Iranian Journal of Veterinary Surgery

Iranian Journal of Veterinary Surgery

Investigating the Potential of Sildenafil in Mitigating Fetal Growth Restriction: A Study on Experimentally Restricted Fetal Growth Rats

Document Type : Original Article

Authors
Ghasem Akbari 1
Siamak Kazemi-Darabadi 2
Mehdi Basaki 1
Meysam Karami 3
Pardis Elmdoustazar 4
1 Department of Basic Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran.
2 Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran.
3 Graduated from Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran.
4 Department of Pharmacognosy, Faculty of Pharmacy, Atatürk University, Erzurum, Turkey.
10.30500/ivsa.2024.447174.1393
Abstract
Intrauterine growth restriction (IUGR) is a common pregnancy complication. Sildenafil is also emerging as a potential candidate for the treatment of IUGR. The objective of this study was to evaluate the effect of sildenafil in the prevention of IUGR due to impaired uterine blood supply in rats. Female rats were randomly divided into three groups once the pregnancy was confirmed. The control group received normal saline, and the Sild40 and Sild80 groups received 40 and 80 mg/kg of sildenafil. The uterine artery was clamped for 60 minutes on day 17 of gestation. Amniotic fluid was collected from viable and nonviable fetuses and subjected to metabolite measurement. The live and dead fetuses, the weight and size of the placenta and fetus were counted during the first celiotomy and Cesarean section on day 21 of gestation. 45%, 90%, and 83.88% of fetuses were alive in the Control, Sild40, and Sild80 groups, respectively. No significant difference in placenta weight, fetus weight, and fetus length, were found. However, differences of the liver-to-body and brain-to-body ratio were significant. Amniotic fluid metabolites showed no significant difference between the groups except for lactate. In addition, post-ischemia glucose was reduced significantly in the Control group. Furthermore, pyruvate was significantly increased and lactate was significantly reduced post-ischemia in the Sild40 and Sild80 groups, respectively. In conclusion, sildenafil seems to counteract the effects of uterine ischemia in pregnant rats and prevent IUGR which results from temporary occlusion of the uterine artery.
Keywords
Intrauterine growth restriction
Fetal growth restriction
Sildenafil
Rat
Subjects
  1. Gardosi J, Madurasinghe V, Williams M, Malik A, Francis A. Maternal and fetal risk factors for stillbirth: population based study. BMJ. 2013; 24: 346. doi: 1136/bmj.f108
  2. Pilliod RA, Cheng YW, Snowden JM, Doss AE, Caughey AB. The risk of intrauterine fetal death in the small-for-gestational-age fetus. American Journal of Obstetrics and Gynecology. 2012; 207(4): 318.e1-318.e6. doi: 10.1016/j.ajog.2012.06.039
  3. Easter SR, Eckert LO, Boghossian N, Spencer R, Oteng-Ntim E, Ioannou C, Patwardhan M, Harrison MS, Khalil A, Gravett M, Goldenberg R. Fetal growth restriction: case definition & guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2017; 35: 6546-6554. doi: 10.1016/j.vaccine.2017.01.042
  4. Singh S, Sensharma GC, Chinara PK. Placental changes in rat following experimental ischaemic hypoxia. Indian Journal of Medical Research. 1983; 77: 144-149.
  5. ElHady AK, El-Gamil DS, Abdel-Halim M, Abadi AH. Advancements in phosphodiesterase 5 inhibitors: unveiling present and future perspectives. Pharmaceuticals. 2023; 16(9): 1266. doi: 10.3390/ph16091266
  6. Mayor S. Pfizer will not apply for a licence for sildenafil for women. BMJ. 2004; 328(7439): 542. doi: 10.1136/bmj.328.7439.542
  7. Belik J. Sildenafil administration during pregnancy increases fetal rat weight gain. Federation of American Societies for Experimental Biology Journal. 2005; 19(5): A1248-A12480
  8. Buhimschi CS, Garfield RE, Weiner CP, Buhimschi IA. The presence and function of phosphodiesterase type 5 in the rat myometrium. American Journal of Obstetrics and Gynecology. 2004; 190(1): 268-274. doi: 10.1016/j.ajog.2003.07.006
  9. Sánchez-Aparicio P, Mota-Rojas D, Nava-Ocampo AA, Trujillo-Ortega ME, Alfaro-Rodríguez A, Arch E, Alonso-Spilsbury M. Effects of sildenafil on the fetal growth of guinea pigs and their ability to survive induced intrapartum asphyxia. American Journal of Obstetrics and Gynecology. 2008; 198(1): 127.e1-127.e6. doi: 10.1016/j.ajog.2007.06.068
  10. Agha AM, Taha RA. Sildenafil inhibits agonist-evoked rat uterine contractility: influence of guanylyl cyclase inhibition. European Journal of Pharmacology. 2001; 428(3): 343-348. doi: 10.1016/S0014-2999(01)01351-6
  11. Kazemi-Darabadi S, Nayebzadeh R, Shahbazfar AA, Kazemi-Darabadi F, Fathi E. Curcumin and nanocurcumin oral supplementation improve muscle healing in a rat model of surgical muscle laceration. Bulletin of Emergency and Trauma. 2019; 7(3): 292–299. doi: 10.29252/beat-0703013
  12. Kazemi-Darabadi S, Akbari G. Evaluation of magnesium sulfate effects on fetus development in experimentally induced surgical fetal growth restriction in rat. Journal of Maternal-Fetal and Neonatal Medicine. 2020; 33(14): 2459-2465. doi: 10.1080/14767058.2018.1554048
  13. Janot M, Cortes-Dubly ML, Rodriguez S, Huynh-Do U. Bilateral uterine vessel ligation as a model of intrauterine growth restriction in mice. Reproductive Biology and Endocrinology. 2014; 12(1): 62. doi: 10.1186/1477-7827-12-62
  14. Vuguin PM. Animal models for small for gestational age and fetal programing of adult disease. Hormone Research in Paediatrics. 2007; 68(3): 113-123. doi: 10.1159/000100545
  15. Neitzke U, Harder T, Schellong K, Melchior K, Ziska T, Rodekamp E, Dudenhausen JW, Plagemann A. Intrauterine growth restriction in a rodent model and developmental programming of the metabolic syndrome: a critical appraisal of the experimental evidence. Placenta. 2008; 29(3): 246-254. doi: 10.1016/j.placenta.2007.11.014
  16. Wigglesworth JS. Fetal growth retardation. Animal model: uterine vessel ligation in the pregnant rat. American Journal of Pathology. 1974; 77(2): 347.
  17. Tanaka M, Natori M, Ishimoto H, Miyazaki T, Kobayashi T, Nozawa S. Experimental growth retardation produced by transient period of uteroplacental ischemia in pregnant Sprague-Dawley rats. American Journal of Obstetrics and Gynecology. 1994; 171(5): 1231-1234. doi: 10.1016/0002-9378(94)90138-4
  18. Price WA, Rong L, Stiles AD, D'ercole AJ. Changes in IGF-I and-II, IGF binding protein, and IGF receptor transcript abundance after uterine artery ligation. Pediatric Research. 1992; 32(3): 291-295.
  19. Zoma W, Baker RS, Friedman A, Clark K. Sildenafil citrate (Viagra) increases uterine blood flow and potentiates estrogen-induced vasodilation. American Journal of Obstetrics and Gynecology. 2004; 190: 1291–1297. doi: 10.1016/j.ajog.2003.12.021
  20. Abbott D, Comby P, Charuel C, Graepel P, Hanton G, Leblanc B, Lodola A, Longeart L, Paulus G, Peters C, Stadler J. Preclinical safety profile of sildenafil. International Journal of Impotence Research. 2004; 16(6): 498-504. doi: 10.1038/sj.ijir.3901232
  21. 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. doi: 10.1159/000091352
  22. Sher G, Fisch JD. Vaginal sildenafil (Viagra): a preliminary report of a novel method to improve uterine artery blood flow and endometrial development in patients undergoing IVF. Human Reproduction. 2000; 15(4): 806-809. doi: 10.1093/humrep/15.4.806
  23. Nassar AH, Masrouha KZ, Itani H, Abi Nader K, Usta IM. Effects of sildenafil in Nω-nitro-L-arginine methyl ester–induced intrauterine growth restriction in a rat model. American Journal of Perinatology. 2012; 29(6): 429-434. doi: 10.1055/s-0032-1304823
  24. Dilworth M, Andersson I, Cowley E, Renshall L, Baker P, Greenwood S, Sibley C, Wareing M. Sildenafil Citrate Increases Fetal and Placental Weight in the Placental Specific Igf2 Knockout (P0) Mouse. Placenta. 2013; 9(34): A21-A22. doi: 10.1016/j.placenta.2013.06.065
  25. Herraiz S, Pellicer B, Serra V, Cauli O, Cortijo J, Felipo V, Pellicer A. Sildenafil citrate improves perinatal outcome in fetuses from pre‐eclamptic rats. British Journal of Obstetrics and Gynaecology. 2012; 119(11): 1394-1402. doi: 10.1111/j.1471-0528.2012.03430.x
  26. Maharaj CH, O'Toole D, Lynch T, Carney J, Jarman J, Higgins BD, Morrison JJ, Laffey JG. Effects and mechanisms of action of sildenafil citrate in human chorionic arteries. Reproductive Biology and Endocrinology. 2009; 7: 1-0. doi: 10.1186/1477-7827-7-34
  27. Wareing M, Myers JE, O’Hara M, Baker PN. Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth restriction. Journal of Clinical Endocrinology and Metabolism. 2005; 90(5): 2550-2555. doi: 10.1210/jc.2004-1831
  28. 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. European Journal of Obstetrics and Gynecology and Reproductive Biology. 2006; 127(1): 41-49. doi: 10.1016/j.ejogrb.2004.06.014
  29. Khan RN, Hamoud H, Warren A, Wong LF, Arulkumaran S. Relaxant action of sildenafil citrate (Viagra) on human myometrium of pregnancy. American Journal of Obstetrics and Gynecology. 2004; 191(1): 315-321. doi: 10.1016/j.ajog.2003.11.005
  30. Trapani Jr A, Gonçalves LF, Trapani TF, Franco MJ, Galluzzo RN, Pires MM. Comparison between transdermal nitroglycerin and sildenafil citrate in intrauterine growth restriction: effects on uterine, umbilical and fetal middle cerebral artery pulsatility indices. Ultrasound in Obstetrics and Gynecology. 2016; 48(1): 61-65. doi: 10.1002/uog.15673
  31. Orczyk-Pawilowicz M, Jawien E, Deja S, Hirnle L, Zabek A, Mlynarz P. Metabolomics of human amniotic fluid and maternal plasma during normal pregnancy. PloS One. 2016; 11(4): 152740. doi: 10.1371/journal.pone.0152740
  32. Di Luigi L, Sansone M, Sansone A, Ceci R, Duranti G, Borrione P, Crescioli C, Sgrò P, Sabatini S. Phosphodiesterase type 5 inhibitors, sport and doping. Current Sports Medicine Reports. 2017; 16(6): 443-447. doi: 10.1249/jsr.0000000000000422
  33. AlRuwaili R, Al-Kuraishy HM, Alruwaili M, Khalifa AK, Alexiou A, Papadakis M, Saad HM, Batiha GE. The potential therapeutic effect of phosphodiesterase 5 inhibitors in the acute ischemic stroke (AIS). Molecular and Cellular Biochemistry. 2023; 479: 1267–1278. doi: 10.1007/s11010-023-04793-1
  34. Sabatini S, Sgrò P, Duranti G, Ceci R, Di Luigi L. Tadalafil alters energy metabolism in C2C12 skeletal muscle cells. Acta Biochimica Polonica. 2011; 58(2): 237-242.
  35. Chhonker SK, Rawat D, Koiri RK. Repurposing PDE5 inhibitor tadalafil and sildenafil as anticancer agent against hepatocellular carcinoma via targeting key events of glucose metabolism and multidrug resistance. Journal of Biochemical and Molecular Toxicology. 2022; 36(8): e23100. doi: 10.1002/jbt.23100

  • Receive Date 05 March 2024
  • Revise Date 27 April 2024
  • Accept Date 02 June 2024
  • First Publish Date 02 June 2024