Anti-inflammatory and utero-relaxant effects in human myometrium of new generation phosphodiesterase 4 inhibitors
| Autor: | Mary S. Barnette, Céline Méhats, Stéphanie Oger, Françoise Ferré, Marie-Josèphe Leroy, Dominique Cabrol |
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| Přispěvatelé: | Reproduction et physiopathologie obstétricale: Déterminisme hormonal et mécanismes moléculaires de la parturition, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Departement of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, Service de Gynécologie et Obstétrique [Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mehats, Celine, Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Cochin [AP-HP] |
| Jazyk: | angličtina |
| Rok vydání: | 2004 |
| Předmět: |
Lipopolysaccharides
Cyclohexanecarboxylic Acids Hydrocarbons Fluorinated MESH : Hydrocarbons Fluorinated MESH : Phosphodiesterase Inhibitors MESH : Bronchodilator Agents Phosphodiesterase Inhibitors Anti-Inflammatory Agents Carboxylic Acids MESH : Cyclic Nucleotide Phosphodiesterases Type 3 MESH : Lipopolysaccharides MESH : Cyclic Nucleotide Phosphodiesterases Type 4 MESH: Phosphodiesterase Inhibitors [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology Uterine Contraction chemistry.chemical_compound 0302 clinical medicine PDE4B MESH: Pregnancy Pregnancy MESH: Rolipram Cyclic AMP MESH : Nitriles MESH : Female MESH: Cyclic AMP MESH : Tumor Necrosis Factor-alpha 0303 health sciences 030219 obstetrics & reproductive medicine Forskolin MESH : Myometrium MESH : Cyclic AMP Myometrium Phosphodiesterase General Medicine MESH: Nitriles Bronchodilator Agents 3. Good health MESH : Carboxylic Acids MESH: Carboxylic Acids In utero MESH: 3' 5'-Cyclic-AMP Phosphodiesterases MESH: Uterine Contraction MESH: Myometrium Female MESH: Cyclic Nucleotide Phosphodiesterases Type 3 Rolipram Ethers medicine.drug MESH: Cyclic Nucleotide Phosphodiesterases Type 4 MESH : 3' 5'-Cyclic-AMP Phosphodiesterases medicine.medical_specialty In Vitro Techniques MESH : Anti-Inflammatory Agents Biology 03 medical and health sciences Internal medicine Nitriles medicine Humans Potency MESH : Ethers 030304 developmental biology MESH: Humans Tumor Necrosis Factor-alpha MESH : Humans Cilomilast Cell Biology [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology Cyclic Nucleotide Phosphodiesterases Type 3 Cyclic Nucleotide Phosphodiesterases Type 4 MESH: Hydrocarbons Fluorinated MESH : Pregnancy Endocrinology MESH : Rolipram Reproductive Medicine chemistry 3' 5'-Cyclic-AMP Phosphodiesterases MESH: Anti-Inflammatory Agents MESH: Tumor Necrosis Factor-alpha MESH: Ethers MESH: Bronchodilator Agents MESH: Lipopolysaccharides MESH: Female MESH : Uterine Contraction |
| Zdroj: | Biology of Reproduction Biology of Reproduction, Society for the Study of Reproduction, 2004, 70 (2), pp.458-64. ⟨10.1095/biolreprod.103.023051⟩ Biology of Reproduction, Society for the Study of Reproduction, 2004, 70 (2), pp.458-64. 〈10.1095/biolreprod.103.023051〉 |
| ISSN: | 0006-3363 1529-7268 |
| DOI: | 10.1095/biolreprod.103.023051⟩ |
| Popis: | International audience; The anti-inflammatory and utero-relaxant effects of two potent phosphodiesterase 4 (PDE4) inhibitors of the latest generation: cilomilast (one of the most advanced PDE4 inhibitors in clinical development, reportedly more selective for PDE4D) and compound A (which displays 12-fold greater selectivity toward PDE4B and/or PDE4A than toward PDE4D) were evaluated in human uterine smooth muscle. We first established that these compounds exhibit greater efficacy in inhibiting total cAMP-PDE activity in pregnant versus nonpregnant myometrium (E(max) = 78.0% +/- 3.6% and 80.3% +/- 2.2% in pregnant versus 57% +/- 4.7% and 70.5% +/- 5.9% in nonpregnant women for compound A and cilomilast, respectively; P < 0.05 for both compounds), confirming the prominent participation of PDE4 isoforms in cAMP hydrolysis in the near-term pregnant myometrium. Using pregnant myometrial explants, we have shown that both these drugs and also rolipram, the prototype PDE4 inhibitor, produce concentration-dependent inhibition of lipopolysaccharide (LPS) induced tumor necrosis factor alpha (TNFalpha) release with similar potency in each case (pD2 = 8.0 +/- 0.5, 7.9 +/- 0.2, and 7.6 +/- 0.2 for compound A, cilomilast, and rolipram, respectively). The maximum inhibition produced is 65%. Pretreatment with forskolin or 8-bromo-cAMP mimics the PDE4 inhibitor effect. Furthermore, compound A and cilomilast both produce concentration-dependent inhibition of the spontaneous contractions of myometrial strips and are more potent in pregnant than in nonpregnant myometrium (pD2 = 7.3 +/- 0.7 and 8.1 +/- 0.3 in pregnant versus 6.2 +/- 0.9 and 6.6 +/- 0.1 in nonpregnant myometrium for compound A and cilomilast, respectively; P < 0.05 for both compounds). This demonstrates that the PDE4 isoforms involved in the mechanism of contraction are different in the pregnant and nonpregnant myometrium. Our study highlights the importance of developing PDE4 inhibitors for the pharmacological management of infection-induced preterm labor. |
| Databáze: | OpenAIRE |
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