sq-29548 and Death--Sudden

Although (-)-(S)-trimetoquinol [1-(3,4,5-trimethoxy-benzyl)- 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline; TMQ] is recognized as a potent bronchodilator, (+)-(R)-TMQ is a selective antagonist of human platelet aggregation and serotonin secretion induced by thromboxane A2 (TXA2) agonists. To confirm the pharmacological actions of TMQ analogs, the interaction of the drugs with TXA2 receptors was examined in human platelets and in a mouse sudden death model. The inhibitory potencies of TMQ analogs (pIC50 values) for displacement of [3H]SQ 29,548 binding to platelets showed excellent correlation with the respective pIC50 (-log IC50) values for U46619-induced aggregation (r = 0.99, P less than 0.01) and serotonin secretion (r = 0.99, P less than 0.01) in human platelet-rich plasma and for whole blood aggregation (r = 0.99, P less than 0.01). In each system, the rank order of inhibitory potencies was rac-iodoTMQ greater than or equal to (+)-(R)-TMQ greater than rac-TMQ much greater than (-)-(S)-TMQ. Antithrombotic effects of TMQ analogs were evaluated in a mouse sudden death model. In vivo antithrombotic potencies of these compounds were consistent with the in vitro potencies as TXA2 receptor antagonists in platelet systems. Administration of rac-iodoTMQ, (+)-(R)-TMQ and rac-TMQ 15 min before the injection of U46619 (800 micrograms/kg, iv) protected mice against U46619-induced sudden death. On the other hand, (-)-(S)-TMQ did not protect animals against death. Protection of U46619-induced cardiopulmonary thrombosis by TMQ analogs was seen at doses of 3-100 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Platelets; Bridged Bicyclo Compounds, Heterocyclic; Death, Sudden; Disease Models, Animal; Fatty Acids, Unsaturated; Humans; Hydrazines; Male; Mice; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Receptors, Prostaglandin; Receptors, Thromboxane; Stereoisomerism; Thromboxane A2; Tretoquinol; Tritium

Topics: Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Death, Sudden; Drug Synergism; Fatty Acids, Unsaturated; Hydrazines; Imidazoles; Indomethacin; Isoquinolines; Male; Pyridines; Rabbits; Tetrahydroisoquinolines; Thrombin; Thrombosis; Thromboxane A2; Thromboxane-A Synthase

We studied the effects of thromboxane-receptor antagonism and thromboxane synthetase inhibition in a thrombotic model of sudden death in mice. Intravenous injection of arachidonic acid (AA; 80 mg/kg) or the prostaglandin-endoperoxide analog U-46,619 (2.3 mg/kg) results in sudden death in approximately 90% of the animals. Pretreatment with the thromboxane receptor antagonist SQ-29,548 (0.3-10 mg/kg) protects dose-dependently against AA and U-46,619-induced sudden death. In contrast, CGS-13,080, a thromboxane synthetase inhibitor, shows a dose-dependent beneficial effect in AA-induced sudden death only. Although PTA2 has partial thromboxane agonistic properties in the rabbit, it protected the mice against AA-induced sudden death, thus demonstrating TxA2 antagonistic properties in this species. These data emphasize the importance of thromboxane A2 as a major mediator of arachidonic acid-induced sudden death and the effectiveness of thromboxane-receptor antagonists in endoperoxide-induced sudden death.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arachidonic Acid; Arachidonic Acids; Bicyclic Monoterpenes; Bridged Bicyclo Compounds, Heterocyclic; Death, Sudden; Fatty Acids, Unsaturated; Fibrinolytic Agents; Hydrazines; Imidazoles; Injections, Intravenous; Male; Mice; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Pyridines; Receptors, Cell Surface; Receptors, Prostaglandin; Receptors, Thromboxane; Thrombosis; Thromboxane A2; Thromboxane-A Synthase