title: Pregnancy induces a modulation of the cAMP phosphodiesterase 4-conformers ratio in human myometrium: consequences for the utero-relaxant effect of PDE4-selective inhibitors.
abstract: The inhibitory impacts of RP 73401, a phosphodiesterase type 4 (PDE4) selective inhibitor of the second generation, versus rolipram, the prototypal PDE4 inhibitor, were evaluated and compared on cAMP phosphodiesterase (PDE) activity and contractility of the myometrium in nonpregnant and pregnant women. In enzymatic studies, RP 73401 and rolipram inhibited the cAMP PDE activity with significantly greater maximal efficiency in the myometrium of pregnant compared with nonpregnant women (75 versus 55%; P <.05). Although myometrial PDE4 presented a single class of interaction with RP 73401 [pD(2) (-log [IC(50)]) = -8.2], it exhibited at least two classes of interaction with rolipram (pD(2) = -8.2 and -5.6). In the myometrium of pregnant versus nonpregnant women, rolipram is significantly more efficacious in the concentration range >0.01 to 100 microM (P <.01), whereas no difference was observed for the concentration range <0.01 microM. In contractility studies, RP 73401 was equally effective in relaxing myometrial strips from both nonpregnant and pregnant women (pD(2) = -8.8). Conversely, the ability of rolipram to inhibit contractions of the myometrium in pregnant women was significantly lower (pD(2) = -7.2) compared with that in nonpregnant women (pD(2) = -8.2; P <.01). Concomitantly, in the myometrium of pregnant women, a rise in immunoreactive PDE4B2 signal was detected, whereas the PDE4D3 signal was less intense. These results demonstrate that parallel to an accumulation of PDE4B2 isoform, a modification in the ratio of PDE4 conformers HPDE4 and LPDE4 (conformer that binds rolipram with high and low affinity, respectively) occurs in the myometrium of near-term pregnant women with an increase of LPDE4 functionally implicated in the contractile process. Such modifications provide a strong rationale to propose LPDE4 as potential pharmacologic targets for the design of new tocolytic treatments.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 361, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Méhats
authors.forename: G
authors.initials: G
authors.lastname: Tanguy
authors.forename: B
authors.initials: B
authors.lastname: Paris
authors.forename: B
authors.initials: B
authors.lastname: Robert
authors.forename: N
authors.initials: N
authors.lastname: Pernin
authors.forename: F
authors.initials: F
authors.lastname: Ferré
authors.forename: M J
authors.initials: MJ
authors.lastname: Leroy
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D009126:Muscle Relaxation / Q000187:drug effects; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011247:Pregnancy / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D020889:Rolipram / Q000494:pharmacology; D014590:Uterine Contraction / Q000187:drug effects
chemical_list: D001549:Benzamides; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; C087566:piclamilast