Protective effects of KW-3635, a novel thromboxane A2 antagonist, in murine traumatic shock

Pentobarbital anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by marked hypotension, increases in plasma cathepsin D (9.6-fold), free amino-nitrogen (4.0-fold), and myocardial depressant factor (5.2-fold) activities, and a survival time of 1.90 +/- 0.23 h. Following the induction of traumatic shock, plasma thromboxane B2 (TxB2) concentrations significantly increased from 3.12 +/- 0.68 to 6.78 +/- 0.27 pmol/ml. Treatment with the thromboxane receptor antagonist KW-3635 10 min post-trauma (2 mg/kg + 2 mg/kg per h, i.v.) prolonged survival time to 3.30 +/- 0.39 h (P less than 0.01) and attenuated the accumulation of cathepsin D compared to untreated trauma rats (6.6 +/- 1.1 and 13.6 +/- 1.3 U/ml, P less than 0.01), free amino-nitrogen (6.4 +/- 1.1 and 14.3 +/- 1.2 U/ml, P less than 0.01), and myocardial depressant factor (45 +/- 5 and 94 +/- 13 U/ml, P less than 0.02). However, KW-3635 did not prevent the increase in plasma TxB2 concentration, suggesting a lack of thromboxane synthetase inhibitory activity of this drug. The beneficial effects of thromboxane A2 (TxA2) antagonism in the present study are highly significant, and consistent with the concept that TxA2 is involved in the pathogenesis of traumatic shock.