Top

Published in:

Open Access 01-12-2009 | Research

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

Authors: Chrisen H Maharaj, Daniel O'Toole, Tadhg Lynch, John Carney, James Jarman, Brendan D Higgins, John J Morrison, John G Laffey

Published in: Reproductive Biology and Endocrinology | Issue 1/2009

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.

Available only for authorised users

Antoniu SA: Sildenafil citrate for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother. 2006, 7 (6): 825-828. 10.1517/14656566.7.6.825.CrossRefPubMed

Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G: Sildenafil citrate therapy for pulmonary arterial hypertension. The New England journal of medicine. 2005, 353 (20): 2148-2157. 10.1056/NEJMoa050010.CrossRefPubMed

Singh TP, Rohit M, Grover A, Malhotra S, Vijayvergiya R: A randomized, placebo-controlled, double-blind, crossover study to evaluate the efficacy of oral sildenafil therapy in severe pulmonary artery hypertension. American heart journal. 2006, 151 (4): 851-10.1016/j.ahj.2005.09.006. e851–855CrossRefPubMed

Sastry BK, Narasimhan C, Reddy NK, Raju BS: Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. Journal of the American College of Cardiology. 2004, 43 (7): 1149-1153. 10.1016/j.jacc.2003.10.056.CrossRefPubMed

Warnes CA: Pregnancy and pulmonary hypertension. Int J Cardiol. 2004, 97 (Suppl 1): 11-13. 10.1016/j.ijcard.2004.08.004.CrossRefPubMed

Lynch TD, Laffey JG: Sildenafil for pulmonary hypertension in pregnancy?. Anesthesiology. 2006, 104 (2): 382-10.1097/00000542-200602000-00037.CrossRefPubMed

Lacassie HJ, Germain AM, Valdes G, Fernandez MS, Allamand F, Lopez H: Management of Eisenmenger syndrome in pregnancy with sildenafil and L-arginine. Obstet Gynecol. 2004, 103 (5 Pt 2): 1118-1120.CrossRefPubMed

Molelekwa V, Akhter P, McKenna P, Bowen M, Walsh K: Eisenmenger's syndrome in a 27 week pregnancy – management with bosentan and sildenafil. Ir Med J. 2005, 98 (3): 87-88.PubMed

Dandel M, Lehmkuhl HB, Hetzer R: Advances in the medical treatment of pulmonary hypertension. Kidney Blood Press Res. 2005, 28 (5–6): 311-324. 10.1159/000090186.CrossRefPubMed

10.

Ghofrani HA, Wiedemann R, Rose F, Schermuly RT, Olschewski H, Weissmann N, Gunther A, Walmrath D, Seeger W, Grimminger F: Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet. 2002, 360 (9337): 895-900. 10.1016/S0140-6736(02)11024-5.CrossRefPubMed

11.

Villanueva-Garcia D, Mota-Rojas D, Hernandez-Gonzalez R, Sanchez-Aparicio P, Alonso-Spilsbury M, Trujillo-Ortega ME, Necoechea RR, Nava-Ocampo AA: A systematic review of experimental and clinical studies of sildenafil citrate for intrauterine growth restriction and pre-term labour. J Obstet Gynaecol. 2007, 27 (3): 255-259. 10.1080/01443610701194978.CrossRefPubMed

12.

Downing JW, Ramasubramanian R, Johnson RF, Minzter BH, Paschall RL, Sundell HW, Engelhardt B, Lewis R: Hypothesis: selective phosphodiesterase-5 inhibition improves outcome in preeclampsia. Med Hypotheses. 2004, 63 (6): 1057-1064. 10.1016/j.mehy.2004.03.042.CrossRefPubMed

13.

Wareing M, Myers JE, O'Hara M, Kenny LC, Taggart MJ, Skillern L, Machin I, Baker PN: Phosphodiesterase-5 inhibitors and omental and placental small artery function in normal pregnancy and pre-eclampsia. Eur J Obstet Gynecol Reprod Biol. 2006, 127 (1): 41-49. 10.1016/j.ejogrb.2004.06.014.CrossRefPubMed

14.

Chomczynski P, Mackey K: Modification of the Tri Reagent procedure for isolation of RNA from polysaccharide- and proteoglycan-rich sources. Biotechniques. 1995, 19: 924-927.

15.

Laffey JG, Honan D, Hopkins N, Hyvelin JM, Boylan JF, McLoughlin P: Hypercapnic acidosis attenuates endotoxin-induced acute lung injury. Am J Respir Crit Care Med. 2004, 169 (1): 46-56. 10.1164/rccm.200205-394OC.CrossRefPubMed

16.

Farragher R, Maharaj CH, Higgins BD, Crowe S, Burke P, Laffey CD, Flynn NM, Laffey JG: Sevoflurane and the feto-placental vasculature: the role of nitric oxide and vasoactive eicosanoids. Anesth Analg. 2008, 107 (1): 171-177. 10.1213/ane.0b013e318173465e.CrossRefPubMed

17.

Loughrey JP, Laffey JG, Moore BJ, Lynch F, Boylan JF, McLoughlin P: Interleukin-1b rapidly inhibits aortic endothelium-dependent relaxation by a DNA transcription-dependent mechanism. Critical Care Medicine. 2003, 31 (3): 910-5. 10.1097/01.CCM.0000053516.15727.E5.CrossRefPubMed

18.

Gleicher N, Midwall J, Hochberger D, Jaffin H: Eisenmenger's syndrome and pregnancy. Obstet Gynecol Surv. 1979, 34 (10): 721-741. 10.1097/00006254-197910000-00001.CrossRefPubMed

19.

Khan RN, Hamoud H, Warren A, Wong LF, Arulkumaran S: Relaxant action of sildenafil citrate (Viagra) on human myometrium of pregnancy. Am J Obstet Gynecol. 2004, 191 (1): 315-321. 10.1016/j.ajog.2003.11.005.CrossRefPubMed

20.

Mehats C, Schmitz T, Breuiller-Fouche M, Leroy MJ, Cabrol D: Should phosphodiesterase 5 selective inhibitors be used for uterine relaxation?. Am J Obstet Gynecol. 2006, 195 (1): 184-185. 10.1016/j.ajog.2005.12.006.CrossRefPubMed

21.

Buhimschi CS, Garfield RE, Weiner CP, Buhimschi IA: The presence and function of phosphodiesterase type 5 in the rat myometrium. Am J Obstet Gynecol. 2004, 190 (1): 268-274. 10.1016/j.ajog.2003.07.006.CrossRefPubMed

22.

Wareing M, Myers JE, O'Hara M, Baker PN: Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth restriction. J Clin Endocrinol Metab. 2005, 90 (5): 2550-2555. 10.1210/jc.2004-1831.CrossRefPubMed

23.

Sanchez-Aparicio P, Mota-Rojas D, Nava-Ocampo AA, Trujillo-Ortega ME, Alfaro-Rodriguez A, Arch E, Alonso-Spilsbury M: Effects of sildenafil on the fetal growth of guinea pigs and their ability to survive induced intrapartum asphyxia. Am J Obstet Gynecol. 2008, 198 (1): 127.e1-127.e6. 10.1016/j.ajog.2007.06.068.CrossRef

24.

Refuerzo JS, Sokol RJ, Aranda JV, Hallak M, Hotra JW, Kruger M, Sorokin Y: Sildenafil citrate and fetal outcome in pregnant rats. Fetal diagnosis and therapy. 2006, 21 (3): 259-263. 10.1159/000091352.CrossRefPubMed

25.

Sher G, Fisch JD: Effect of vaginal sildenafil on the outcome of in vitro fertilization (IVF) after multiple IVF failures attributed to poor endometrial development. Fertil Steril. 2002, 78 (5): 1073-1076. 10.1016/S0015-0282(02)03375-7.CrossRefPubMed

26.

Coppage KH, Sun X, Baker RS, Clark KE: Expression of phosphodiesterase 5 in maternal and fetal sheep. Am J Obstet Gynecol. 2005, 193 (3 Pt 2): 1005-1010. 10.1016/j.ajog.2005.05.054.CrossRefPubMed

27.

Boyce EG, Umland EM: Sildenafil citrate: a therapeutic update. Clinical therapeutics. 2001, 23 (1): 2-23. 10.1016/S0149-2918(01)80027-8.CrossRefPubMed

Title: Effects and mechanisms of action of sildenafil citrate in human chorionic arteries
Authors: Chrisen H Maharaj
Daniel O'Toole
Tadhg Lynch
John Carney
James Jarman
Brendan D Higgins
John J Morrison
John G Laffey
Publication date: 01-12-2009
Publisher: BioMed Central
Published in: Reproductive Biology and Endocrinology / Issue 1/2009
Electronic ISSN: 1477-7827
DOI: https://doi.org/10.1186/1477-7827-7-34

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Objectives

Study Design

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objectives

Study Design

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2009

Isolation and characterization of a strain of Lichtheimia corymbifera (ex Absidia corymbifera) from a case of bovine abortion

Transforming growth factor beta isoforms regulation of Akt activity and XIAP levels in rat endometrium during estrous cycle, in a model of pseudopregnancy and in cultured decidual cells

Ets-2 and p53 mediate cAMP-induced MMP-2 expression, activity and trophoblast invasion

Modulation of Apolipoprotein D levels in human pregnancy and association with gestational weight gain

Early-cleavage is a reliable predictor for embryo implantation in the GnRH agonist protocols but not in the GnRH antagonist protocols

A retrospective study on IVF outcome in euthyroid patients with anti-thyroid antibodies: effects of levothyroxine, acetyl-salicylic acid and prednisolone adjuvant treatments