Characterization by DEAE-Cellulose Chromatography of a Single Molecular Form of Cyclic Nucleotide Phosphodiesterase in the Myometrium of Nonpregnant Women

Leroy, Marie-Josèphe; Blot, Philippe; Ferré, Françoise

doi:10.1159/000298802

Cited by 10 publications

(4 citation statements)

References 14 publications

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“…The observed predominance of the PDE4 family agrees with our previous data in human myometrial tissue, in which PDE4 contributes to the major cAMP catalytic activity (9). Like whole myometrium (8), cultured myometrial cells presented additional minor cAMP activities of PDE1, PDE3, and PDE5 families, and only PDE2 was not recovered in the cells. This difference, also observed in other smooth muscle tissues and their corresponding primary cell culture, might have been due to the presence of nonsmooth muscle cellular constituents in the whole tissue or else was inherent to the cellular model (41).…”

Section: Discussionsupporting

confidence: 90%

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Selective Up-Regulation of Phosphodiesterase-4 Cyclic Adenosine 3′,5′-Monophosphate (cAMP)-Specific Phosphodiesterase Variants by Elevated cAMP Content in Human Myometrial Cells in Culture

et al. 1999

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In human myometrium, the modulation of intracellular cAMP content resulting from agonist-mediated stimulation of the receptor-adenylyl cyclase complex is largely influenced by the rate of cAMP hydrolysis by phosphodiesterase (PDE) isoenzymes. We have previously shown that the PDE4 family contributes to the predominant cAMP-hydrolyzing activity in human myometrium and that elevation of the PDE4B2 messenger RNA steady state level occurs in pregnant myometrial tissue. In the present study, we used a model of human myometrial cells in culture to determine whether an elevated cAMP concentration could influence PDE expression. As in myometrial tissue, high levels of PDE4 activity were detected in these smooth muscle cells. Long term treatment with 8-bromo-cAMP or forskolin resulted in a selective induction of PDE4B and of PDE4D short form messenger RNA variants. Concurrently, an increased immunoreactive signal for the PDE4B- and PDE4D-related isoenzymes was detected. This induction was consistent with an observed significant up-regulation of PDE4 activity. Accordingly, our results demonstrate that in human cultured myometrial cells, cAMP-elevating agents manipulate PDE4 activity through selective induction of synthesis of PDE4B and PDE4D short forms. Such a mechanism might have physiological importance during pregnancy by dampening hormonal stimulation and could thereby be involved in tolerance to the tocolytic effect of beta-adrenoceptor agonists.

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Section: Discussionsupporting

confidence: 90%

“…In human myometrium, we previously observed modifications in the kinetic behavior of the cAMP PDE enzyme during pregnancy compared with nonpregnant tissue (7,8). Five distinct families (PDE1-5) have been identified in human myometrium extracts.…”

mentioning

confidence: 99%

Selective Up-Regulation of Phosphodiesterase-4 Cyclic Adenosine 3′,5′-Monophosphate (cAMP)-Specific Phosphodiesterase Variants by Elevated cAMP Content in Human Myometrial Cells in Culture

et al. 1999

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“…Human pregnant myometrium contains mainly phosphodiesterase 4 (PDE4) but also other phosphodiesterase isoenzymes (Leroy et al 1989;Leroy et al 1994). Interestingly, human nonpregnant myometrium appears to have a different profile of phosphodiesterase isoenzymes with less relevance for phosphodiesterase 4 (Leroy et al 1987). Recently, phosphodiesterase 6 and 7 have been identified (Beavo et al 1994;Beavo 1995) but their relevance in myometrial tissue is yet to be determined.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological and biochemical study on the effects of selective phosphodiesterase inhibitors on human term myometrium

Bardou¹,

Cortijo

Loustalot

et al. 1999

Naunyn-Schmiedeberg's Arch Pharmacol

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This study was aimed at evaluating the in vitro effects of phosphodiesterase inhibitors and beta2-adrenoceptor agonists on spontaneous contractions of human term myometrium. Rolipram, RP 73401 (3-cyclopentyloxy-N-(3,5(-dichloro-4-pyridil)-4-methoxybenzamide) and Ro 20-1724 (1-4-(3-butoxy-4-methoxybenzyl)-2-imidozolidinone) (phosphodiesterase 4 inhibitors) inhibited spontaneous myometrial contractions (Emax approximately 100%; pD2 of 6.80+/-0.28, 6.84+/-0.32 and 6.31+/-0.03, respectively). Salbutamol and formoterol were less effective (Emax=40+/-6% and 35+/-12%, respectively) than phosphodiesterase 4 inhibitors to reduce myometrial contractility. Inhibitors of phosphodiesterase 3 (milrinone and siguazodan) and 5 (zaprinast) were marginally effective. Rolipram (10-30 nM) and siguazodan (0.1 microM) potentiated the response to salbutamol (Emax=75+/-12%, 88+/-8% and 73+/-12% and pD2=6.51+/-0.20, 6.93+/-0.29 and 6.48+/-0.16, respectively). Sodium nitroprusside (pD2=6.76+/-0.29) and theophylline (pD2=5.15+/-0.22) were effective inhibitors of myometrial contractions. Chromatographic separation of phosphodiesterase isoenzymes demonstrated that phosphodiesterase 4 is predominant but other phosphodiesterase isoenzymes were also identified. In conclusion, phosphodiesterase 4 inhibitors alone or combined with beta2-adrenoceptor agonists have potential interest as tocolytic agents.

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“…In the human myometrium, such studies have not yet been performed. However data from our group showed the existence of a Ca2+-calmodulin-dependent cyclic nucleo tide PDE form and the myometrial calmodulin was iso lated [4], In the present study, we have investigated the possible regulatory effect of Ca2+ and/or calmodulin on the adenylate cyclase activity in near term human myometrium. …”

Section: Introductionmentioning

confidence: 88%

Sensitivity of the Human Myometrial Adenylate Cyclase to Calcium and Calmodulin

Maka

Breuiller²,

Leroy³

et al. 1990

Gynecol Obstet Invest

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The calcium-calmodulin-dependent regulation of adenylate cyclase was studied in membranes from pregnant human myometrium. In the absence or presence of exogenous calmodulin, free calcium concentrations greater than 50 nmol/l inhibited the adenylate cyclase activity. Activation of the enzyme by calmodulin (0.1–1 µmol/l) was calcium-dependent and maximal at 10 nmol/l free calcium. The myometrial adenylate cyclase activity was stimulated by the guanyl nucleotide, Gpp(NH)p. In the presence of the guanyl nucleotide, the activatory effect of the calcium-calmodulin complex disappeared. The activatory effect of exogenous calmodulin was dependent on endogenous calmodulin present in the myometrial membranes. Trifluoroperazine and calmidazolium were able to inhibit the adenylate cyclase activity.

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Characterization by DEAE-Cellulose Chromatography of a Single Molecular Form of Cyclic Nucleotide Phosphodiesterase in the Myometrium of Nonpregnant Women

Cited by 10 publications

References 14 publications

Selective Up-Regulation of Phosphodiesterase-4 Cyclic Adenosine 3′,5′-Monophosphate (cAMP)-Specific Phosphodiesterase Variants by Elevated cAMP Content in Human Myometrial Cells in Culture

Selective Up-Regulation of Phosphodiesterase-4 Cyclic Adenosine 3′,5′-Monophosphate (cAMP)-Specific Phosphodiesterase Variants by Elevated cAMP Content in Human Myometrial Cells in Culture

Pharmacological and biochemical study on the effects of selective phosphodiesterase inhibitors on human term myometrium

Sensitivity of the Human Myometrial Adenylate Cyclase to Calcium and Calmodulin

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