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

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    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
    Issue Date
    2009
    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
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    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
    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
    ISSN
    1477-7827
    ae974a485f413a2113503eed53cd6c53
    10.1186/1477-7827-7-34
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