ono-3708 and dazoxiben

Topics: Chromones; Clinical Trials as Topic; Drug Design; Humans; Imidazoles; Leukotriene Antagonists; Prostaglandins; Thromboxane A2; Thromboxane-A Synthase

The effects of S-145, a newly synthesized thromboxane, A2 (TXA2) receptor antagonist, were studied on collagen-induced changes of electrocardiograms (ECG) in rats and thrombocytopenia in rats and mice. Intravenous injection of collagen induced abnormal ECG changes such as elevation or depression of the ST segment, arrhythmia and in severe cases, cardiac arrest. These changes peaked at 3-5 min and lasted for 10 min. S-145 showed remarkable improvement of the ECG changes by both intravenous and oral administration, and the action lasted over 4 hr with 10 mg/kg, p.o. Reference compounds ONO-3708, dazoxiben and aspirin also improved the ECG changes significantly, but ticlopidine was ineffective. S-145 prevented the collagen-induced thrombocytopenia in rats but did not affect the increase in plasma TXB2 levels. S-145 also prevented collagen-induced thrombocytopenia in mice after either intravenous or oral administration in a dose-dependent manner. The efficacy of S-145 was 4-13 times greater than those of the reference compounds, and the duration of action was over 4 hr with 10 mg/kg, p.o. These results indicate that S-145 is a potent, orally, active and long-lasting TXA2 receptor antagonist, which will be promising as a drug for thromboembolism and ischemic heart disease caused by platelet activation.

Topics: Administration, Oral; Animals; Aspirin; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Collagen; Electrocardiography; Fatty Acids, Monounsaturated; Imidazoles; In Vitro Techniques; Injections, Intravenous; Male; Mice; Mice, Inbred Strains; Prostaglandins; Rats; Receptors, Prostaglandin; Receptors, Thromboxane; Thrombocytopenia; Thromboxane A2

The effects of subarachnoid hemorrhage on platelet-derived vasoconstriction of the isolated rabbit basilar artery were examined using an isometric tension recording method. The subarachnoid hemorrhage was induced by injecting arterial blood in the cisterna magna. The following points were confirmed: (1) the maximal contraction produced by the platelets (10(7)/mL) treated with indomethacin or dazoxiben (thromboxane synthetase inhibitor) were suppressed (65% or 70% of the control); (2) the contraction of the arteries treated with ONO-3708 (thromboxane A2 antagonist) or ketanserin was inhibited (73% or 8.4%), as was contraction after subarachnoid hemorrhage (67% or 14%); (3) platelet-induced contraction was potentiated after subarachnoid hemorrhage; and (4) serotonin-induced contraction was potentiated after subarachnoid hemorrhage. However, synthetic thromboxane A2-induced contraction was not potentiated. The present experiments suggest that both serotonin and thromboxane A2 contribute to vasoconstrictions induced by the platelets, before and after subarachnoid hemorrhage. The platelet-derived contraction response is potentiated after subarachnoid hemorrhage and serotonin is responsible for the increased reactivity.

Topics: Animals; Basilar Artery; Blood Platelets; Imidazoles; Indomethacin; Isometric Contraction; Ketanserin; Male; Rabbits; Serotonin; Subarachnoid Hemorrhage; Thromboxane A2; Vasoconstriction