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.