Disparate effects of the prostaglandin synthesis inhibitors, meclofenamate, and flurbiprofen on monkey luteal tissue in vitro

Intraluteal infusion of the prostaglandin (PG) synthesis inhibitor, sodium meclofenamate (Mec) causes premature luteolysis in rhesus monkeys. To evaluate further the actions of PG synthesis inhibitors in primate luteal function, we examined the in vitro effects of Mec and another inhibitor, flurbiprofen (Flur), on PG, cAMP, and progesterone (P) production by macaque luteal tissue obtained at midluteal phase of the menstrual cycle. First, collagenase dispersed luteal cells were incubated with 0-100 µM Mec or Flur, either alone or in the presence of 10 µM arachidonic acid (AA) to assess PGF_2αand PGE₂synthesis. Levels of both PGF_2αand PGE₂were stimulated (P < 0.05) by AA (3.3- and 5.8-fold, respectively). Maximal suppression (P < 0.01) of basal and AA-stimulated PGF_2αand PGE₂synthesis was elicited by 1 µM Mec and Flur. Second, adenylate cyclase activity, measured by the conversion of α³²P-ATP to α³²P-cAMP, was monitored in luteal homogenates exposed to increasing doses of Mec and Flur either alone or with maximal stimulatory doses of hCG, PGE₂, or PGI₂. Mec elicited a dose-dependent reduction (P < 0.01) in control activity (incubated with 50 µM GTP), as well as inhibiting hCG-and PG-stimulated activity. The presence of 100 µM Mec suppressed (P < 0.01) hCG-, PGE₂-and PGI₂-stimulated activity to control levels, but had no effect on activity stimulated by GMP-P(NH)P or forskolin. In contrast, Flur at any dose did not alter control activity or that stimulated by hormonal or nonhormonal activators. Third, P production by dispersed luteal cells was quan-tified during exposure to 0, 1, and 100 µm Mec or Flur alone or with maximal stimulatory doses of hCG, PGE₂, PGD₂, 6βPGI, PGA₂, or dibutyryl cAMP (dbcAMP). All hormones and dbcAMP stimulated (P < 0.01) P synthesis 2-3 fold over basal levels, except PGA₂, which had no effect. The presence of 100 µM Mec reduced (P < 0.01) basal P production by 62% and abolished (P < 0.05) hCG-, PG-, and dbcAMP-induced stimulation. Conversely, neither 1 Mec nor either dose of Flur affected P synthesis in the absence or presence of hormones or dbcAMP. These data indicate that: 1) Mec and Flur are potent inhibitors of PG synthesis in primate luteal cells in vitro and 2) higher doses of Mec suppress PG-and gonadotropin-sensitive adenylate cyclase activity and P production. While Mec is a potent inhibitor of primate luteal function in vivo, actions in addition to inhibition of PG synthesis may be involved in mediating premature luteolysis.