Abstract
ObjectivesSildenafil 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 DesignEx 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.ResultsPhosphodiesterase-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.ConclusionPhosphodiesterase-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.
Highlights
Sildenafil citrate, a specific phosphodiesterase-5 inhibitor, has demonstrated considerable promise as a pulmonary vasodilator [1,2,3,4]
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
Sildenafil citrate significantly enhanced the vasodilation produced by the nitric oxide (NO) donor sodium nitroprusside
Summary
Sildenafil citrate, a specific phosphodiesterase-5 inhibitor, has demonstrated considerable promise as a pulmonary vasodilator [1,2,3,4]. Sildenafil has been proposed as a potentially useful therapy for pulmonary hypertension in pregnancy, a disease characterized by poor maternal and fetal outcome [5,6]. Sildenafil has been proposed as a potential therapeutic strategy to maintain placental function in pre-eclampsia [12]. Should sildenafil citrate possess vasodilatory effects in the feto-placental circulation, this would significantly enhance its therapeutic potential in the setting of placental insufficiency. Sildenafil citrate has recently been demonstrated not to alter the contractile response to vasoconstrictors or to endothelial dependent vasodilators[13]. The direct effects of sildenafil citrate in the feto-placental circulation have not been determined
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