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.