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

Autor: Daniel O'Toole, C. H. Maharaj, Brendan D. Higgins, Tadhg D. Lynch, John G. Laffey, John Carney, John J. Morrison, James Jarman
Jazyk: angličtina
Rok vydání: 2009
Předmět:
Phosphodiesterase Inhibitors
Vasodilator Agents
Potential candidate
Vasodilation
Pharmacology
Piperazines
Gynaecology
chemistry.chemical_compound
Endocrinology
inhibitors
lcsh:Reproduction
Medicine
Sulfones
Cyclic GMP
phosphodiesterase-5
Premature labor
myometrium
Obstetrics and Gynecology
Arteries
Chorion
cardiovascular system
Female
pregnancy
Adult
medicine.medical_specialty
Adolescent
lcsh:QH471-489
Sildenafil
In Vitro Techniques
Nitric Oxide
lcsh:Gynecology and obstetrics
Sildenafil Citrate
growth restriction
Nitric oxide
preeclampsia
relaxation
Internal medicine
Humans
Placental Circulation
RNA
Messenger
pulmonary-hypertension
lcsh:RG1-991
Cyclic Nucleotide Phosphodiesterases
Type 5
Pregnancy
business.industry
Research
National Centre for Biomedical Engineering Science
NCBES
Phosphodiesterase 5 Inhibitors
medicine.disease
Pulmonary hypertension
respiratory tract diseases
Reproductive Medicine
chemistry
Purines
viagra
business
Developmental Biology
Zdroj: Reproductive Biology and Endocrinology, Vol 7, Iss 1, p 34 (2009)
Reproductive Biology and Endocrinology : RB&E
Popis: 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.
Databáze: OpenAIRE
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