Diversion of prostaglandin endoperoxide metabolism by selective inhibition of thromboxane A2 biosynthesis in lung, spleen or platelets.
Infusion of arachidonic acid through the guinea pig lung or the cat spleen causes a release of thromboxane A2 and prostaglandins, as measured by bioassay. After incubation of human platelets with arachidonate similar metabolites are formed, as demonstrated chromatographically. Infusion of imidazole (50-75 microgram/ml) through the lung or spleen specifically inhibits thromboxane A2 production and diverts the pathway to the prostaglandins, mainly prostaglandin F2alpha. In human platelets imidazole causes a dose-dependent inhibition of thromboxane A2 formation (ID50 5.5 X 10(-4) M). This inhibition is accompanied by a dose-dependent increase in prostaglandin F2alpha. Since thromboxane A2 induces platelet aggregation and is a potent vasoconstrictor, diversion of pathways to prostaglandins with opposite or less potent action might be of relevance in the treatment of cardiovascular diseases.
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001345:Autoradiography; D001681:Biological Assay; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D002415:Cats; D002417:Cattle; D002855:Chromatography, Thin Layer; D003864:Depression, Chemical; D006168:Guinea Pigs; D006801:Humans; D006880:Hydroxy Acids / Q000096:biosynthesis* / Q000097:blood; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood; D011453:Prostaglandins / Q000378:metabolism*; D011714:Pyrans / Q000096:biosynthesis / Q000097:blood; D011817:Rabbits; D051381:Rats; D013154:Spleen / Q000187:drug effects / Q000378:metabolism*
D001095:Arachidonic Acids; D006880:Hydroxy Acids; D007093:Imidazoles; D011453:Prostaglandins; D011714:Pyrans; D011451:Prostaglandin-Endoperoxide Synthases