Gujic Marko, Houssière Anne, Xhaët Olivier, Argacha Jean-François, Denewet Nathalie, Noseda André, Jespers Pascale, Melot Christian, Naeije Robert, van de Borne Philippe
Department of Cardiology, Erasme University Hospital, 808 Lennik Road, B-1070 Brussels, Belgium.
Chest. 2007 May;131(5):1467-72. doi: 10.1378/chest.06-1775.
The peripheral chemoreceptors are the dominant reflex mechanism responsible for the rise in ventilation and muscle sympathetic nerve activity (MSNA) in response to hypoxia. Animal studies have suggested that endothelin (ET) plays an important role in chemosensitivity. Moreover, several human clinical conditions in which circulating ET levels are increased are accompanied by enhanced chemoreflex sensitivity. Whether ET plays a role in normal human chemosensitivity is unknown.
We determined whether bosentan, a nonspecific ET receptor antagonist, would decrease chemoreflex sensitivity in 14 healthy subjects. We assessed the effects of bosentan on the response to isocapnic hypoxia, using a randomized, crossover, double-blinded study design.
Bosentan increased mean (+/- SEM) plasma ET levels from 1.97 +/- 0.28 to 2.53 +/- 0.23 pg/mL (p = 0.01). Hypoxia increased mean minute ventilation from 6.7 +/- 0.3 to 8+/0.4 L/min (p < 0.01), mean MSNA from 100 to 111 +/- 5% (p < 0.01), mean heart rate from 67 +/- 3 to 86 +/- 3 beats/min (p < 0.01), and mean systolic BP from 116 +/- 3 to 122 +/- 3 mm Hg (p < 0.01). However, none of these responses differed between therapy with bosentan and therapy with placebo (p = 0.26). Bosentan did not affect the mean MSNA responses to the apneas, during normoxia (change from baseline: placebo, 259 +/- 58%; bosentan, 201 +/- 28%; p = 0.17) or during hypoxia (change from baseline: placebo, 469 +/- 139%; bosentan, 329 +/- 46%; p = 0.24). The durations of the voluntary end-expiratory apneas in normoxia and hypoxia, and the subsequent reductions in oxygen saturation, were also similar with therapy using bosentan and placebo (p = 0.42).
In healthy men, ET does not play an important role in peripheral chemoreceptor activation by acute hypoxia.
外周化学感受器是对低氧作出反应时，负责通气增加和肌肉交感神经活动（MSNA）增强的主要反射机制。动物研究表明，内皮素（ET）在化学感受性中起重要作用。此外，几种循环ET水平升高的人类临床病症都伴有化学反射敏感性增强。ET在正常人类化学感受性中是否起作用尚不清楚。
我们确定非特异性ET受体拮抗剂波生坦是否会降低14名健康受试者的化学反射敏感性。我们采用随机、交叉、双盲研究设计，评估波生坦对等碳酸血症性低氧反应的影响。
波生坦使平均（±标准误）血浆ET水平从1.97±0.28 pg/mL增至2.53±0.23 pg/mL（p = 0.01）。低氧使平均分钟通气量从6.7±0.3增至8±0.4 L/分钟（p < 0.01），平均MSNA从每100增至111±5%（p < 0.01），平均心率从67±3增至86±3次/分钟（p < 0.01），平均收缩压从116±3增至122±3 mmHg（p < 0.01）。然而，波生坦治疗与安慰剂治疗之间，这些反应均无差异（p = 0.26）。波生坦不影响常氧或低氧期间对呼吸暂停的平均MSNA反应（相对于基线的变化：安慰剂，259±58%；波生坦，201±28%；p = 0.17）。常氧和低氧时，自愿呼气末呼吸暂停的持续时间以及随后的氧饱和度降低，在波生坦治疗与安慰剂治疗时也相似（p = 0.42）。
在健康男性中，ET在急性低氧激活外周化学感受器过程中不起重要作用。
