thromboxane-a2 and Shock--Traumatic

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.

Topics: Amines; Animals; Benzimidazoles; Benzoxepins; Biomarkers; Blood Pressure; Cathepsin D; Lysosomes; Male; Membranes; Myocardial Depressant Factor; Rats; Rats, Inbred Strains; Shock, Traumatic; Thromboxane A2

The effects of R-68070 were studied in a well-characterized model of drum-induced traumatic shock in rats. R-68070 is a combination thromboxane A2 (TxA2) synthetase inhibitor-TxA2 receptor antagonist. Pentobarbital-anesthetized (50 mg/kg) rats subjected to Noble-Collip drum trauma developed a lethal circulatory shock state characterized by a marked decrease in mean arterial blood pressure (MABP) to about 75 mmHg, resulting in a survival time of 1.58 +/- 0.18 h. This compares with MABP of 120 +/- 4 mmHg 5 h after anesthetization in rats subjected to a sham traumatic shock protocol. Administration of R-68070 (1.5 mg/kg) significantly attenuated the plasma accumulation of the lysosomal protease, cathepsin D (p less than 0.05), as well as free amino-nitrogen concentration (p less than 0.05) and myocardial depressant factor activity (p less than 0.02). Additionally, R-68070 significantly prolonged survival time to 2.85 +/- 0.48 h (p less than 0.015) compared with traumatized rats given only the vehicle. These results suggest that TxA2 may be an important mediator in traumatic shock, and that R-68070 may prove to be a useful therapeutic agent in this situation if given early in the course of the shock state.

Topics: Animals; Cathepsin D; Male; Myocardial Depressant Factor; Pentanoic Acids; Pyridines; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Shock, Traumatic; Thromboxane A2; Thromboxane-A Synthase; Valerates

Pinane thromboxane A2 (PTA2) an analog of thromboxane A2 that inhibits the formation of thromboxanes as well as antagonizes their biological actions, at an infusion rate of 1.0 mumole . kg-1 . h-1, prolonged survival in traumatic shock in rats. PTA2 also prevented the accumulation of thromboxane B2, the lysosomal protease, cathepsin D, and the cardiotoxic peptide MDF in the circulating blood.

Topics: Animals; Bicyclic Monoterpenes; Cathepsins; Myocardial Depressant Factor; Rats; Shock, Traumatic; Thromboxane A2; Thromboxane B2; Thromboxanes