title: Low-dose inhalation of an endothelin-A receptor antagonist in experimental acute lung injury: ET-1 plasma concentration and pulmonary inflammation.
abstract: Inhalation of endothelin (ET)-A receptor antagonists has been shown to improve gas exchange in experimental acute lung injury (ALI) but may induce side effects by increasing circulating ET-1 levels. We investigated whether the inhaled ET(A) receptor antagonist, LU-135252, at low doses, improves gas exchange without affecting ET-1 plasma concentrations and lung injury in an animal model of ALI. Twenty-two piglets were examined in a prospective, randomized, controlled study. In anesthetized animals, ALI was induced by surfactant depletion. Animals received either LU-135252 at a dose of 0.3 mg/kg during 20 mins (LU group; n = 11), or nebulization of saline buffer (control group; n = 11). The Mann-Whitney U test was used to compare groups (P < 0.05). In the LU group, arterial partial pressure of oxygen (PaO2) and mean pulmonary artery pressure (MPAP) improved compared with the control group (PaO2, 319 +/- 44 mm Hg vs. 57 +/- 3 mm Hg; MPAP, 32 +/- 2 mm Hg vs. 41 +/- 2 mm Hg; values at 6 hrs after induction of ALI; P < 0.05). Mean arterial pressure and cardiac output were not different between groups. ET-1 plasma concentrations increased from 0.96 +/- 0.06 fmol/ml after induction of ALI to a maximum of 1.17 +/- 0.09 fmol/ml at 3 hrs after ALI onset in the LU group and did not differ significantly from the control group (1.21 +/- 0.08 fmol/ml, not significant). On histologic examination, we found no differences in total lung injury score between groups. However, the LU group revealed significantly reduced interstitial inflammation and hemorrhage (P < 0.05 vs. control group). In this animal model of ALI, inhalation of LU-135252 at a dose of 0.3 mg/kg induced a significant and sustained improvement in gas exchange, whereas there were no changes in ET-1 plasma concentrations. Furthermore, our data indicate a trend toward decreased pulmonary inflammation in the group receiving the inhaled ET(A) receptor antagonist.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Charite, Campus Virchow-Klinikum, University Medical Center, Berlin, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Donaubauer
authors.forename: Thilo
authors.initials: T
authors.lastname: Busch
authors.forename: Robert
authors.initials: R
authors.lastname: Lachmann
authors.forename: Maria
authors.initials: M
authors.lastname: Deja
authors.forename: Bodil
authors.initials: B
authors.lastname: Petersen
authors.forename: Roland
authors.initials: R
authors.lastname: Francis
authors.forename: Annette
authors.initials: A
authors.lastname: Träger
authors.forename: Michael
authors.initials: M
authors.lastname: Ebsen
authors.forename: Willehad
authors.initials: W
authors.lastname: Boemke
authors.forename: Udo
authors.initials: U
authors.lastname: Kaisers
mesh_terms: D000208:Acute Disease; D000280:Administration, Inhalation; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood*; D007249:Inflammation / Q000188:drug therapy; D008171:Lung Diseases / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology*; D010666:Phenylpropionates / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011446:Prospective Studies; D011659:Pulmonary Gas Exchange / Q000187:drug effects*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011897:Random Allocation; D013552:Swine
chemical_list: D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011743:Pyrimidines; C107831:darusentan