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dc.contributor.authorMaharaj, Chrisen H
dc.contributor.authorO'Toole, Daniel
dc.contributor.authorLynch, Tadhg
dc.contributor.authorCarney, John
dc.contributor.authorJarman, James
dc.contributor.authorHiggins, Brendan D
dc.contributor.authorMorrison, John J
dc.contributor.authorLaffey, John G
dc.date.accessioned2010-03-23T16:36:52Z
dc.date.available2010-03-23T16:36:52Z
dc.date.issued2009
dc.identifier.citationEffects and mechanisms of action of sildenafil citrate in human chorionic arteries. 2009, 7:34 Reprod. Biol. Endocrinol.en
dc.identifier.issn1477-7827
dc.identifier.pmid19389232
dc.identifier.doi10.1186/1477-7827-7-34
dc.identifier.urihttp://hdl.handle.net/10147/94743
dc.description.abstractOBJECTIVES: Sildenafil citrate, a specific phosphodiesterase-5 inhibitor, is increasingly used for pulmonary hypertension in pregnancy. Sildenafil is also emerging as a potential candidate for the treatment of intra-uterine growth retardation and for premature labor. Its effects in the feto-placental circulation are not known. Our objectives were to determine whether phosphodiesterase-5 is present in the human feto-placental circulation, and to characterize the effects and mechanisms of action of sildenafil citrate in this circulation. STUDY DESIGN: Ex vivo human chorionic plate arterial rings were used in all experiments. The presence of phosphodiesterase-5 in the feto-placental circulation was determined by western blotting and immunohistochemical staining. In a subsequent series of pharmacologic studies, the effects of sildenafil citrate in pre-constricted chorionic plate arterial rings were determined. Additional studies examined the role of cGMP and nitric oxide in mediating the effects of sildenafil. RESULTS: Phosphodiesterase-5 mRNA and protein was demonstrated in human chorionic plate arteries. Immunohistochemistry demonstrated phosphodiesterase-5 within the arterial muscle layer. Sildenafil citrate produced dose dependent vasodilatation at concentrations at and greater than 10 nM. Both the direct cGMP inhibitor methylene blue and the cGMP-dependent protein kinase inhibitor Rp-8-Br-PET-cGMPS significantly attenuated the vasodilation produced by sildenafil citrate. Inhibition of NO production with L-NAME did not attenuate the vasodilator effects of sildenafil. In contrast, sildenafil citrate significantly enhanced the vasodilation produced by the NO donor sodium nitroprusside. CONCLUSION: Phosphodiesterase-5 is present in the feto-placental circulation. Sildenafil citrate vasodilates the feto-placental circulation via a cGMP dependent mechanism involving increased responsiveness to NO.
dc.language.isoenen
dc.subject.meshAdolescent
dc.subject.meshAdult
dc.subject.meshArteries
dc.subject.meshChorion
dc.subject.meshCyclic GMP
dc.subject.meshCyclic Nucleotide Phosphodiesterases, Type 5
dc.subject.meshFemale
dc.subject.meshHumans
dc.subject.meshNitric Oxide
dc.subject.meshPhosphodiesterase Inhibitors
dc.subject.meshPiperazines
dc.subject.meshPlacental Circulation
dc.subject.meshPregnancy
dc.subject.meshPurines
dc.subject.meshRNA, Messenger
dc.subject.meshSulfones
dc.subject.meshVasodilation
dc.subject.meshVasodilator Agents
dc.titleEffects and mechanisms of action of sildenafil citrate in human chorionic arteries.en
dc.contributor.departmentDepartment of Anaesthesia, University College Hospital, Galway, Ireland. chrisenm@gmail.comen
dc.identifier.journalReproductive biology and endocrinology : RB&Een
refterms.dateFOA2018-08-31T05:09:08Z
html.description.abstractOBJECTIVES: Sildenafil citrate, a specific phosphodiesterase-5 inhibitor, is increasingly used for pulmonary hypertension in pregnancy. Sildenafil is also emerging as a potential candidate for the treatment of intra-uterine growth retardation and for premature labor. Its effects in the feto-placental circulation are not known. Our objectives were to determine whether phosphodiesterase-5 is present in the human feto-placental circulation, and to characterize the effects and mechanisms of action of sildenafil citrate in this circulation. STUDY DESIGN: Ex vivo human chorionic plate arterial rings were used in all experiments. The presence of phosphodiesterase-5 in the feto-placental circulation was determined by western blotting and immunohistochemical staining. In a subsequent series of pharmacologic studies, the effects of sildenafil citrate in pre-constricted chorionic plate arterial rings were determined. Additional studies examined the role of cGMP and nitric oxide in mediating the effects of sildenafil. RESULTS: Phosphodiesterase-5 mRNA and protein was demonstrated in human chorionic plate arteries. Immunohistochemistry demonstrated phosphodiesterase-5 within the arterial muscle layer. Sildenafil citrate produced dose dependent vasodilatation at concentrations at and greater than 10 nM. Both the direct cGMP inhibitor methylene blue and the cGMP-dependent protein kinase inhibitor Rp-8-Br-PET-cGMPS significantly attenuated the vasodilation produced by sildenafil citrate. Inhibition of NO production with L-NAME did not attenuate the vasodilator effects of sildenafil. In contrast, sildenafil citrate significantly enhanced the vasodilation produced by the NO donor sodium nitroprusside. CONCLUSION: Phosphodiesterase-5 is present in the feto-placental circulation. Sildenafil citrate vasodilates the feto-placental circulation via a cGMP dependent mechanism involving increased responsiveness to NO.


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