Inhalation of the endothelin-A receptor antagonist LU-135252 at various doses in experimental acute lung injury.
We studied the effects of the inhaled endothelin-A receptor antagonist LU-135252 at different doses on hemodynamics and gas exchange in an animal model of acute lung injury. Thirtysix piglets (27 +/- 1 kg) were anesthetized, mechanically ventilated (FiO2 1.0), and surfactant-depleted by repeated lung lavage. The animals were randomly assigned to receive either nebulized LU- 135252 for 30 minutes at a dose of 0.3 mg/kg (n = 12), or at a dose of 3.0 mg/kg (n = 12); n = 12 animals received no further treatment (Controls). Induction of acute lung injury decreased PaO2 from 566 +/- 8 mmHg to 53 +/- 2 mmHg (mean +/- SEM) and increased intrapulmonary shunt (QS/QT) from 13 +/- 1% to 57 +/- 2%. Inhalation of LU-135252 at either dose induced a significant and sustained increase in PaO2 (0.3 mg/kg: 349 +/- 39 mmHg; 3.0 mg/kg: 219 +/- 40 mmHg), and a significant decrease in QS/QT (0.3 mg/kg: 19 +/- 2%; 3.0 mg/kg: 27 +/- 3%) when compared with Controls (PaO2: 50 +/- 3 mmHg, QS/QT: 50 +/- 5%) (P < 0.05; values at 4 hours). Mean pulmonary artery pressure in LU-135252-treated animals (0.3 mg/kg: 31 +/- 2 mmHg; 3.0 mg/kg: 30 +/- 1 mmHg) was significantly lower than in Controls (40 +/- 2 mmHg), while there were no differences in mean arterial pressure and cardiac output. We conclude that inhalation of LU-135252 at either dose improved gas exchange and hemodynamics comparably, indicating that the lower dose was already sufficient to block the majority of endothelin-A receptors in ventilated regions of the injured lung.
Deja
Maria
M
Department of Anesthesiology and Intensive Care Medicine, University Medical Center, Berlin, Germany.
Busch
Thilo
T
Wolf
Steffen
S
Donaubauer
Bernd
B
Petersen
Bodil
B
Skomrock
Joerg
J
Boemke
Willehad
W
Kaisers
Udo
U
D000280:Administration, Inhalation; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D006439:Hemodynamics / Q000187:drug effects; D009330:Nebulizers and Vaporizers; D010666:Phenylpropionates / Q000008:administration & dosage*; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D011743:Pyrimidines / Q000008:administration & dosage*; D044022:Receptor, Endothelin A / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D019141:Respiratory System Agents / Q000008:administration & dosage*; D013552:Swine; D013997:Time Factors
D065130:Endothelin A Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D019141:Respiratory System Agents; C107831:darusentan