Abstract

Prostaglandins E₁, (PGE₁) and E₂ stimulated contractions of estrogen-treated rat uteri. They also caused the accumulation of adenosine cyclic 3',5'-monophosphate (cAMP) in the isolated myometrium and endometrium. Both stimulations were also induced by arachidonic (C_20:4) and homo-γ-linoleic (C_20:3) acids, which are direct precursors of prostaglandins. Other unsaturated fatty acids, including oleic, linoleic, γ-linolenic, and eicosadienoic, were without effect. The stimulations of contraction and adenylate cyclase activity by arachidonic and homo-γ-linolenic acids were very rapid, detectable at 30 sec, dose-dependent, and abolished by the specific cyclooxygenase inhibitors indomethacin, meclofenamic acid, and eicosatetraynoic acid. Hence the conversion of C_20:3 and C_20:4 fatty acids to prostaglandin or prostaglandin-like material occurred in both myometrium and endometrium and was responsible for the observed activations. The levels of cAMP can therefore be modulated by local prostaglandin effectors in a manner similar to that produced by exogenous PGE compounds. The stimulatory effects of arachidonic acid were followed by an unresponsive phase, as shown by the subsequent inhibited responses of the myometrium to contractile agents such as prostaglandins and carbamylcholine as well as by the suppression of adenylate cyclase activation by either epinephrine or PGE₂, in both endometrium and myometrium. The latter inhibition was not readily reversible. It did not involve the prostaglandin synthetase system, inasmuch as indomethacin failed to prevent the subsequent inhibitory effect of arachidonic acid. Furthermore, similar marked inhibition was exerted by linoleic, γ-linolenic, and eicosatetraynoic acids. These results suggest the possible alteration by fatty acids of a membrane architecture crucial for adenylate cyclase activation and signal transmission during hormone-induced contraction.