Role of endothelin in endotoxin-induced sustained pulmonary hypertension in sheep
Role of endothelin in endotoxin-induced sustained pulmonary hypertension in sheep
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DOI：
10.1164/ajrccm.157.1.95-05117
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发表时间：
1998-01-01
影响因子：
24.7
通讯作者：
Lu, WX
中科院分区：
文献类型：
--
作者：
Snapper, JR;Thabes, JS;Lu, WX
BMS182874是一种内皮素受体拮抗剂，它阻断了外源性给药对清醒绵羊内皮素的影响。通过研究静脉注射BMS182874和不给予BMS182874的静脉注射内毒素的动物，研究了内毒素在绵羊内毒素诱导的肺动脉高压中的可能作用。单用BMS182874可降低肺动脉压(P-PA)和体动脉压(P-SA)。内毒素单独引起P-PA急剧升高近3倍，随后在内毒素后2-5小时，P-PA持续升高，但不是很严重。伴随这些变化的是肺淋巴流量的三倍增加以及血浆和肺淋巴血栓素B-2浓度的急剧增加。BMS182874可显著减轻内毒素诱导的早期P-PA的急性升高，并完全阻断晚期持续性肺动脉高压(p<；0.05)，而对血栓素水平的升高无明显影响。BMS182874将前列腺素H-2类似物U46619的剂量反应曲线右移。BMS182874除了作为一种内皮受体拮抗剂外，似乎还在受体水平上对抗血栓素的作用。我们推测BMS182874通过对抗血栓素的作用来减轻早期内毒素诱导的肺动脉高压，因为先前的研究表明P-PA的早期急性升高是由血栓素引起的。另一方面，内毒素血症的晚期持续性肺动脉高压似乎是由内毒素介导的。
BMS182874, an endothelin receptor antagonist, blocks the effects of exogenously administered endothelins in chronically instrumented awake sheep. A possible role for endothelin in endotoxin-induced pulmonary hypertension in sheep was investigated by studying animals given intravenous endotoxin with and without pretreatment with BMS182874. BMS182874 administration alone caused a reduction in pulmonary artery pressure (P-PA) and systemic arterial pressure (P-SA). Endotoxin alone caused an acute, nearly threefold increase in P-PA which was followed, from 2-5 h after endotoxin, by a sustained but less severe increase in P-PA. These changes were accompanied by a threefold increase in lung lymph flow and dramatic increases in plasma and lung lymph thromboxane B-2 concentrations. Pretreatment with BMS182874 significantly attenuated the early endotoxin-induced acute increase in P-PA and completely blocked the late sustained pulmonary hypertension (p < 0.05), while having no affect on the increases in thromboxane levels. BMS182874 shifts the dose response curve for U46619, a prostaglandin H-2 analogue, to the right. BMS182874, in addition to functioning as an endothelium receptor antagonist, appears to counteract the action of thromboxane at the receptor level. We theorize that BMS182874 attenuates the early endotoxin-induced pulmonary hypertension by counteracting the effects of thromboxane, since previous studies demonstrated that the early acute rise in P-PA is caused by thromboxane. The late sustained pulmonary hypertension of endotoxemia, on the other hand, appears to be mediated by endothelin.