Thomas H M, Sourour M S, Lopez D, Foster S H
Will Rogers Pulmonary Research Laboratory, Cornell University Medical College, White Plains, New York 10605.
Lung. 1989;167(3):187-98. doi: 10.1007/BF02714947.
The role of leukotrienes in hypoxic vasoconstriction remains controversial. Our previous study using the lipoxygenase inhibitor BW 755C in dogs failed to show a substantive role for leukotrienes in hypoxic vasoconstriction. To clarify further the role of leukotrienes, we designed 3 protocols. In the first protocol, we examined the effects of LTD4 boluses on the pulmonary circulation in 6 anesthetized dogs. LTD4, 1 microgram/kg, (a large dose relative to other species) produced no detectable constriction of the pulmonary artery, while systemic vascular resistance increased 41 +/- 17% (SD), left atrial pressure rose 3.5 +/- 1.5 mmHg, and cardiac output fell 18 +/- 8%. Two leukotriene receptor antagonists, LY171883 and L-648051, decreased these effects by more than 50%. In the second protocol, we tested these antagonists in 7 anesthetized, paralyzed, closed-chest dogs with acute left lower lobe atelectasis. Two manifestations of hypoxic vasoconstriction were examined: shunt fraction (as an inverse indicator of regional constriction in response to local hypoxia) and the pulmonary pressor response to global alveolar hypoxia (as an index of general hypoxic vasoconstriction). During normoxia before administration of the inhibitor, shunt fraction, measured using an SF6 infusion, was 25 +/- 7%. The pulmonary pressor response to hypoxia, defined as the increase in pulmonary end-diastolic gradient (PDG) produced by 10% O2 inhalation, averaged +10.5 +/- 3.6 mmHg. The increase in pulmonary vascular resistance (PVR) with hypoxia was +2.4 +/- 1.7 mmHg/L/min. Then, during normoxia, 1 of the 2 antagonists was administered. Shunt fraction was unchanged (26 +/- 4%; p = 0.5). The pressor response to hypoxia was slightly less but remained substantial (the increase in PDG with hypoxia was +7.9 +/- 2.8 mmHg; p less than 0.05; the increase in PVR was +1.8 +/- 1.2 mmHg/L/min, p less than 0.10). In the third protocol we gave RG 5901, a relatively specific 5-lipoxygenase inhibitor, to 5 dogs with lobar atelectasis. The indices of hypoxic vasoconstriction were not affected by RG 5901. Shunt fraction was 29.5 +/- 8.1% before and 27.0 +/- 7.4% after RG 5901 (p greater than 0.05). The pressor response to hypoxia was +8.9 +/- 2.1 mmHg before and +8.7 +/- 3.7 mmHg after RG 5901 (p greater than 0.05). We conclude that in dogs, hypoxic vasoconstriction does not appear to be mediated by leukotrienes.
白三烯在低氧性血管收缩中的作用仍存在争议。我们之前在犬类中使用脂氧合酶抑制剂BW 755C的研究未能表明白三烯在低氧性血管收缩中起实质性作用。为了进一步阐明白三烯的作用，我们设计了3个方案。在第一个方案中，我们研究了大剂量 LTD4（1微克/千克，相对于其他物种而言）推注对6只麻醉犬肺循环的影响。LTD4未引起肺动脉可检测到的收缩，而全身血管阻力增加了41±17%（标准差），左心房压力升高了3.5±1.5毫米汞柱，心输出量下降了18±8%。两种白三烯受体拮抗剂LY171883和L - 648051使这些作用降低了50%以上。在第二个方案中，我们在7只麻醉、麻痹、开胸的急性左下叶肺不张犬中测试了这些拮抗剂。研究了低氧性血管收缩的两种表现：分流分数（作为对局部低氧反应的区域收缩的反向指标）和对整体肺泡低氧的肺升压反应（作为一般低氧性血管收缩的指标）。在给予抑制剂前的常氧期间，使用六氟化硫注入法测得的分流分数为25±7%。对低氧的肺升压反应定义为吸入10%氧气引起的肺舒张末期梯度（PDG）增加，平均为+10.5±3.6毫米汞柱。低氧时肺血管阻力（PVR）增加为+2.4±1.7毫米汞柱/升/分钟。然后，在常氧期间，给予两种拮抗剂中的一种。分流分数未改变（26±4%；p = 0.5）。对低氧的升压反应略有降低但仍很显著（低氧时PDG增加为+7.9±2.8毫米汞柱；p < 0.05；PVR增加为+1.8±1.2毫米汞柱/升/分钟，p < 0.10）。在第三个方案中，我们给5只患有肺叶肺不张的犬给予相对特异性的5 - 脂氧合酶抑制剂RG 5901。低氧性血管收缩指标未受RG 5901影响。给予RG 5901前分流分数为29.5±8.1%，之后为27.0±7.4%（p > 0.05）。对低氧的升压反应在给予RG 5901前为+8.9±2.1毫米汞柱，之后为+8.7±3.7毫米汞柱（p > 0.05）。我们得出结论，在犬类中，低氧性血管收缩似乎不是由白三烯介导的。
