Beneficial actions of BN 50739, a new PAF receptor antagonist, in murine traumatic shock.
We studied the effects of BN 50739, a novel PAF antagonist, in a rat model of traumatic shock. Pentobarbital anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by marked hypotension, significant increases in plasma cathepsin D (4.2-fold), free amino-nitrogen (2.8-fold) and myocardial depressant factor (4.7-fold) activities and a survival time of 1.62 +/- 0.16 h. Treatment with BN 50739 (10 mg/kg, i.v.) 10 min post-trauma prolonged survival time to 3.14 +/- 0.44 h (p less than 0.01) and attenuated the accumulations of cathepsin D (5.8 vs. 12.5 U/ml, p less than 0.01), free amino-nitrogen (4.6 vs. 12.5 U/ml, p less than 0.001) and myocardial depressant factor (19.4 vs. 65.1 U/ml, p less than 0.001). Moreover, in washed rabbit platelets, BN 50739 inhibited PAF (1.85 nM)-induced aggregation (IC50: 50 nM) without affecting ADP (5 microM)-induced aggregation. In anesthetized rats, BN 50739 (10 mg/kg, i.v.) attenuated PAF (10-30 ng/kg, i.v.)-induced hypotension for longer than 5 h, without influencing acetylcholine (10 micrograms/kg, i.v.)-induced hypotension. These findings indicate that BN 50739 is a specific PAF receptor antagonist with a long duration of action in vivo. The beneficial effects of PAF antagonism on traumatic shock are significant in the present study, and are consistent with the concept that PAF is involved in the pathogenesis of traumatic shock.
Karasawa
A
A
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA.
Rochester
J A
JA
Lefer
A M
AM
D000818:Animals; D001381:Azepines / Q000097:blood / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002402:Cathepsin D / Q000097:blood; D066298:In Vitro Techniques; D008297:Male; D009201:Myocardial Depressant Factor / Q000097:blood; D009584:Nitrogen / Q000097:blood; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000627:therapeutic use*; D010980:Platelet Membrane Glycoproteins; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D012774:Shock, Traumatic / Q000188:drug therapy* / Q000503:physiopathology; D013929:Thromboxane B2 / Q000097:blood; D014230:Triazoles / Q000097:blood / Q000627:therapeutic use*
D001381:Azepines; D009201:Myocardial Depressant Factor; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; C039351:platelet activating factor receptor; C064509:BN 50739; D013929:Thromboxane B2; D002402:Cathepsin D; D009584:Nitrogen