Effects of a thromboxane synthetase inhibitor and a thromboxane antagonist on release and activity of thromboxane A2 and prostacyclin in vitro.
The TxA2 synthetase inhibitor, dazoxiben, and the TxA2 antagonist, +/- SQ 29,548, were examined for effects on release and vasoactivity of TxA2 and prostacyclin. Isolated perfused guinea pig lungs were used as the enzyme source from which TxA2 and prostacyclin were released in response to injections of arachidonic acid or bradykinin. Both dazoxiben and +/- SQ 29, 548 inhibited contraction of the superfused rat aorta and bovine coronary artery after arachidonic acid injection through the lung. +/- SQ 29,548 abolished contractions of the rat aorta, but significant aorta contracting activity persisted during dazoxiben treatment. Dazoxiben significantly inhibited arachidonate-induced release of TxA2 (immunoreactive TxB2) into the superfusate, but TxA2 release was significantly potentiated by +/- SQ 29,548. Thus, in the presence of enhanced TxA2 concentrations, +/- SQ 29,548 effectively antagonized the vasospastic effect of TxA2. Dazoxiben diverted a significantly greater amount of arachidonic acid into prostacyclin synthesis (immunoreactive 6-keto-PGF1 alpha), changing original coronary vasoconstriction into relaxation. +/- SQ 29,548 did not significantly modify lung prostacyclin synthesis. Moreover, with +/- SQ 29,548, the absence of TxA2-mediated coronary contraction unmasked active relaxation of the superfused bovine coronary artery, coincident with thromboxane and prostacyclin release. Dazoxiben consistently inhibited TxA2 synthesis and enhanced prostacyclin synthesis. +/- SQ 29,548 augmented TxB2 release in response to arachidonate, but not bradykinin, and did not significantly alter 6-keto-PGF1 alpha release in response to either arachidonate or bradykinin. In terms of vasoactivity measured in vitro, +/- SQ 29,548 and dazoxiben produced similar anti-vasospastic effects, although this was accomplished by completely different mechanisms.
D015121:6-Ketoprostaglandin F1 alpha / Q000032:analysis; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002417:Cattle; D011464:Epoprostenol / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated; D006168:Guinea Pigs; D006834:Hydrazines / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D051381:Rats; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013929:Thromboxane B2 / Q000032:analysis; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000378:metabolism*
D001095:Arachidonic Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D007093:Imidazoles; D013931:Thromboxanes; C029166:dazoxiben; D016718:Arachidonic Acid; D013929:Thromboxane B2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; C045749:SQ 29548; D011464:Epoprostenol; D010088:Oxidoreductases; D013930:Thromboxane-A Synthase; D001920:Bradykinin