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 microM Mec or Flur, either alone or in the presence of 10 microM arachidonic acid (AA) to assess PGF2 alpha and PGE2 synthesis. Levels of both PGF2 alpha and PGE2 were stimulated (P less than 0.05) by AA (3.3- and 5.8-fold, respectively). Maximal suppression (P less than 0.01) of basal and AA-stimulated PGF2 alpha and PGE2 synthesis was elicited by 1 microM Mec and Flur. Second, adenylate cyclase activity, measured by the conversion of alpha 32P-ATP to alpha 32P-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 less than 0.01) in control activity (incubated with 50 microM GTP), as well as inhibiting hCG- and PG-stimulated activity. The presence of 100 microM Mec suppressed (P less than 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 quantified during exposure to 0, 1, and 100 microM Mec or Flur alone or with maximal stimulatory doses of hCG, PGE2, PGD2, 6 beta PGI1, PGA2, or dibutyryl cAMP (dbcAMP). All hormones and dbcAMP stimulated (P less than 0.01) P synthesis 2-3 fold over basal levels, except PGA2, which had no effect. The presence of 100 microM Mec reduced (P less than 0.01) basal P production by 62% and abolished (P less than 0.05) hCG-, PG-, and dbcAMP-induced stimulation. Conversely, neither 1 microM 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Zelinski-Wooten
M B
MB
Division of Reproductive Biology and Behavior, Oregon Regional Primate Research Center, Beaverton 97006.
Sargent
E L
EL
Molskness
T A
TA
Stouffer
R L
RL
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D003338:Corpus Luteum / Q000378:metabolism*; D005260:Female; D005480:Flurbiprofen / Q000494:pharmacology*; D008183:Luteal Phase; D008253:Macaca mulatta; D008469:Meclofenamic Acid / Q000494:pharmacology*; D011374:Progesterone / Q000096:biosynthesis; D011448:Prostaglandin Antagonists / Q000494:pharmacology*; D011453:Prostaglandins / Q000096:biosynthesis; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
D011448:Prostaglandin Antagonists; D011453:Prostaglandins; D062367:ortho-Aminobenzoates; D008469:Meclofenamic Acid; D011374:Progesterone; D005480:Flurbiprofen; D000262:Adenylyl Cyclases