Effects and mechanisms of action of sildenafil citrate in human chorionic arteries.

Hdl Handle:
http://hdl.handle.net/10147/94743
Title:
Effects and mechanisms of action of sildenafil citrate in human chorionic arteries.
Authors:
Maharaj, Chrisen H; O'Toole, Daniel; Lynch, Tadhg; Carney, John; Jarman, James; Higgins, Brendan D; Morrison, John J; Laffey, John G
Affiliation:
Department of Anaesthesia, University College Hospital, Galway, Ireland. chrisenm@gmail.com
Citation:
Effects and mechanisms of action of sildenafil citrate in human chorionic arteries. 2009, 7:34 Reprod. Biol. Endocrinol.
Journal:
Reproductive biology and endocrinology : RB&E
Issue Date:
2009
URI:
http://hdl.handle.net/10147/94743
DOI:
10.1186/1477-7827-7-34
PubMed ID:
19389232
Abstract:
OBJECTIVES: 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.
Language:
en
MeSH:
Adolescent; Adult; Arteries; Chorion; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Female; Humans; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Placental Circulation; Pregnancy; Purines; RNA, Messenger; Sulfones; Vasodilation; Vasodilator Agents
ISSN:
1477-7827

Full metadata record

DC FieldValue Language
dc.contributor.authorMaharaj, Chrisen Hen
dc.contributor.authorO'Toole, Danielen
dc.contributor.authorLynch, Tadhgen
dc.contributor.authorCarney, Johnen
dc.contributor.authorJarman, Jamesen
dc.contributor.authorHiggins, Brendan Den
dc.contributor.authorMorrison, John Jen
dc.contributor.authorLaffey, John Gen
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

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