Low-dose Inhalation of an Endothelin-a Receptor Antagonist in Experimental Acute Lung Injury: Et-1 Plasma Concentration and Pulmonary Inflammation.
From: Department of Anesthesiology and Intensive Care Medicine, Charite, Campus Virchow-Klinikum, University Medical Center, Berlin, Germany.
Experimental biology and medicine (Maywood, N.J.)
- Publish Date: Jun 2006
- ISSN: 1535-3702
- Volume: 231
- Issue: 6
- Pages: 960-6
- Medium: Print
- Language: English
- Citation (JAMA): Donaubauer Bernd, Busch Thilo, Lachmann Robert, et al. Low-dose Inhalation of an Endothelin-a Receptor Antagonist in Experimental Acute Lung Injury: Et-1 Plasma Concentration and Pulmonary Inflammation.. Exp. Biol. Med. (Maywood) Jun 2006;231:960-6
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.
Mesh Headings (Keywords): Acute Disease, Administration, Inhalation, Animals, Blood Pressure, Cardiac Output, Dose-Response Relationship, Drug, Endothelin-1, Inflammation, Lung Diseases, Phenylpropionates, Prospective Studies, Pulmonary Gas Exchange, Pyrimidines, Random Allocation, Receptor, Endothelin A, Swine
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