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Vol. 292, Issue 2, 817-823, February 2000
Institut National de la Santé et de la Recherche
Médicale, Unité 361, Paris, France (C.M., G.T., B.P., F.F.,
M.-J.L.); Maternité Port-Royal-Cochin, Université
René Descartes, Paris, France (N.P.).
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 [pD2 (
log [IC50]) = 8.2], it exhibited at least two classes of interaction with rolipram
(pD2 = 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 µM
(P < .01), whereas no difference was observed for
the concentration range <0.01 µM. In contractility studies, RP 73401 was equally effective in relaxing myometrial strips from both nonpregnant and pregnant women (pD2 = 8.8).
Conversely, the ability of rolipram to inhibit contractions of the
myometrium in pregnant women was significantly lower
(pD2 = 7.2) compared with that in nonpregnant women
(pD2 = 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.
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