Submitted on October 11, 2007
Accepted on December 9, 2007
Inhalation of the ETA receptor antagonist LU-135252 selectively attenuates hypoxic pulmonary vasoconstriction
Bodil Petersen1, Maria Deja2, Roland Bartholdy1, Bernd Donaubauer1, Sven Laudi1, Roland C.E. Francis2, Willehad Boemke2, Udo Kaisers1*, and Thilo Busch1
1 Anesthesiology and Intensive Care Medicine, University of Leipzig Medical Faculty, Leipzig, Germany
2 Anesthesiology and Intensive Care Medicine, Charite-University Medical Center, Campus Virchow-Klinikum and Campus Mitte, Berlin, Germany
* To whom correspondence should be addressed. E-mail: udo.kaisers{at}uniklinik-leipzig.de.
Endogenous endothelin-1 (ET-1) modulates hypoxic pulmonary vasoconstriction (HPV). Accordingly, intravenously applied ETA receptor antagonists reduce HPV, but this is accompanied by systemic vasodilation. We hypothesized that inhalation of an ETA receptor antagonist might act selectively on the pulmonary vasculature and investigated the effects of aerosolized LU-135252 in an experimental model of HPV. Sixteen piglets (weight: 25±1 kg) were anesthetized and mechanically ventilated at an inspiratory oxygen fraction (FiO2) of 0.3. After 1 h of hypoxia at FiO2 0.15, animals were randomly assigned to either receive aerosolized LU-135252 as bolus (0.3 mg/kg for 20 min) (n=8, LU group), or to receive aerosolized saline (n=8, Controls). In all animals, 1 h of hypoxia significantly increased mean pulmonary artery pressure (MPAP: 32±1 vs. 23±1 mmHg; p<0.01; mean±SE) and increased arterial plasma ET-1 (0.52±0.04 vs. 0.37±0.05 fmol/ml; p<0.01) when compared to mild hyperoxia at FiO2 0.3. Inhalation of LU-135252 induced a significant and sustained decrease in MPAP compared to Controls (LU group: 27±1 mmHg; Controls: 32±1 mmHg; values at 4 h of hypoxia; p<0.01). In parallel, mean systemic arterial pressure and cardiac output remained stable and were not significantly different from Controls. Consequently, in our experimental model of HPV the inhaled ETA receptor antagonist LU-135252 induced selective pulmonary vasodilation without adverse systemic hemodynamic effects.
