Petersen Bodil, Deja Maria, Bartholdy Roland, Donaubauer Bernd, Laudi Sven, Francis Roland C E, Boemke Willehad, Kaisers Udo, Busch Thilo
Klinik und Poliklinik fuer Anaesthesiologie und Intensivtherapie, Universitaetsklinikum Leipzig, Liebigstrasse 20, Leipzig, Germany.
Am J Physiol Regul Integr Comp Physiol. 2008 Feb;294(2):R601-5. doi: 10.1152/ajpregu.00739.2007. Epub 2007 Dec 12.
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.
内源性内皮素（ET）-1可调节低氧性肺血管收缩（HPV）。因此，静脉应用ET(A)受体拮抗剂可降低HPV，但同时会伴有全身血管舒张。我们推测吸入ET(A)受体拮抗剂可能会选择性作用于肺血管系统，并在HPV实验模型中研究了雾化吸入LU-135252的效果。16只仔猪（体重：25±1kg）麻醉后在吸入氧分数（Fi(O(2))）为0.3的条件下进行机械通气。在Fi(O(2))为0.15的低氧环境中持续1小时后，将动物随机分为两组，一组接受雾化的LU-135252推注（0.3mg/kg，持续20分钟；n = 8，LU组），另一组接受雾化生理盐水（n = 8，对照组）。与Fi(O(2))为0.3的轻度高氧环境相比，所有动物在低氧状态下平均肺动脉压均显著升高（32±1 mmHg对23±1 mmHg；P < 0.01；均值±标准误），动脉血浆ET-1水平也升高（0.52±0.04 fmol/ml对0.37±0.05 fmol/ml；P < 0.01）。与对照组相比，吸入LU-135252可使平均肺动脉压显著且持续降低（LU组：低氧4小时时为27±1 mmHg；对照组：32±1 mmHg；P < 0.01）。与此同时，平均体动脉压和心输出量保持稳定，与对照值无显著差异。因此，在我们的HPV实验模型中，吸入的ET(A)受体拮抗剂LU-135252可诱导选择性肺血管舒张，且无不良的全身血流动力学效应。
