Download PDF
Am J Perinatol 2012; 29(06): 429-434
DOI: 10.1055/s-0032-1304823
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Effects of Sildenafil in Nω-Nitro-l-Arginine Methyl Ester–Induced Intrauterine Growth Restriction in a Rat Model

Anwar H. Nassar
1   Department of Obstetrics and Gynecology, American University of Beirut-Medical Center, Beirut, Lebanon
,
Karim Z. Masrouha
1   Department of Obstetrics and Gynecology, American University of Beirut-Medical Center, Beirut, Lebanon
,
Hana Itani
1   Department of Obstetrics and Gynecology, American University of Beirut-Medical Center, Beirut, Lebanon
,
Khalil Abi Nader
1   Department of Obstetrics and Gynecology, American University of Beirut-Medical Center, Beirut, Lebanon
,
Ihab M. Usta
1   Department of Obstetrics and Gynecology, American University of Beirut-Medical Center, Beirut, Lebanon
› Author Affiliations
Further Information

Publication History

12 August 2011

08 November 2011

Publication Date:
07 March 2012 (online)

    Permissions and Reprints

Abstract

Objective To assess the effect of sildenafil citrate in a rat model of Nω-nitro-l-arginine methyl ester (L-NAME)-induced intrauterine growth restriction (IUGR).

Study Design An in vivo experimental study was conducted where 40 pregnant Sprague-Dawley rats were randomly assigned to receive either: (1) control, (2) L-NAME 50 mg/kg/d by gavage (days 14 to 19), (3) L-NAME and sildenafil 15 mg/kg/d by gavage, or (4) sildenafil (days 14 to 21). On day 21, a hysterotomy was performed and all fetuses (live and dead) were counted, examined, and weighed. The primary outcome measure was the difference in pup birth weight.

Results The median number of live pups per dam was 11.5 (range: 1 to 15), 13.5 (2 to 17), 13.5 (7 to 16), and 11.5 (4 to 17) in controls, L-NAME, sildenafil, and combined drug groups, respectively (p = 0.02). Rats treated with L-NAME had a significantly higher number of stillbirths compared with control (p = 0.013) and sildenafil (p = 0.008) groups. L-NAME reduced pup birth weight compared with controls (4.53 ± 1.49 versus 5.65 ± 1.63 g, p < 0.001); this effect was more pronounced in the L-NAME and sildenafil groups (3.37 ± 1.25 g, p < 0.001).

Conclusion Our data indicate that sildenafil citrate does not ameliorate L-NAME-induced IUGR, and in the doses utilized in this study might even have a synergistic negative effect on pup birth weight.

Keywords

intrauterine growth restriction - preeclampsia - rat model - sildenafil citrate - L-NAME
 

  • References

  • 1 Romo A, Carceller R, Tobajas J. Intrauterine growth retardation (IUGR): epidemiology and etiology. Pediatr Endocrinol Rev 2009; 6 (Suppl. 03) 332-336
    PubMedGoogle Scholar
  • 2 Gagnon R. Placental insufficiency and its consequences. Eur J Obstet Gynecol Reprod Biol 2003; 110 (Suppl. 01) S99-S107
    CrossrefPubMedGoogle Scholar
  • 3 Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A ; The Vermont Oxford Network. Morbidity and mortality among very-low-birth-weight neonates with intrauterine growth restriction. Am J Obstet Gynecol 2000; 182 (1 Pt 1) 198-206
    CrossrefPubMedGoogle Scholar
  • 4 van Wassenaer A. Neurodevelopmental consequences of being born SGA. Pediatr Endocrinol Rev 2005; 2: 372-377
    PubMedGoogle Scholar
  • 5 Barker DJ, Eriksson JG, Forsén T, Osmond C. Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol 2002; 31: 1235-1239
    CrossrefPubMedGoogle Scholar
  • 6 Takei H, Nakai Y, Hattori N , et al. The herbal medicine Toki-shakuyaku-san improves the hypertension and intrauterine growth retardation in preeclampsia rats induced by Nomega-nitro-L-arginine methyl ester. Phytomedicine 2004; 11: 43-50
    CrossrefPubMedGoogle Scholar
  • 7 Pan SL, Yu YH. [Establishment of a new rat model of intrauterine growth retardation]. J First Mil Med Univ 2002; 22: 339-340, 343
    PubMedGoogle Scholar
  • 8 Sasaki J, Fukami E, Mimura S, Hayakawa M, Kitoh J, Watanabe K. Abnormal cerebral neuronal migration in a rat model of intrauterine growth retardation induced by synthetic thromboxane A(2). Early Hum Dev 2000; 58: 91-99
    CrossrefPubMedGoogle Scholar
  • 9 Regnault TR, Orbus RJ, de Vrijer B , et al. Placental expression of VEGF, PlGF and their receptors in a model of placental insufficiency-intrauterine growth restriction (PI-IUGR). Placenta 2002; 23: 132-144
    CrossrefPubMedGoogle Scholar
  • 10 Rutland CS, Mukhopadhyay M, Underwood S, Clyde N, Mayhew TM, Mitchell CA. Induction of intrauterine growth restriction by reducing placental vascular growth with the angioinhibin TNP-470. Biol Reprod 2005; 73: 1164-1173
    CrossrefPubMedGoogle Scholar
  • 11 Mayr AJ, Lederer W, Wolf HJ, Dünser M, Pfaller K, Mörtl MG. Morphologic changes of the uteroplacental unit in preeclampsia-like syndrome in rats. Hypertens Pregnancy 2005; 24: 29-37
    PubMedGoogle Scholar
  • 12 Buhimschi IA, Shi SQ, Saade GR, Garfield RE. Marked variation in responses to long-term nitric oxide inhibition during pregnancy in outbred rats from two different colonies. Am J Obstet Gynecol 2001; 184: 686-693
    CrossrefPubMedGoogle Scholar
  • 13 Villanueva-García D, Mota-Rojas D, Hernández-González R , et al. A systematic review of experimental and clinical studies of sildenafil citrate for intrauterine growth restriction and pre-term labour. J Obstet Gynaecol 2007; 27: 255-259
    CrossrefPubMedGoogle Scholar
  • 14 Zoma WD, Baker RS, Clark KE. Effects of combined use of sildenafil citrate (Viagra) and 17beta-estradiol on ovine coronary and uterine hemodynamics. Am J Obstet Gynecol 2004; 190: 1291-1297
    PubMedGoogle Scholar
  • 15 Refuerzo JS, Sokol RJ, Aranda JV , et al. Sildenafil citrate and fetal outcome in pregnant rats. Fetal Diagn Ther 2006; 21: 259-263
    CrossrefPubMedGoogle Scholar
  • 16 Lacassie HJ, Germain AM, Valdés G, Fernández MS, Allamand F, López H. Management of Eisenmenger syndrome in pregnancy with sildenafil and L-arginine. Obstet Gynecol 2004; 103 (5 Pt 2) 1118-1120
    CrossrefPubMedGoogle Scholar
  • 17 Lynch TD, Laffey JG. Sildenafil for pulmonary hypertension in pregnancy?. Anesthesiology 2006; 104 (2) 382
    CrossrefPubMedGoogle Scholar
  • 18 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: 87-88
    PubMedGoogle Scholar
  • 19 Briganti A, Salonia A, Deho’ F , et al. Clinical update on phosphodiesterase type-5 inhibitors for erectile dysfunction. World J Urol 2005; 23: 374-384
    CrossrefPubMedGoogle Scholar
  • 20 Noori S, Friedlich P, Wong P, Garingo A, Seri I. Cardiovascular effects of sildenafil in neonates and infants with congenital diaphragmatic hernia and pulmonary hypertension. Neonatology 2007; 91: 92-100
    CrossrefPubMedGoogle Scholar
  • 21 Leibovitch L, Matok I, Paret G. Therapeutic applications of sildenafil citrate in the management of paediatric pulmonary hypertension. Drugs 2007; 67: 57-73
    CrossrefPubMedGoogle Scholar
  • 22 Nagdyman N, Fleck T, Bitterling B , et al. Influence of intravenous sildenafil on cerebral oxygenation measured by near-infrared spectroscopy in infants after cardiac surgery. Pediatr Res 2006; 59: 462-465
    CrossrefPubMedGoogle Scholar
  • 23 Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol 1989; 161: 1200-1204
    CrossrefPubMedGoogle Scholar
  • 24 Miller SL, Loose JM, Jenkin G, Wallace EM. The effects of sildenafil citrate (Viagra) on uterine blood flow and well being in the intrauterine growth-restricted fetus. Am J Obstet Gynecol 2009; 200: 102 , e1–e7
    PubMedGoogle Scholar
  • 25 Pinheiro da Costa BE, Scocco C, Poli de Figueiredo CE, Guimarães JA. Increased serum phosphodiesterase activity in women with pre-eclampsia. BJOG 2006; 113: 577-579
    CrossrefPubMedGoogle Scholar
  • 26 Wareing M, Myers JE, O’Hara M , et al. Phosphodiesterase-5 inhibitors and omental and placental small artery function in normal pregnancy and pre-eclampsia. Eur J Obstet Gynecol Reprod Biol 2006; 127: 41-49
    CrossrefPubMedGoogle Scholar
  • 27 Wareing M, Myers JE, O’Hara M, Baker PN. Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth restriction. J Clin Endocrinol Metab 2005; 90: 2550-2555
    CrossrefPubMedGoogle Scholar
  • 28 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: 315-321
    CrossrefPubMedGoogle Scholar
  • 29 Sánchez-Aparicio P, Mota-Rojas D, Nava-Ocampo AA , et al. Effects of sildenafil on the fetal growth of guinea pigs and their ability to survive induced intrapartum asphyxia. Am J Obstet Gynecol 2008; 198: 127, e1–e6
    PubMedGoogle Scholar
  • 30 Sasser JM, Baylis C. Effects of sildenafil on maternal hemodynamics and fetal growth in normal rat pregnancy. Am J Physiol Regul Integr Comp Physiol 2010; 298: R433-R438
    CrossrefPubMedGoogle Scholar
  • 31 Ramesar SV, Mackraj I, Gathiram P, Moodley J. Sildenafil citrate improves fetal outcomes in pregnant, L-NAME treated, Sprague-Dawley rats. Eur J Obstet Gynecol Reprod Biol 2010; 149: 22-26
    CrossrefPubMedGoogle Scholar
  • 32 Pellicer B, Herraiz S, Cauli O , et al. Haemodynamic effects of long-term administration of sildenafil in normotensive pregnant and non-pregnant rats. BJOG 2011; 118: 615-623
    CrossrefPubMedGoogle Scholar
  • 33 Thaete LG, Kushner DM, Dewey ER, Neerhof MG. Endothelin and the regulation of uteroplacental perfusion in nitric oxide synthase inhibition-induced fetal growth restriction. Placenta 2005; 26: 242-250
    CrossrefPubMedGoogle Scholar
  • 34 Sellman JE, DeRuisseau KC, Betters JL , et al. In vivo inhibition of nitric oxide synthase impairs upregulation of contractile protein mRNA in overloaded plantaris muscle. J Appl Physiol 2006; 100: 258-265
    CrossrefPubMedGoogle Scholar
  • 35 Bahtiyar MO, Buhimschi C, Ravishankar V , et al. Contrasting effects of chronic hypoxia and nitric oxide synthase inhibition on circulating angiogenic factors in a rat model of growth restriction. Am J Obstet Gynecol 2007; 196: 72, e1–e6
    PubMedGoogle Scholar
  • 36 Buhimschi C, Buhimschi I, Yallampalli C, Chwalisz K, Garfield RE. Contrasting effects of diethylenetriamine-nitric oxide, a spontaneously releasing nitric oxide donor, on pregnant rat uterine contractility in vitro versus in vivo. Am J Obstet Gynecol 1997; 177: 690-701
    CrossrefPubMedGoogle Scholar
  • 37 Nicolaides KH, Campbell S, Bradley RJ, Bilardo CM, Soothill PW, Gibb D. Maternal oxygen therapy for intrauterine growth retardation. Lancet 1987; 1: 942-945
    CrossrefPubMedGoogle Scholar
  • 38 Battaglia C, Artini PG, D’Ambrogio G, Galli PA, Segre A, Genazzani AR. Maternal hyperoxygenation in the treatment of intrauterine growth retardation. Am J Obstet Gynecol 1992; 167: 430-435
    CrossrefPubMedGoogle Scholar
  • 39 Say L, Gülmezoglu AM, Hofmeyr GJ. Maternal oxygen administration for suspected impaired fetal growth. Cochrane Database Syst Rev 2003; CD000137
    PubMedGoogle Scholar
  • 40 ECPPA Collaborative Group. ECPPA: randomised trial of low dose aspirin for the prevention of maternal and fetal complications in high risk pregnant women. ECPPA (Estudo Colaborativo para Prevenção da Pré-eclampsia com Aspirina) Collaborative Group. Br J Obstet Gynaecol 1996; 103: 39-47
    PubMedGoogle Scholar
  • 41 Duley L, Henderson-Smart DJ, Knight M, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2004; (1) CD004659
    PubMedGoogle Scholar
  • 42 Takei H, Iizuka S, Yamamoto M, Takeda S, Yamamoto M, Arishima K. The herbal medicine Tokishakuyakusan increases fetal blood glucose concentrations and growth hormone levels and improves intrauterine growth retardation induced by N(omega)-nitro-L-arginine methyl ester. J Pharmacol Sci 2007; 104: 319-328
    CrossrefPubMedGoogle Scholar
  • 43 Tsukimori K, Komatsu H, Fukushima K, Kaku T, Nakano H, Wake N. Inhibition of nitric oxide synthetase at mid-gestation in rats is associated with increases in arterial pressure, serum tumor necrosis factor-alpha, and placental apoptosis. Am J Hypertens 2008; 21: 477-481
    CrossrefPubMedGoogle Scholar
  • 44 Chen D, Wang H, Huang H, Dong M. Vascular endothelial growth factor attenuates Nomega-nitro-L-arginine methyl ester-induced preeclampsia-like manifestations in rats. Clin Exp Hypertens 2008; 30: 606-615
    CrossrefPubMedGoogle Scholar