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ENVIRONMENTAL, EXERCISE AND RESPIRATORY PHYSIOLOGY

Inhalation of the ET_A receptor antagonist LU-135252 selectively attenuates hypoxic pulmonary vasoconstriction

¹Department of Anesthesiology and Intensive Care Medicine, University of Leipzig Medical Faculty, Leipzig; and ²Department of Anesthesiology and Intensive Care Medicine, Charité-University Medical Center, Berlin, Germany

Submitted 11 October 2007 ; accepted in final form 9 December 2007

Endogenous endothelin (ET)-1 modulates hypoxic pulmonary vasoconstriction (HPV). Accordingly, intravenously applied ET_A receptor antagonists reduce HPV, but this is accompanied by systemic vasodilation. We hypothesized that inhalation of an ET_A 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 (FI_O2) of 0.3. After 1 h of hypoxia at FI_O2 0.15, animals were randomly assigned either to 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, hypoxia significantly increased mean pulmonary arterial pressure (32 ± 1 vs. 23 ± 1 mmHg; P < 0.01; means ± SE) and increased arterial plasma ET-1 (0.52 ± 0.04 vs. 0.37 ± 0.05 fmol/ml; P < 0.01) compared with mild hyperoxia at FI_O2 0.3. Inhalation of LU-135252 induced a significant and sustained decrease in mean pulmonary arterial pressure compared with 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 control values. Consequently, in our experimental model of HPV, the inhaled ET_A receptor antagonist LU-135252 induced selective pulmonary vasodilation without adverse systemic hemodynamic effects.

inhalation; selective pulmonary vasodilation; pulmonary arterial hypertension