Holm P, Liska J, Franco-Cereceda A
Department of Thoracic Surgery, Karolinska Hospital, Stockholm, Sweden.
Cardiovasc Res. 1998 Mar;37(3):765-71. doi: 10.1016/s0008-6363(97)00291-5.
Elevated levels of the potent vasoactive peptide endothelin (ET), have been found in pathophysiological conditions associated with pulmonary hypertension. In this study, we have investigated the effects of the ETA receptor antagonist, BMS-182874, on hypoxic pulmonary hypertension in pigs.
Pigs were subjected to acute, intermittent 15-min periods of hypoxia (FiO2 0.1). Following a first hypoxia establishing hypoxic baseline values, vehicle or BMS-182874 (10 or 30 mg/kg) was administered i.v. before a second hypoxic period. In separate groups of animals, the effects of the nitric oxide synthase inhibitor N omega-nitro-L-arginine (L-NNA) in combination with BMS-182874 (10 mg) during repeated hypoxia were investigated. The ET-1-blocking properties of BMS-182874 were studied in vivo by infusion of ET-1 during normoxia and in vitro using isolated porcine pulmonary arteries.
The hypoxia-evoked increase in mean pulmonary artery pressure was reduced by administration of BMS-182874 (10 mg/kg i.v.; from 42 +/- 8 to 34 +/- 4 mmHg, P < 0.05 and 30 mg/kg i.v.; from 38 +/- 4 to 30 +/- 5 mmHg, P < 0.05). In addition, BMS-182874 at 30 mg/kg reduced the pulmonary vascular resistance during hypoxia (from 7.4 +/- 1.5 to 5.3 +/- 1.1 mmHg.min.l-1 P < 0.05). The hemodynamic response to repeated hypoxia was reproducible in control animals and unaffected by the cyclo-oxygenase inhibitor diclophenac (3 mg/kg). Infusion of L-NNA alone resulted in an augmented pulmonary vasoconstriction during hypoxia; pulmonary arterial pressure from 35 +/- 6 to 43 +/- 9 mmHg; P < 0.05 and vascular resistance from 7.2 +/- 1.1 to 9.9 +/- 1.8 mmHg.min.l-1; P < 0.05. L-NNA in combination with BMS-182874 (10 mg/kg) resulted in a hypoxic pulmonary vasoconstriction of similar magnitude as hypoxic baseline. In addition, BMS-182874 reduced the hemodynamic response to ET-1 in normoxic pigs and competitively antagonized the vasoconstrictor effect of ET-1 in isolated porcine pulmonary arteries.
The non-peptide, selective ETA receptor antagonist, BMS-182874, reduces hypoxic pulmonary vasoconstriction in pigs. The reduction in pulmonary vascular response to hypoxia following BMS-182874 is at least partly independent of nitric oxide.
在与肺动脉高压相关的病理生理状况中发现了强效血管活性肽内皮素（ET）水平升高。在本研究中，我们研究了ETA受体拮抗剂BMS-182874对猪低氧性肺动脉高压的影响。
猪接受急性、间歇性15分钟的低氧（吸入氧分数0.1）。在首次低氧建立低氧基线值后，在第二次低氧期前静脉注射溶剂或BMS-182874（10或30mg/kg）。在单独的动物组中，研究了一氧化氮合酶抑制剂Nω-硝基-L-精氨酸（L-NNA）与BMS-182874（10mg）联合在重复低氧期间的作用。通过在常氧期间输注ET-1在体内研究BMS-182874的ET-1阻断特性，并使用离体猪肺动脉在体外进行研究。
静脉注射BMS-182874（10mg/kg；从42±8降至34±4mmHg，P<0.05；30mg/kg；从38±4降至30±5mmHg，P<0.05）可降低低氧引起的平均肺动脉压升高。此外，30mg/kg的BMS-182874可降低低氧期间的肺血管阻力（从7.4±1.5降至5.3±1.1mmHg·min·l-1，P<0.05）。对照动物对重复低氧的血流动力学反应可重现，且不受环氧化酶抑制剂双氯芬酸（3mg/kg）影响。单独输注L-NNA导致低氧期间肺血管收缩增强；肺动脉压从35±6升至43±9mmHg；P<0.05，血管阻力从7.2±1.1升至9.9±1.8mmHg·min·l-1；P<0.05。L-NNA与BMS-182874（10mg/kg）联合导致的低氧性肺血管收缩幅度与低氧基线相似。此外，BMS-182874降低了常氧猪对ET-1的血流动力学反应，并在离体猪肺动脉中竞争性拮抗ET-1的血管收缩作用。
非肽类选择性ETA受体拮抗剂BMS-182874可降低猪的低氧性肺血管收缩。BMS-182874后肺血管对低氧的反应降低至少部分独立于一氧化氮。
