Klemm P, Warner T D, Corder R, Vane J R
William Harvey Research Institute, Medical College, St. Bartholomew's Hospital, London, England.
J Cardiovasc Pharmacol. 1995;26 Suppl 3:S419-21.
In many pathologic conditions, elevations in the circulating level of endothelin-1 (ET-1) are linked to increased production of cytokines. Therefore, we have investigated the relationship between cytokines and ET-1. Administration of tumor necrosis factor-alpha (TNF-alpha, 4 micrograms/kg) to anesthetized rats caused, within 15 min, a marked elevation in the circulating plasma level of ET-1. This was associated with pronounced coronary vasoconstriction in hearts removed from these animals and perfused in vitro by the Langendorff technique. This coronary vasoconstriction was attenuated by in vivo pretreatment with either ETA receptor antagonists or with an antibody against ET-1 (ET-Ab). Treatment of the anesthetized rats with interleukin-2 (IL-2) to increase the endogenous release of TNF-alpha also elevated the in vitro coronary vascular resistance, an effect that was greatly reduced by administration of an antibody against TNF-alpha (hr-TNF-alpha-Ab) or FR 139317. Finally, in rats with adjuvant-induced arthritis, in which the levels of circulating cytokines are greatly elevated, we also found large increases in the ex vivo coronary perfusion pressure. Significantly, these were abolished by in vivo treatment for 2 days with the nonpeptide ET receptor antagonist SB209670. Cytokines cause marked and acute changes in the production of ET-1, leading to pronounced coronary vasoconstriction. Cytokine-driven changes in the production of ET-1 may therefore be key events in the development of vascular pathologies.
在许多病理状况下，内皮素 -1（ET-1）循环水平的升高与细胞因子产生增加相关。因此，我们研究了细胞因子与ET-1之间的关系。给麻醉大鼠注射肿瘤坏死因子-α（TNF-α，4微克/千克），15分钟内可使ET-1的循环血浆水平显著升高。这与从这些动物取出并通过Langendorff技术在体外灌注的心脏中明显的冠状动脉收缩有关。用ETA受体拮抗剂或抗ET-1抗体（ET-Ab）进行体内预处理可减轻这种冠状动脉收缩。用白细胞介素-2（IL-2）处理麻醉大鼠以增加TNF-α的内源性释放，也会提高体外冠状动脉血管阻力，而给予抗TNF-α抗体（hr-TNF-α-Ab）或FR 139317可大大降低这种作用。最后，在佐剂诱导性关节炎大鼠中，其循环细胞因子水平大幅升高，我们还发现离体冠状动脉灌注压大幅增加。值得注意的是，用非肽类ET受体拮抗剂SB209670进行2天的体内治疗可消除这些增加。细胞因子导致ET-1产生显著且急性的变化，从而导致明显的冠状动脉收缩。因此，细胞因子驱动的ET-1产生变化可能是血管病变发展中的关键事件。
