Beneficial actions of thromboxane receptor antagonism in hemorrhagic shock.
The new specific thromboxane receptor antagonist, BM-13505, was infused intravenously (1 mg/kg bolus and 1 mg/kg hr continuous infusion) to determine its effect in a feline model of hemorrhagic shock. Hemorrhaged cats treated with BM-13505 maintained post-reinfusion mean arterial blood pressure and superior mesenteric artery flow at significantly higher values compared to cats receiving only the vehicle. BM-13505 was also found to attenuate the increase in plasma cathepsin D activity in hemorrhaged cats as well as to curtail plasma proteolysis to values not significantly different from sham shock animals at the end of the post-reinfusion period. Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in BM-13505-treated shocked cats than in the vehicle group (37 +/- 4 vs 71 +/- 7 U/ml, P less than .01). Additionally, BM-13505 was shown to antagonize thromboxane-induced vasoconstriction in isolated perfused cat coronary arteries and to exert an anti-aggregatory effect in platelet-rich cat plasma induced by the endoperoxide analog, U-46619. However, BM-13505 failed to show a direct antiproteolytic effect in cat pancreatic homogenates. Thus, the beneficial effects of BM-13505 in hemorrhagic shock are likely due to both its prevention of thromboxane-induced vasoconstriction and its ability to attenuate thromboxane-induced platelet aggregation. Our results further substantiate the role of thromboxane A2 as a mediator of hemorrhagic shock and suggest that antagonism of thromboxane receptors may be useful in the treatment of hemorrhagic shock.
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002402:Cathepsin D / Q000097:blood; D002415:Cats; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000502:physiology; D009201:Myocardial Depressant Factor / Q000097:blood; D009584:Nitrogen / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D017482:Receptors, Thromboxane; D012039:Regional Blood Flow / Q000187:drug effects; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000503:physiopathology; D013449:Sulfonamides / Q000627:therapeutic use*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D014661:Vasoconstriction / Q000187:drug effects
D009201:Myocardial Depressant Factor; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013449:Sulfonamides; C024587:thromboxane A2, carbocyclic; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D002402:Cathepsin D; D009584:Nitrogen