Protective actions of a new potent thromboxane receptor antagonist in arachidonate induced sudden death.
Sodium arachidonate (NaAr) at a dose of 1.1 mg/kg injected i.v. is uniformly lethal in rabbits within 5 min. This sudden death is typified by a precipitous drop in mean arterial blood pressure, a dramatic decrease in the circulating platelet count, and by a marked rise in plasma thromboxane A2 (TxA2) concentration as measured by radioimmunoassay of its breakdown product, TxB2. Pretreatment with S-145, a new thromboxane receptor antagonist, at doses ranging from 50 to 500 micrograms/kg resulted in 100% survival of all the rabbits subjected to sodium arachidonate injection. However, at 20 micrograms/kg S-145 only 25% of the rabbits challenged with NaAr survived. S-145 pretreatment also inhibited the decreases in circulating platelet count and in blood pressure associated with the i.v. injection of sodium arachidonate (NaAr). S-145 blunted the rise in plasma TxB2 concentration at all doses. S-145 was also shown to be a potent and long-lasting antagonist of TxA2 receptors in isolated rabbit aortic rings. Our data show that S-145 is a very effective protective agent against NaAr-induced sudden death in rabbits.
Liao
P
P
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107.
Johnson
G
G
Siegfried
M
M
Lefer
A M
AM
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors*; D001794:Blood Pressure / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000627:therapeutic use*; D001952:Bridged-Ring Compounds / Q000627:therapeutic use*; D003645:Death, Sudden; D004195:Disease Models, Animal; D005229:Fatty Acids, Monounsaturated / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008297:Male; D010976:Platelet Count / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors; D011817:Rabbits; D011863:Radioimmunoassay; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D017482:Receptors, Thromboxane; D013929:Thromboxane B2 / Q000032:analysis
D001095:Arachidonic Acids; D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D005229:Fatty Acids, Monounsaturated; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; C056566:S 145; D016718:Arachidonic Acid; D013929:Thromboxane B2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid