Furlan L E, Johnson G, Siegfried M, Lefer A M
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
J Pharmacol Exp Ther. 1990 May;253(2):525-9.
We studied the effects of a new potent thromboxane A2 receptor antagonist as a protective measure in circulatory shock induced by splanchnic artery occlusion and reperfusion. The celiac and superior mesenteric arteries of anesthetized rats were occluded for 40 min followed by reperfusion, resulting in a large decrease in mean arterial blood pressure usually leading to a fatal outcome within 60 to 90 min. Rats were treated with the specific thromboxane A2 receptor antagonist, (+)-S145Na, at one of three doses (50, 200 or 500 micrograms/kg) or with its vehicle (0.9% NaCl). In isolated rat aortic rings, (+)-S145Na was found to be a highly specific and potent thromboxane receptor antagonist having an IC50 of 1 ng/ml. The highest dose of the drug exhibited protection characterized by an attenuation in the increases in hematocrit (P less than .05), plasma cathepsin D activity (P less than .05), plasma aminonitrogen concentration (P less than .05), and plasma myocardial depressant factor activity (P less than .01) as well as increased survival rate and time (P less than .01), compared to the splanchnic artery occlusion shock group given the vehicle. The lowest dose of (+)-S145Na failed to provide protection, whereas the intermediate dose (i.e., 200 micrograms/kg) exerted less dramatic protective effects than the 500 micrograms/kg dose. These findings suggest an important role of thromboxane A2 in the pathogenesis of splanchnic artery occlusion shock, and that (+)-S145Na may be a useful agent in the treatment of bowel ischemia and its complications.
我们研究了一种新型强效血栓素A2受体拮抗剂作为一种保护措施，用于内脏动脉闭塞和再灌注诱导的循环性休克。将麻醉大鼠的腹腔干动脉和肠系膜上动脉闭塞40分钟，然后再灌注，导致平均动脉血压大幅下降，通常在60至90分钟内导致致命后果。大鼠分别接受三种剂量（50、200或500微克/千克）之一的特异性血栓素A2受体拮抗剂（+）-S145Na或其赋形剂（0.9%氯化钠）治疗。在离体大鼠主动脉环中，发现（+）-S145Na是一种高度特异性和强效的血栓素受体拮抗剂，IC50为1纳克/毫升。与给予赋形剂的内脏动脉闭塞休克组相比，该药物的最高剂量表现出保护作用，其特征为血细胞比容升高（P<0.05）、血浆组织蛋白酶D活性升高（P<0.05）、血浆氨基氮浓度升高（P<0.05）和血浆心肌抑制因子活性升高（P<0.01）得到缓解，以及生存率和存活时间增加（P<0.01）。（+）-S145Na的最低剂量未能提供保护作用，而中间剂量（即200微克/千克）的保护作用不如500微克/千克剂量显著。这些发现表明血栓素A2在内脏动脉闭塞性休克的发病机制中起重要作用，并且（+）-S145Na可能是治疗肠道缺血及其并发症的有用药物。
