title: Nonpeptide antagonists of AT1 receptor for angiotensin II delay the onset of acute respiratory distress syndrome.
abstract: 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 microg/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.
authors.affiliation: Laboratory of Immunology, Institute of Hematologic Research, National Academy of Medicine, Buenos Aires, Argentina.
authors.forename: Silvina
authors.initials: S
authors.lastname: Raiden
authors.forename: Karen
authors.initials: K
authors.lastname: Nahmod
authors.forename: Víctor
authors.initials: V
authors.lastname: Nahmod
authors.forename: Guillermo
authors.initials: G
authors.lastname: Semeniuk
authors.forename: Yanina
authors.initials: Y
authors.lastname: Pereira
authors.forename: Clarisa
authors.initials: C
authors.lastname: Alvarez
authors.forename: Mirta
authors.initials: M
authors.lastname: Giordano
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Geffner
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001885:Bordetella Infections / Q000473:pathology / Q000503:physiopathology; D016950:Bordetella bronchiseptica; D002118:Calcium / Q000097:blood; D007700:Kinetics; D019808:Losartan / Q000494:pharmacology*; D008168:Lung / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000502:physiology*; D010100:Oxygen / Q000097:blood; D009195:Peroxidase / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D012084:Renin-Angiotensin System / Q000187:drug effects; D012128:Respiratory Distress Syndrome / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D057911:Angiotensin Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D009195:Peroxidase; D019808:Losartan; D010100:Oxygen; D002118:Calcium