Modulation of phorbol ester-induced contraction by endogenously released cyclooxygenase products in rat aorta

This study tests the hypothesis that prostaglandins (PGs) released in response to phorbol esters act as modulators of the phorbol ester-induced smooth muscle contraction. The rate and magnitude of the phorbol 12-myristate 13-acetate (PMA)-induced contraction of deendothelialized rat aorta were decreased by the cyclooxygenase inhibitor, indomethacin. The thromboxane (Tx) A₂/PGH₂ receptor antagonist, SQ-29548, also inhibited PMA-induced contraction, and the magnitude of inhibition was greater than that due to indomethacin. PMA induced the release of PGI₂, PGE₂, PGF(2α), and arachidonic acid, but not TxA₂. The amount of PGI₂ released was greater than that of PGE₂ and PGF(2α). Indomethacin blocked the PMA-induced release of PG, but not of arachidonic acid. In PMA-contracted tissues, PGF(2α), PGE₂, and the stable PGI₂ and PGH₂ analogues, carbacyclin and U-46619, respectively, induced further contraction. Pretreatment of PMA-contracted tissues with SQ-29548 partially inhibited the PGF(2α)- and PGE₂-induced contractions, completely inhibited contraction to U-46619, and reversed the carbacyclin-induced contraction to relaxation. These results demonstrate that, in rat aorta, PMA induces the release of PGs that exert both contractile and relaxant effects but whose net effect is to accelerate and augment the contraction induced by PMA. The PG-induced increase in PMA contraction is mediated, in large part, through TxA₂/PGH₂ receptor activation. The ability of various PGs, including carbacyclin, to activate the TxA₂/PGH₂ receptor suggests that one or more of these PGs, in addition to, presumably, PGH₂, may be responsible for the increase in PMA contraction. PGI₂ is the only endogenously released PG that can account for the relaxant effect.