Is up-regulation of phosphodiesterase 4 activity by PGE2 involved in the desensitization of beta-mimetics in late pregnancy human myometrium?
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 beta-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 PGE2, 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 beta-mimetic activation. Accordingly, coapplication of a selective PDE4 inhibitor might greatly improve the usefulness of beta-mimetic in tocolysis.
Méhats
C
C
INSERM, U-361, Maternité Port Royal Hôpital Cochin, Université René Descartes, 75014 Paris, France.
Tanguy
G
G
Dallot
E
E
Cabrol
D
D
Ferré
F
F
Leroy
M J
MJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000096:biosynthesis* / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000328:Adult; D000420:Albuterol / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015232:Dinoprostone / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009215:Myometrium / Q000187:drug effects / Q000201:enzymology*; D010120:Oxytocics / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011247:Pregnancy / Q000502:physiology*; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects*
D000318:Adrenergic beta-Agonists; D001549:Benzamides; D007527:Isoenzymes; D010120:Oxytocics; D010726:Phosphodiesterase Inhibitors; D011448:Prostaglandin Antagonists; D011506:Proteins; D011725:Pyridines; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human; C517376:PDE4D protein, human; D015232:Dinoprostone; D000420:Albuterol; C087566:piclamilast