Protective effects of a combination thromboxane synthesis inhibitor-receptor antagonist, R-68070, during murine traumatic shock.
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.
Aoki
N
N
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107.
Johnson
G
G
Siegfried
M R
MR
Lefer
A M
AM
D000818:Animals; D002402:Cathepsin D / Q000097:blood; D008297:Male; D009201:Myocardial Depressant Factor / Q000097:blood; D010421:Pentanoic Acids / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D011982:Receptors, Prostaglandin / Q000187:drug effects* / Q000502:physiology; D017482:Receptors, Thromboxane; D012774:Shock, Traumatic / Q000188:drug therapy* / Q000503:physiopathology; D013928:Thromboxane A2 / Q000502:physiology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000502:physiology; D014631:Valerates / Q000627:therapeutic use*
D009201:Myocardial Depressant Factor; D010421:Pentanoic Acids; D011725:Pyridines; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D014631:Valerates; D013928:Thromboxane A2; D002402:Cathepsin D; D013930:Thromboxane-A Synthase; C060219:ridogrel