Inhalation of the ETA receptor antagonist LU-135252 selectively attenuates hypoxic pulmonary vasoconstriction.
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(O(2))) of 0.3. After 1 h of hypoxia at Fi(O(2)) 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(O(2)) 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.
Petersen
Bodil
B
Klinik und Poliklinik fuer Anaesthesiologie und Intensivtherapie, Universitaetsklinikum Leipzig, Liebigstrasse 20, Leipzig, Germany.
Deja
Maria
M
Bartholdy
Roland
R
Donaubauer
Bernd
B
Laudi
Sven
S
Francis
Roland C E
RC
Boemke
Willehad
W
Kaisers
Udo
U
Busch
Thilo
T
D000280:Administration, Inhalation; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D000860:Hypoxia / Q000188:drug therapy*; D010666:Phenylpropionates / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D011652:Pulmonary Circulation / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D044022:Receptor, Endothelin A / Q000378:metabolism; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects*
D065130:Endothelin A Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; C107831:darusentan