Kengatharan M, Battistini B, Warner T D, Thiemermann C, Vane J R
William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London, England.
J Cardiovasc Pharmacol. 1995;26 Suppl 3:S422-4.
Cytokines such as tumor necrosis factor-alpha (TNF-alpha), given exogenously or liberated endogenously, cause the release of endothelin (ET) into the circulation. In the rat, increase in ET causes marked ex vivo coronary vasoconstriction. Hemorrhage also increases the circulating levels of cytokines such as TNF-alpha. Here we show that in rats subjected to hemorrhagic shock there is a marked increase in ex vivo coronary vascular resistance, which is mediated by ET. Hemorrhagic shock was induced in anesthetized rats by withdrawing sufficient blood to reduce mean arterial blood pressure to 40 mm Hg for a period of 30 min, after which all the withdrawn blood was retransfused over a period of 15 min. Hearts were perfused ex vivo at a constant flow of 10 ml/min according to the Langendorff technique. After 90 min in vitro, the coronary perfusion pressure in hearts removed from control rats was 76 +/- 1 mm Hg (n = 5), whereas in hearts taken from rats after hemorrhage it was 114 +/- 6 mm Hg (n = 5; p < 0.05 from control). After the same time in vitro, the coronary perfusion pressure of hearts from rats treated with TNF-alpha (4 micrograms/kg, i.v.) was 122 +/- 4 mm Hg (n = 4; p < 0.05 from control). The increases in coronary perfusion pressure caused by hemorrhagic shock or TNF-alpha were abolished by pretreating rats with the nonselective ET receptor (ETA/ETB) antagonist SB209670 (3 mg/kg, i.v.) (coronary perfusion pressure at 90 min 80 +/- 1 mm Hg after hemorrhage; 73 +/- 4 mm Hg after TNF-alpha, p < 0.05 compared to hemorrhage or TNF-alpha controls, respectively; n = 3-5). Interestingly, pretreatment with polyclonal antibodies to TNF-alpha (3 mg/kg, i.v.) did not significantly attenuate the rise in coronary perfusion pressure caused by hemorrhage. Therefore, hemorrhage followed by retransfusion causes marked coronary vasoconstriction assessed ex vivo owing to the release of ET by factors including TNF-alpha.
诸如肿瘤坏死因子-α（TNF-α）等细胞因子，无论是外源性给予还是内源性释放，都会导致内皮素（ET）释放进入循环系统。在大鼠中，ET水平升高会导致明显的离体冠状动脉血管收缩。出血也会增加诸如TNF-α等细胞因子的循环水平。在此我们表明，在遭受失血性休克的大鼠中，离体冠状动脉血管阻力显著增加，这是由ET介导的。通过抽取足够的血液使麻醉大鼠的平均动脉血压降至40 mmHg并持续30分钟来诱导失血性休克，之后在15分钟内将所有抽出的血液重新输注。根据Langendorff技术，以10 ml/min的恒定流量对离体心脏进行灌注。体外90分钟后，取自对照大鼠的心脏的冠状动脉灌注压为76±1 mmHg（n = 5），而取自出血后大鼠的心脏的冠状动脉灌注压为114±6 mmHg（n = 5；与对照相比，p < 0.05）。在体外相同时间后，用TNF-α（4微克/千克，静脉注射）处理的大鼠的心脏的冠状动脉灌注压为122±4 mmHg（n = 4；与对照相比，p < 0.05）。用非选择性ET受体（ETA/ETB）拮抗剂SB209670（3毫克/千克，静脉注射）预处理大鼠可消除失血性休克或TNF-α引起的冠状动脉灌注压升高（出血后90分钟时冠状动脉灌注压为80±1 mmHg；TNF-α处理后为73±4 mmHg，分别与出血或TNF-α对照相比，p < 0.05；n = 3 - 5）。有趣的是，用抗TNF-α多克隆抗体（3毫克/千克，静脉注射）预处理并没有显著减弱出血引起的冠状动脉灌注压升高。因此，出血后再输血会导致离体状态下明显的冠状动脉血管收缩，这是由于包括TNF-α在内的多种因素释放ET所致。
