Abstract

Using ¹⁴C-labeled fatty acids (19:4 ω6, 19:4 ω5, 21:4 ω6, and 21:4 ω7), radiochemical evidence of the formation of α-nor-, ω-nor-, α-homo-, and ω-homoprostaglandin endoperoxides (PGH₂), prostacyclins (PGI₂), and thromboxanes (TA₂) was obtained. Investigation of the biological activities of these compounds indicates that, although 21:4 ω6 is a substrate for cyclooxygenase and its endoperoxide, α-homo-PGH₂, is a substrate for prostacyclin synthetase and thromboxane synthetase, α-homo-PGH₂, α-homo-PGI₂, and α-homo-TA₂ are inactive on all receptors studied. In contrast, 19:4 ω5, precursor to ω-nor-PGs, and 19:4 ω6, precursor to α-nor-PGs, form endoperoxides which are not only substrates of prostacyclin synthetase and thromboxane synthetase, but also aggregate platelets and contract rabbit aorta spiral strips. Surprisingly, both α-nor-TA₂ and ω-nor-TA₂ are partial agonists at vascular smooth muscle receptors but, unlike their respective endoperoxides, do not aggregate washed human platelets. In contrast, 21:4 ω7 is converted to ω-homo-PGH₂ and ω-homo-TA₂, which aggregate platelets and are full agonists of vascular smooth muscle receptors. In addition to the radiochemical studies, the thromboxanes are identified by their lability in aqueous solution and the inhibition of their formation by the thromboxane synthetase inhibitor imidazole. Bovine aorta microsomes synthesize ω-nor-PGI₂, which is a partial agonist, and ω-homo-PGI₂, which is a full agonist when evaluated for the ability to relax bovine coronary artery spirals. Although we found radiochemical evidence for the synthesis of α-nor-PGI₂ and α-homo-PGI₂, these compounds appear to be biologically inactive. The prostacyclin synthetase inhibitor 15-hydroperoxy-arachidonic acid blocks the formation of α-nor-PGI₂, ω-nor-PGI₂, α-homo-PGI₂, and ω-homo-PGI₂ as measured by either radiochemical or biological assay.