Investigation of the effect of sildenafil citrate on flap survival and SOD, GPx antioxidant enzymes in random pattern skin flaps

Abstract

In this study, the effect of sildenafil citrate, a phosphodiesterase type 5 (PDE 5) enzyme inhibitor, on the survival area of random pattern skin flaps and the effect of superoxide dismutase (SOD) and glutathione peoxidase (GPx) enzyme activities were investigated. Sildenafil citrate increases the level of cyclic guanosine monophosphate (cGMP) by inhibiting PDE 5. This causes dilation of the vessels and increased blood flow. In the study, 42 Wistar albino female rats weighing between 200-250 g were used. Rats were divided into 3 groups as sham group (S), experimental group (E) and control group (C). Subgroups were formed as day 1, day 4 and day 7 in groups E and C. In group E, 9 mg/kg/day sildenafil citrate was given intraperitoneally. Tissue samples were taken from the base, centre and the farthest living area of the flap of the sacrificed rats. SOD and GPx enzyme activity values were determined in the tissue samples. When SOD and GPx activities were compared between the groups, the difference was not significant (p>0.05). When the surviving flap areas were compared between the groups, an increase in necrotic area in the C7 group flaps was remarkable. However, there was no statistical difference between the groups in terms of flap survival area percentages (p>0.05).

Keywords

• flap
• sildenafil citrate
• superoxide dismutase
• glutathione peroxidase

References

1. 1. Mathes SJ, Hansen SL. Flap Classification and Applications. In: Mathes Plastic Surgery. 2nd ed. Vol 1. Philadelphia: Saunders Elsevier; 2006. p. 365-481.
2. 2. Vedder NB. Flap Physiology. In: Mathes Plastic Surgery. 2nd ed. Vol 1. Philadelphia: Saunders Elsevier; 2006. p. 483-506.
3. 3. Galiano RD, Mustoe TA. Wound care. In: Grabb & Smith's Plastic Surgery. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 23-32.
4. 4. Taylor GI. The Blood Supply of The Skin. In: Grabb & Smith's Plastic Surgery. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 33-41.
5. 5. Achauer BM, Eriksson E, Guyuron B, Coleman JJ, Russell RC, Vander Kolk CA. Plastic Surgery: Indications, Operations, and Outcomes. Vol 1. St. Louis, Missouri: Mosby; 2000. p. 261-290.
6. 6. Saito I, Hasegawa T, Ueha T, Takeda D, Iwata E, Arimoto S, et al. Effect of local application of transcutaneous carbon dioxide on survival of random-pattern skin flaps. J Plast Reconstr Aesthet Surg. 2018;71(11):1644-1651.
7. 7. Bin C, Dingsheng L, Leyi C, Bin L, Yuting L, Liren W, et al. Beneficial effects of Xuebijing injection on random skin flap survival in rats. J Surg Res. 2015;196(2):421-426.
8. 8. Kayser MR, Hodges PL. Surgical Flaps. In: Selected Readings in Plastic Surgery. 1995;8(3):1-58.

9. 9. Chen X, Zhu X, Chen Y, Ruan Z, Zhang Y, Wu H, et al. Erastin promotes random-pattern skin flaps survival by inducing mTORC1-TFEB mediated autophagy. Biomed Pharm. 2024;177:116918.
10. 10. Chen Z, Wu H, Yang J, Li B, Ding J, Cheng S, et al. Activating Parkin-dependent mitophagy alleviates oxidative stress, apoptosis, and promotes random-pattern skin flaps survival. Commun Biol. 2022;5(1):616.
11. 11. Cai L, Xie L, Dong Q. Crocin enhances the viability of random pattern skin flaps: Involvement of enhancing angiogenesis and inhibiting oxidative stress. Am J Transl Med. 2020;12(6):2929.
12. 12. Jiang RH, Chen XK, Wang KY, Fu KJ, Dong CJ, Chen ZL, et al. Calycosin increases random-pattern skin flap survival by activating TFEB-mediated regulation of cell death. J Funct Foods. 2024;115:106087.
13. 13. Yin J, Zhuang J, Lv S, Mu Y. Study on a 65‐mer peptide mimetic enzyme with GPx and SOD dual function. J Mol Recognit. 2018;31(8):e2714.
14. 14. Schäfer M, Werner S. Oxidative stress in normal and impaired wound repair. Pharmacol Res. 2008;58(2):165-171.
15. 15. Alfei S, Marengo B, Zuccari G. Oxidative stress, antioxidant capabilities, and bioavailability: Ellagic acid or urolithins? Antioxidants. 2020;9(8):707.
16. 16. Jena AB, Samal RR, Bhol NK, Duttaroy AK. Cellular Red-Ox system in health and disease: The latest update. Biomed Pharm. 2023;162:114606.
17. 17. Demirci-Cekic S, Özkan G, Avan AN, Uzunboy S, Çapanoğlu E, Apak R. Biomarkers of oxidative stress and antioxidant defense. J Pharm Biomed Anal. 2022;209:114477.
18. 18. Borgstahl GE, Oberley-Deegan RE. Superoxide dismutases (SODs) and SOD mimetics. Antioxidants. 2018;7(11):156.
19. 19. Haida Z, Hakiman M. A comprehensive review on the determination of enzymatic assay and nonenzymatic antioxidant activities. Food Sci Nutr. 2019;7:1555-1563.
20. 20. Jena AB, Samal RR, Bhol NK, Duttaroy AK. Cellular Red-Ox system in health and disease: The latest update. Biomed Pharm. 2023;162:114606.
21. 21. Ighodaro OM, Akinloye OA. First line defense antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): Their fundamental role in the entire antioxidant defense grid. Alexandria J Med. 2018;54(4):287-293.
22. 22. Maurya SK, Tripathi A, Karuthapandi S, Singh HB. Synthesis and glutathione peroxidase (GPx)-like activity of selenocystine (SeC) bioconjugates of biotin and lipoic acid. Amino Acids. 2023;55(12):1981-1989.
23. 23. Trenz TS, Delaix CL, Turchetto-Zolet AC, Zamocky M, Lazzarotto F, Margis-Pinheiro M. Going forward and back: the complex evolutionary history of the GPx. Biology. 2021;10(11):1165.
24. 24. Kulshrestha S, Chawla R, Alam MT, Adhikari JS, Basu ME. Efficacy and dermal toxicity analysis of Sildenafil citrate based topical hydrogel formulation against traumatic wounds. Biomed Pharm. 2019;112:108571.
25. 25. Atipairin A, Chunhachaichana C, Nakpheng T, Changsan N, Srichana T, Sawatdee S. Development of a sildenafil citrate microemulsion-loaded hydrogel as a potential system for drug delivery to the penis and its cellular metabolic mechanism. Pharmaceutics. 2020;12(11):1055.
26. 26. Glossmann H, Petrischor G, Bartsch G. Molecular mechanisms of the effects of sildenafil. Exp Gerontol. 1999;34:305-318.
27. 27. Souza RA, Martinelli-Kläy CP, d’Acampora AJ, Bernardes GJ, Sgrott SM, Souza LA, et al. Effects of sildenafil and tadalafil on skin flap viability. Arch Dermatol Res. 2022;314(2):151-157.
28. 28. Ayyıldız A, Nuhoğlu B, Huri E, Uysal A, Üstün H, Germiyanoğlu C. Deneysel Çalışma: Flep Canlılığının Artırılmasında Lokal Sildenafil Sitrat (Sildegra®)’nın Etkinliği ve Doz Aralığının Saptanması. Türk Üroloji Dergisi. 2005;31(2):163-169.
29. 29. Tu Q, Liu S, Chen T, Li Z, Lin D. Effects of adiponectin on random pattern skin flap survival in rats. Int Immunopharmacol. 2019;76:105875.
30. 30. McFarlane RM, Heagy FC, Radin S, Aust JC, Wermuth RE. A study of the delay phenomenon in experimental pedicle flaps. Plast Reconstr Surg. 1965;35:245-262.
31. 31. McCord JM, Fridovich I. Superoxide dismutase: An enzymic function for erythrocuprein. J Biol Chem. 1969;244(22):6049-6055.
32. 32. Fhole L, Otting F. Superoxide dismutase assays. Methods Enzymol. 1984;105:93-104.
33. 33. Lawrence RA, Burk RF. Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun. 1976;71(4):925-958.
34. 34. Zhao H, Shi Q, Sun ZY, Yin GQ, Yang HL. Effect of natural hirudin on random pattern skin flap survival in a porcine model. J Int Med Res. 2012;40(6):2267-2273.
35. 35. Sarifakioğlu N, Gokrem S, Ateş L, Akbuga UB, Aslan G. The influence of sildenafil on random skin flap survival in rats: An experimental study. Br J Plast Surg. 2004;57:769-772.
36. 36. Ulusoy MG, Uysal A, Koçer U, Karaaslan Ö, Cuzdan SS, Ayyıldız A, Üstün H. Improved flap viability site-specific delivery of sildenafil citrate using fibrin glue. Ann Plast Surg. 2005;55:292-296.
37. 37. Hart K, Baur D, Hodam J, Lesoon-Wood L, Parham M, Keith K, et al. Short- and long-term effects of sildenafil on skin flap survival in rats. Laryngoscope. 2006;116(4):522-528.
38. 38. Serin M, Altinel D, Leblebici C, Biltekin B, Celikten M, Irmak F, Kurt S. Preoperative subcutaneous sildenafil injection increases random flap survival in rats. Acta Cir Bras. 2018;33:216-222.
39. 39. Baykan H, Ozyazgan I, Selçuk CT, Altıparmak M, Özköse M, Özyurt K. Effect of sildenafil citrate in nicotine-induced ischemia: An experimental study using a rat model. Can J Plast Surg. 2013;21(4):217-220.
40. 40. Kaya B, Cerkez C, Işılgan SE, Göktürk H, Yığman Z, Serel S, et al. Comparison of the effects of systemic sildenafil, tadalafil, and vardenafil treatments on skin flap survival in rats. J Plast Surg Hand Surg. 2015;49(6):358-362.
41. 41. Barral SM, Araujo ID, Vidigal PVT, Mayrink CAC, Araujo AD, Costa PRD. Effects of sildenafil on the viability of random skin flaps. Acta Cir Bras. 2011;26:314-319.
42. 42. Hafez MH, El-Kazaz SE. The impact of phosphodiesterase-5 inhibitor (sildenafil citrate) on some hippocampal neurotransmitters, oxidative stress status, minerals, and anxiety-like behavior in rats. J Adv Vet Anim Res. 2020;7(2):281.