically different between both treatment groups, except for a slight rise in ALAT, which was comparable in L-lysine and saline-treated rats.5In conclusion, L-lysine, an inhibitor of cellular L-arginine uptake, reduces NO production and exerts beneficial haemodynamic effects 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 effects in the absence of endotoxin and thus appears to act as a selective modulator of iNOS activity.British Journal of Pharmacology (1997) 122, 742–748; doi:10.1038/sj.bjp.0701419
    British Journal of Pharmacology 09/1997; 122(4):742 - 748. · 5.07 Impact Factor
  • Article: Free Papers
    Intensive Care Medicine 09/1996; 22(3). · 5.26 Impact Factor
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    ABSTRACT: 1. The cardiovascular failure in sepsis may result from increased nitric oxide biosynthesis, through the diffuse expression of an inducible nitric oxide synthase. In such conditions, nitric oxide synthase inhibitors might be of therapeutic value, but detrimental side effects have been reported with their use, possibly related to the blockade of constitutive nitric oxide synthase. Therefore, the use of selective inhibitors of inducible nitric oxide synthase might be more suitable. The aim of this study was to evaluate the effects of L-canavanine, a potentially selective inhibitor of inducible nitric oxide synthase, in an animal model of septic shock. 2. Anaesthetized rats were challenged with 10 mg/kg lipopolysaccharide intravenously. One hour later, they randomly received a 5 h infusion of either L-canavanine (20 mg h-1 kg-1, n = 15), nitro-L-arginine methyl ester (5 mg h-1 kg-1, n = 13) or 0.9% NaCl (2 ml h-1 kg-1, n = 21). Lipopolysaccharide induced a progressive fall in blood pressure and cardiac index, accompanied by a significant lactic acidosis and a marked rise in plasma nitrate. All these changes were significantly attenuated by L-canavanine, which also improved the tolerance of endotoxaemic animals to acute episodes of hypovolaemia. In addition, L-canavanine significantly increased survival of mice challenged with a lethal dose of lipopolysaccharide. In contrast to L-canavanine, nitro-L-arginine methyl ester increased blood pressure at the expense of a severe fall in cardiac index, while largely enhancing lactic acidosis. This agent did not improve survival of endotoxaemic mice. In additional experiments, we found that the pressor effect of L-canavanine in advanced endotoxaemia (4 h) was reversed by L-arginine, confirming that it was related to nitric oxide synthase inhibition. In contrast, L-canavanine did not exert any influence on blood pressure in the very early stage (first hour) of endotoxaemia or in the absence of lipopolysaccharide exposure, indicating a lack of constitutive nitric oxide synthase inhibition by this agent. 3. In conclusion, L-canavanine produced beneficial haemodynamic and metabolic effects and improved survival in rodent endotoxic shock. The actions of L-canavanine were associated with a selective inhibition of inducible nitric oxide synthase and were in marked contrast to the deleterious consequences of nitro-L-arginine methyl ester, a non-selective nitric oxide synthase inhibitor, in similar conditions.
    Clinical Science 06/1996; 90(5):369-77. · 4.86 Impact Factor