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

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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.

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Most cited references 23

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Short technical reports. Modification of the TRI reagent procedure for isolation of RNA from polysaccharide- and proteoglycan-rich sources.

Tim K. Mackey, P. Chomczynski (1995)

A modification of the TRI Reagent procedure has been elaborated for isolation of RNA from polysaccharide- and proteoglycan-rich material. In the modified procedure, RNA is precipitated from the aqueous phase by the combined action of isopropanol and a high-salt concentration. Under these conditions, RNA is effectively precipitated while contaminating polysaccharides and proteoglycans remain in the soluble form. The modified precipitation does not prolong or increase the complexity of the TRI Reagent procedure. The new procedure was tested by isolation of RNA from polysaccharide- and proteoglycan-rich tissues such as rat liver and aorta.

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Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial.

Horst Olschewski, Ralf T Schermuly, Falk Wiedemann … (2002)

Lung fibrosis can be complicated by pulmonary hypertension, limiting exercise tolerance and life expectancy. Furthermore, vasodilators might cause deterioration in gas exchange. Our aim was to compare acute effects of sildenafil, nitric oxide, and epoprostenol in individuals with pulmonary hypertension secondary to lung fibrosis. We did a randomised controlled, open-label trial, in 16 individuals admitted to our hospital with pulmonary hypertension secondary to lung fibrosis. After inhalation of nitric oxide (10-20 ppm), we assigned patients to either maximum tolerated dose of intravenous epoprostenol (mean 8.0 ng/kg per min; n=8) or oral sildenafil (50 mg; n=8). Our primary objective was to assess pulmonary vasodilative potency (decrease in pulmonary vascular resistance index) of sildenafil by comparison with inhaled nitric oxide and infused epoprostenol. Analyses were by intention to treat. Pulmonary vascular resistance index was reduced by nitric oxide (-21.9%, 95% CI -14.1 to -36.2), epoprostenol (-36.9%, -24.4 to -59.6), and sildenafil (-32.5%, -10.2 to -54.1). However, ratio of pulmonary to systemic vascular resistance decreased only in individuals who received nitric oxide and sildenafil. Baseline measurement of multiple-inert-gas elimination showed right-to-left shunt flow (4.8%, 0.0-28.2) and little perfusion of low ventilation(V)/perfusion(Q) areas (0.1%, 0.0-13.0). Prostacyclin increased V/Q mismatch (shunt 16.8%, 10.8-35.9; low V/Q 3.8%, 0.0-13.0) and decreased arterial oxygenation. By contrast, nitric oxide (4.5%, 0.0-18.0; 0.0%, 0.0-17.3) and sildenafil (3.3%, 0.0-11.3; 0.0%, 0.0-12.4) maintained V/Q matching, with raised arterial partial pressure of oxygen (14.3 mm Hg, -1.7 to 31.3) noted for sildenafil. We recorded no adverse events. Sildenafil causes preferential pulmonary vasodilation and improves gas exchange in patients with severe lung fibrosis and secondary pulmonary hypertension.

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Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study.

Krishna N. Reddy, P S R K Sastry, C Narasimhan … (2004)

In a randomized, double-blind, crossover design, we compared the efficacy of sildenafil with placebo in patients with primary pulmonary hypertension (PPH). The primary end point was the change in exercise time on treadmill using the Naughton protocol. Secondary end points were change in cardiac index and pulmonary artery systolic pressure as assessed by Doppler echocardiography and quality of life (QOL) as assessed by a questionnaire. Primary pulmonary hypertension is a disorder with limited treatment options. Uncontrolled studies had shown sildenafil to be beneficial in the treatment of PPH. After initial clinical evaluation, including Doppler echocardiography and treadmill exercise test, patients were randomized to placebo or sildenafil with dosages ranging from 25 to 100 mg thrice daily on the basis of body weight. The evaluation was repeated after six weeks. Then patients were crossed over to alternate therapy. Final evaluation was performed after another six weeks of treatment. Twenty-two patients completed the study. Exercise time increased by 44% from 475 +/- 168 s at the end of placebo phase to 686 +/- 224 s at the end of sildenafil phase (p < 0.0001). With sildenafil, cardiac index improved from 2.80 +/- 0.9 l/m2 to 3.45 +/- 1.1 l/m(2) (p < 0.0001), whereas pulmonary artery systolic pressure decreased insignificantly from 105.23 +/- 17.82 mm Hg to 98.50 +/- 24.38 mm Hg. There was significant improvement in the dyspnea and fatigue components of the QOL questionnaire. During the placebo phase, one patient died and another had syncope. There were no serious side effects with sildenafil. Sildenafil significantly improves exercise tolerance, cardiac index, and QOL in patients with PPH.

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Author and article information

Journal

Journal ID (nlm-ta): Reprod Biol Endocrinol

Title: Reproductive Biology and Endocrinology : RB&E

Publisher: BioMed Central

ISSN (Electronic): 1477-7827

Publication date Collection: 2009

Publication date (Electronic): 23 April 2009

Volume: 7

Page: 34

Affiliations

[1 ]Department of Anaesthesia, University College Hospital, Galway, Ireland

[2 ]Department of Anaesthesia, Clinical Sciences Institute and National Centre for Biomedical Engineering Sciences, National University of Ireland, Galway, Ireland

[3 ]Department of Obstetrics and Gynaecology, Clinical Sciences Institute, National University of Ireland, Galway, Ireland

Article

Publisher ID: 1477-7827-7-34

DOI: 10.1186/1477-7827-7-34

PMC ID: 2680410

PubMed ID: 19389232

SO-VID: 669521ea-ffbd-496c-84e8-1b892be0a9bf

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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

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Abstract

Objectives

Study Design

Results

Conclusion

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Most cited references 23

Short technical reports. Modification of the TRI reagent procedure for isolation of RNA from polysaccharide- and proteoglycan-rich sources.

Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial.

Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study.

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