Effects and mechanisms of action of sildenafil citrate in human chorionic arteries.
Authors
Maharaj, Chrisen HO'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.comIssue Date
2009MeSH
AdolescentAdult
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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Effects and mechanisms of action of sildenafil citrate in human chorionic arteries. 2009, 7:34 Reprod. Biol. Endocrinol.Journal
Reproductive biology and endocrinology : RB&EDOI
10.1186/1477-7827-7-34PubMed ID
19389232Abstract
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
enISSN
1477-7827ae974a485f413a2113503eed53cd6c53
10.1186/1477-7827-7-34
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