Beneficial effects of a new potent and specific thromboxane receptor antagonist (SQ-29,548) in vitro and in vivo.
SQ-29,548, a newly synthetized thromboxane receptor antagonist, was investigated for its effects on platelet and vascular thromboxane receptors in vivo and in vitro. Arachidonic acid (AA)-induced sudden death in rabbits was dose-dependently inhibited by SQ-29,548 at doses ranging from 0.2 to 2 mg/kg. Sudden death was accompanied by a 46 +/- 6% decrease in continuously measured circulating platelet count, which was also dose-dependently inhibited by SQ-29,548. The AA-induced increase in continuously recorded whole blood ATP content was 1.2 +/- 0.4 microM and was significantly diminished by all SQ-29,548 doses used. Platelet aggregation induced by AA, the endoperoxide analog U-46,619 or collagen in platelet-rich plasma was dose-dependently inhibited by SQ-29,548 which exerted an IC50 of 0.8, 0.3 or 2.9 microM, respectively. In contrast, ADP and platelet-activating factor acether-induced platelet aggregation were unaffected at concentrations of SQ-29,548 up to 260 microM. Thromboxane B2 formation was not significantly altered by SQ-29,548 (1-100 microM) in platelet-rich plasma stimulated with AA or in spontaneously clotting whole blood. Thromboxane synthetase, cyclooxygenase and lipoxygenase product formation were unaffected by SQ-29,548 when washed rabbit platelets were stimulated with radiolabeled AA and the products were measured after separation by thin-layer chromatography. U-46,619 (500 nM), carbocyclic thromboxane A2 (15 nM) and prostaglandin F2 alpha (3 microM)-induced contractions of rabbit pulmonary artery were antagonized by SQ-29,548 exerting a IC50 value between 120 and 40 nM, whereas norepinephrine-induced contractions were unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000633:toxicity; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002855:Chromatography, Thin Layer; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines / Q000494:pharmacology*; D008247:Lysosomes / Q000201:enzymology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010972:Platelet Activating Factor / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010976:Platelet Count; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D017482:Receptors, Thromboxane; D013929:Thromboxane B2 / Q000096:biosynthesis; D013930:Thromboxane-A Synthase / Q000378:metabolism
D001095:Arachidonic Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D010972:Platelet Activating Factor; D011956:Receptors, Cell Surface; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013929:Thromboxane B2; D000244:Adenosine Diphosphate; C045749:SQ 29548; D011451:Prostaglandin-Endoperoxide Synthases; D013930:Thromboxane-A Synthase