Vol. 303, Issue 1, 45-51, October 2002

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

Silvina Raiden, Karen Nahmod, Víctor Nahmod, Guillermo Semeniuk, Yanina Pereira, Clarisa Alvarez, Mirta Giordano and Jorge R. Geffner

Laboratory of Immunology, Institute of Hematologic Research, National Academy of Medicine (S.R., K.N., M.G., J.R.G.); Institute of Medical Research "Alfredo Lanari" (V.N., G.S., Y.P., C.A.), and Department of Microbiology, Buenos Aires University School of Medicine (M.G., J.R.G.), Buenos Aires, Argentina

We have previously reported that losartan, a selective antagonist of AT1 receptors for angiotensin II (AII), strongly suppresses the activation of neutrophils by N-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 of Bordetella 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 by N-formyl-peptides.