Beneficial effect of a thromboxane synthetase inhibitor in traumatic shock.
Traumatic shock was induced in anesthetized rats using the Noble-Collip method. This resulted in an abrupt decline in mean arterial blood pressure (MABP) and heart rate. Plasma cathepsin D activity increased sixfold, plasma thromboxane B2 (TxB2) concentration increased 2.5-fold, plasma myocardial depressant factor (MDF) activity increased 3.5 fold, and the mean survival time was 1.4 +/- 0.2 hours. Administration of the selective thromboxane synthetase inhibitor 5-(3-pyridinylmethyl) benzofuran-2-carboxylate (U-63,557A) (4 mg/kg) resulted in a significant improvement in survival time, 3.3 +/- 0.5, p less than 0.01. Plasma cathepsin D activity was not affected by U-63,557A (7.4 +/- 0.8 vs. 8.5 +/- 1.1 U/ml). However, both plasma and peritoneal fluid TxB2 concentration were significantly reduced and accumulation of the toxic peptide, MDF, was significantly blunted (69 +/- 6 vs. 40 +/- 5 U/ml, p less than 0.01). Our data indicate that blockade of thromboxane A2 (TxA2) production by selective synthetase inhibition is beneficial in trauma and support a role for TxA2 in the pathogenesis of circulatory shock.
D000818:Animals; D001572:Benzofurans / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002402:Cathepsin D / Q000097:blood; D004305:Dose-Response Relationship, Drug; D008247:Lysosomes / Q000187:drug effects; D008297:Male; D009201:Myocardial Depressant Factor / Q000097:blood; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011379:Prognosis; D051381:Rats; D011919:Rats, Inbred Strains; D012774:Shock, Traumatic / Q000188:drug therapy*; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D001572:Benzofurans; D009201:Myocardial Depressant Factor; D013929:Thromboxane B2; D010088:Oxidoreductases; D002402:Cathepsin D; D013930:Thromboxane-A Synthase; C039936:furegrelate