Protective effects of the specific thromboxane receptor antagonist (+)-S145Na in splanchnic artery occlusion shock in rats.
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.
Furlan
L E
LE
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
Johnson
G
G
Siegfried
M
M
Lefer
A M
AM
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000627:therapeutic use*; D001952:Bridged-Ring Compounds / Q000627:therapeutic use*; D005229:Fatty Acids, Monounsaturated / Q000627:therapeutic use*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D008641:Mesenteric Vascular Occlusion / Q000188:drug therapy*; D009201:Myocardial Depressant Factor / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D012769:Shock / Q000188:drug therapy*
D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D005229:Fatty Acids, Monounsaturated; D009201:Myocardial Depressant Factor; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; C056566:S 145