Thromboxane A2 analogues inhibit the metabolism of thromboxane B2 in perfused guinea-pig lung.
The effect of four thromboxane A2-like analogues as inhibitors of thromboxane B2 uptake and metabolism to 13,14-dihydro-15-keto-thromboxane B2 was studied in the perfused guinea-pig lung. We used 5-min infusions containing 1 muCi [3H]thromboxane B2 (10 ng/ml) and measured uptake/accumulation (as tissue to medium ratio) and metabolism to 13,14-dihydro-15-ketothromboxane B2 by radio-TLC. The results showed that thromboxane B2 metabolism is saturable and exhibits substantial dose-dependent inhibition of both processes by U46619 and U44069 endoperoxide analogues (50% inhibition, ID50, in the range 0.5-0.9 microM), pinane thromboxane A2 (a thromboxane A2 partial agonist, ID50 against metabolism, 0.7 microM) and the thromboxane A2 mimetic EPO11 (ID50 against metabolism, 2.6 microM). These agents affected uptake and enzyme transformation steps differentially, thus strengthening the evidence that thromboxane B2 metabolism is a multi-step, uptake-dependent process in this tissue. U46619 did not affect prostaglandin F2 alpha metabolism, nor did prostaglandin F2 alpha inhibit thromboxane B2 metabolism, confirming that thromboxane B2 uptake/metabolism is distinct from the process which handles prostaglandins. Of the four analogues, only pinane thromboxane was a significant substrate for 15-hydroxyprostaglandin dehydrogenase and it was also the best inhibitor of 15-hydroxyprostaglandin dehydrogenase in purified enzyme preparations. These results advance our understanding of the inactivation in lung of thromboxane B2 and invite study of thromboxane A2 itself.
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D006168:Guinea Pigs; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011460:Prostaglandins F / Q000378:metabolism; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000378:metabolism*; D013931:Thromboxanes / Q000378:metabolism* / Q000494:pharmacology*
D011450:Prostaglandin Endoperoxides, Synthetic; D011460:Prostaglandins F; D013931:Thromboxanes; D013929:Thromboxane B2; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase