Meclofenamate inhibits prostaglandin E binding and adenylyl cyclase activation in human myometrium.
The effect of sodium meclofenamate on the binding of [3H]prostaglandin E2 [( 3H]PGE2) to membranes from human myometrium was investigated. Meclofenamate inhibited the binding of [3H]PGE2 to high-affinity (dissociation constant 1.5 nmol/l) sites in a reversible dose-dependent manner (inhibition constant 11 mumol/l). The mechanism of inhibition was mainly competitive, but at high doses of meclofenamate (greater than or equal to 100 mumol/l) there was loss of PGE receptor sites. Of several PG synthesis inhibitors tested, only meclofenamate and, to a lesser extent, mefenamic acid had a significant inhibitory effect. PGE2 stimulated cyclic AMP generation in slices of human myometrium and this was inhibited by meclofenamate in a dose-dependent manner (50% inhibition occurred at 9 mumol/l). Again, this effect was specific for meclofenamate and fitted a competitive mechanism at doses in the range 1-10 mumol/l and a non-competitive mechanism at higher doses. The data show that meclofenamate, in addition to its traditional role as a PG synthesis inhibitor, affects directly PGE receptor binding and activation.
López Bernal
A
A
University of Oxford, Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Headington.
Buckley
S
S
Rees
C M
CM
Marshall
J M
JM
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000242:Cyclic AMP / Q000096:biosynthesis; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D008528:Mefenamic Acid / Q000494:pharmacology; D009215:Myometrium / Q000187:drug effects* / Q000378:metabolism; D011448:Prostaglandin Antagonists / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011982:Receptors, Prostaglandin / Q000187:drug effects; D018078:Receptors, Prostaglandin E
D011448:Prostaglandin Antagonists; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; D008528:Mefenamic Acid; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D015232:Dinoprostone