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Is Up-Regulation of Phosphodiesterase 4 Activity by PGE₂ Involved in the Desensitization of ß-Mimetics in Late Pregnancy Human Myometrium?

INSERM, U-361, Maternité Port Royal Hôpital Cochin, Université René Descartes (C.M., G.T., E.D., D.C., F.F., M.-J.L.), 75014 Paris, France; and Division of Reproductive Biology, Stanford University School of Medicine (C.M.), Stanford, California 94305-5317

Address all correspondence and requests for reprints to: Dr. Marie-Josèphe Leroy, INSERM, U-361, Pavillon Baudelocque, 123 boulevard Port Royal, 75014 Paris, France. E-mail: leroy-zamia{at}u361.cochin.inserm.fr

Abstract

Elevation of cAMP content resulting from stimulation of the receptor-adenylyl cyclase complex is involved in maintaining the quiescence of the human myometrium during pregnancy. The magnitude of this elevation is critically influenced by the rate of cAMP hydrolysis by phosphodiesterase (PDE) isoenzymes. In the present study we report that in term myometrium, enhanced cAMP-specific PDE4 activity takes part in the heterologous desensitization to the ß-mimetic, salbutamol. Indeed, pretreatment with a PDE4-selective inhibitor potentiates the relaxant effect of salbutamol on myometrial strips of women at term. Furthermore, the reduced relaxant effect of salbutamol after long-term treatment of myometrial strips with PGE_2, a potent myometrial effector, can be reversed by PDE4 inhibition. Using a model of cultured myometrial cells, we also demonstrated that PGE₂ is able to up-regulate PDE4 activity, at least through the induction of synthesis of PDE4B and PDE4D short forms, which, in turn, dampen the cAMP accumulation provoked by the stimulation of adenylyl cyclase. Such data suggest that in late pregnancy endogenous PGE₂ might up-regulate PDE4 activity and lessen the responsiveness of myometrium to ß-mimetic activation. Accordingly, coapplication of a selective PDE4 inhibitor might greatly improve the usefulness of ß-mimetic in tocolysis.

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