Nonpeptide Antagonists of AT1 Receptor for Angiotensin II Delay the Onset of Acute Respiratory Distress Syndrome

  1. Silvina Raiden1,
  2. Karen Nahmod1,
  3. Vı́ctor Nahmod2,
  4. Guillermo Semeniuk2,
  5. Yanina Pereira2,
  6. Clarisa Alvarez2,
  7. Mirta Giordano1,3 and
  8. Jorge R. Geffner1,3
  1. 1Laboratory of Immunology, Institute of Hematologic Research, National Academy of Medicine (S.R., K.N., M.G., J.R.G.); 2Institute of Medical Research “Alfredo Lanari” (V.N., G.S., Y.P., C.A.), and3Department of Microbiology, Buenos Aires University School of Medicine (M.G., J.R.G.), Buenos Aires, Argentina
  1. Jorge Geffner, Laboratorio de Inmunologı́a, IIHEMA, Academia Nacional de Medicina, Pacheco de Melo 3081, 1425 Buenos Aires, Argentina. E-mail:geffnerj{at}fibertel.com.ar

Abstract

We have previously reported that losartan, a selective antagonist of AT1 receptors for angiotensin II (AII), strongly suppresses the activation of neutrophils byN-formylmethionyl-leucyl-phenylalanine (fMLP) through a mechanism that does not involve inhibition of AT1 receptors. Herein, we analyze whether losartan would prevent the development of the acute respiratory distress syndrome (ARDS) triggered by lung bacterial infection. We found that losartan (0.2–200 μg/kg/min) delays the onset of ARDS in Wistar rats challenged by i.t. instillation ofBordetella bronchiseptica. Although this effect was associated with a significant inhibition of lung-neutrophil recruitment, lung bacterial clearance was not impaired but rather, it was significantly improved. We also found that another nonpeptide AT1 receptor blocker, irbesartan, exerted similar effects to losartan, i.e., it was also able to inhibit neutrophil activation by fMLP and to delay the onset of ARDS in B. bronchiseptica-challenged rats. Neither the inhibitor of angiotensin-converting enzyme captopril, nor the nonselective peptide inhibitor of AII receptors saralasin reproduced these effects. Our data are consistent with the possibility that nonpeptide AT1 receptor blockers delay the onset of ARDS triggered by bacterial infection through a mechanism dependent, at least in part, on their ability to prevent neutrophil activation byN-formyl-peptides.

Footnotes

  • This work was supported by grants from the Consejo Nacional de Investigaciones Cientı́ficas y Técnicas, Agencia Nacional de Promoción Cientı́fica y Tecnológica, Universidad de Buenos Aires, Fundación “Roemmers”, and Ministerio de Salud, Subsecretarı́a de Investigación y Tecnologı́a, Argentina.

  • DOI: 10.1124/jpet.102.037382

  • Abbreviations:
    AII
    angiotensin II
    fMLP
    N-formylmethionyl-leucyl-phenylalanine
    FPR
    N-formylmethionyl-leucyl-phenylalanine receptor
    ARDS
    acute respiratory distress syndrome
    IL
    interleukin
    ZAS
    zymosan-activated serum
    aIgG
    human heat-aggregated IgG
    [Ca2+]i
    intracellular Ca2+concentration
    AM
    acetoxymethyl ester
    CFU
    colony-forming unit
    TxA2
    thromboxane A2
    • Received April 12, 2002.
    • Accepted June 25, 2002.
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  1. doi: 10.1124/jpet.102.037382 JPET October 1, 2002 vol. 303 no. 1 45-51
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