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-indu ced smooth muscle contraction. The rate and magnitude of the phorbol 1 2-myristate 13-acetate (PMA)-induced contraction of deendothelialized rat aorta were decreased by the cyclooxygenase inhibitor, indomethacin . The thromboxane (Tx) A(2)/PGH(2) receptor antagonist, SQ-29548, also inhibited PMA-induced contraction, and the magnitude of inhibition wa s greater than that due to indomethacin. PMA induced the release of PG I(2), PGE(2), PGF(2 alpha), and arachidonic acid, but not TxA(2). The amount of PGI(2) released was greater than that of PGE(2) and PGF(2 al pha). Indomethacin blocked the PMA-induced release of PG, but not of a rachidonic acid. In PMA-contracted tissues, PGF(2 alpha), PGE(2), and the stable PGI(2) and PGH(2) analogues, carbacyclin and U-46619, respe ctively, induced further contraction. Pretreatment of PMA-contracted t issues with SQ-29548 partially inhibited the PGF(2 alpha)- and PGE(2)- induced contractions, completely inhibited contraction to U-46619, and reversed the carbacyclin-induced contraction to relaxation. These res ults demonstrate that, in rat aorta, PMA induces the release of PGs th at exert both contractile and relaxant effects but whose net effect is to accelerate and augment the contraction induced by PMA. The PG-indu ced increase in PMA contraction is mediated, in large part, through Tx A(2)/PGH(2) receptor activation. The ability of various PGs, including carbacyclin, to activate the TxA(2)/PGH(2) receptor suggests that one or more of these PGs, in addition to, presumably, PGH(2), may be resp onsible for the increase in PMA contraction. PGI(2) is the only endoge nously released PG that can account for the relaxant effect.