CC BY-NC-ND 4.0 · Indian J Plast Surg 2013; 46(01): 075-081
DOI: 10.4103/0970-0358.113714
Original Article
Association of Plastic Surgeons of India

Tadalafil significantly reduces ischemia reperfusion injury in skin island flaps

Oguz Kayiran
Department of Plastic and Reconstructive Surgery Clinic, Izmir Ekol KBB Hospital
,
Suat S. Cuzdan
Sanmed Hospital, Sanliurfa
,
Afsin Uysal
TOBB ETU Hospital
,
Ugur Kocer
Ankara Training and Research Hospital, Ankara, Turkey
› Author Affiliations
Further Information

Publication History

Publication Date:
07 October 2019 (online)

ABSTRACT

Introduction: Numerous pharmacological agents have been used to enhance the viability of flaps. Ischemia reperfusion (I/R) injury is an unwanted, sometimes devastating complication in reconstructive microsurgery. Tadalafil, a specific inhibitor of phosphodiesterase type 5 is mainly used for erectile dysfunction, and acts on vascular smooth muscles, platelets and leukocytes. Herein, the protective and therapeutical effect of tadalafil in I/R injury in rat skin flap model is evaluated. Materials and Methods: Sixty epigastric island flaps were used to create I/R model in 60 Wistar rats (non-ischemic group, ischemic group, medication group). Biochemical markers including total nitrite, malondialdehyde (MDA) and myeloperoxidase (MPO) were analysed. Necrosis rates were calculated and histopathologic evaluation was carried out. Results: MDA, MPO and total nitrite values were found elevated in the ischemic group, however there was an evident drop in the medication group. Histological results revealed that early inflammatory findings (oedema, neutrophil infiltration, necrosis rate) were observed lower with tadalafil administration. Moreover, statistical significance (P < 0.05) was recorded. Conclusions: We conclude that tadalafil has beneficial effects on epigastric island flaps against I/R injury.

 
  • 1 Carroll WR, Esclamado RM. Ischemia/reperfusion injury in microvascular surgery. Head Neck 2000;22:700-13.
  • 2 al-Qattan MM. Ischaemia-reperfusion injury. Implications for the hand surgeon. J Hand Surg Br 1998;23:570-3.
  • 3 Kulkarni SK, Patil CS. Phosphodiesterase 5 enzyme and its inhibitors: Update on pharmacological and therapeutical aspects. Methods Find Exp Clin Pharmacol 2004;26:789-99.
  • 4 Li Z, Xi X, Gu M, Feil R, Ye RD, Eigenthaler M, et al. A stimulatory role for cGMP-dependent protein kinase in platelet activation. Cell 2003;112:77-86.
  • 5 Petry JJ, Wortham KA. The anatomy of the epigastric flap in the experimental rat. Plast Reconstr Surg 1984;74:410-3.
  • 6 Gideroglu K, Yilmaz F, Aksoy F, Bugdayci G, Saglam I, Yimaz F. Montelukast protects axial pattern rat skin flaps against ischemia/reperfusion injury. J Surg Res 2009;157:181-6.
  • 7 Mollnes TE, Song WC, Lambris JD. Complement in inflammatory tissue damage and disease. Trends Immunol 2002;23:61-4.
  • 8 Anaya-Prado R, Toledo-Pereyra LH, Lentsch AB, Ward PA. Ischemia/reperfusion injury. J Surg Res 2002;105:248-58.
  • 9 Lefer AM, Lefer DJ. The role of nitric oxide and cell adhesion molecules on the microcirculation in ischaemia-reperfusion. Cardiovasc Res 1996;32:743-51.
  • 10 McVary KT, Monnig W, Camps JL Jr, Young JM, Tseng LJ,van den Ende G. Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: A randomized, double-blind trial. J Urol 2007; 177:1071-7.
  • 11 Arikan DC, Bakan V, Kurutas EB, Sayar H, Coskun A. Protective effect of tadalafil on ischemia/reperfusion injury of rat ovary. J Pediatr Surg 2010;45:2203-9.
  • 12 Serarslan Y, Yönden Z, Ozgiray E, Oktar S, Güven EO, Söğüt S, et al. Protective effects of tadalafil on experimental spinal cord injury in rats. J Clin Neurosci 2010;17:349-52.
  • 13 Beheshtian A, Salmasi AH, Payabvash S, Kiumehr S, Ghazinezami B, Rahimpour S, et al. Protective effects of sildenafil administration on testicular torsion/detorsion damage in rats. World J Urol 2008;26:197-202.
  • 14 Weiss B. Differential activation and inhibition of the multiple forms of cyclic nucleotide phosphodiesterase. Adv Cyclic Nucleotide Res 1975;5:195-211.
  • 15 Freitas FA, Piccinato CE, Cherri J, Marchesan WG. Effects of pentoxyfilline and heparin on reperfusion injury island skin flaps in rats exposed to tobacco. J Surg Res 2010;164:139-45.
  • 16 Fertel R, Weiss B. Properties and drug responsiveness of cyclic nucleotide phosphodiesterases of rat lung. Mol Pharmacol 1976;12:678-87.
  • 17 Weiss B, Hait WN. Selective cyclic nucleotide phosphodiesterase inhibitors as potential therapeutic agents. Annu Rev Pharmacol Toxicol 1977;17:441-77.
  • 18 Sáenz de Tejada I, Anglin G, Knight JR, Emmick JT. Effects of tadalafil on erectile dysfunction in men with diabetes. Diabetes Care 2002;25:2159-64.
  • 19 Behrend L, Vibe-Petersen J, Perrild H. Sildenafil in the treatment of erectile dysfunction in men with diabetes: Demand, efficacy and patient satisfaction. Int J Impot Res 2005;17:264-9.
  • 20 Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med 1998;338:1397-404.
  • 21 Kovanecz I, Rambhatla A, Ferrini MG, Vernet D, Sanchez S, Rajfer J, et al. Chronic daily tadalafil prevents the corporal fibrosis and veno-occlusive dysfunction that occurs after cavernosal nerve resection. BJU Int 2008;101:203-10.
  • 22 Filippi S, Morelli A, Sandner P, Fibbi B, Mancina R, Marini M, et al. Characterization and functional role of androgen-dependent PDE5 activity in the bladder. Endocrinology 2007;148:1019-29.
  • 23 Sairam K, Kulinskaya E, McNicholas TA, Boustead GB, Hanbury DC. Sildenafil influences lower urinary tract symptoms. BJU Int 2002;90:836-9.
  • 24 Eskitascioglu T, Karaci S, Canoz O, Kılıc E, Gunay GK. The impact of lidocaine on flap survival following reperfusion injury. J Surg Res 2011;167:323-8.
  • 25 Uygur F, Noyan N, Hahaolu A. The effect of simvastatin on the survival of ischaemic skin flap: An experimental study in rats. J Plast Reconstr Aesthet Surg 2010;63:1723-32.
  • 26 Aydogan H, Gurlek A, Parlakpinar H, Askar I, Bay-Karabulut A, Aydogan N, et al. Beneficial effects of caffeic acid phenethyl ester (CAPE) on the ischaemia-reperfusion injury in rat skin flaps. J Plast Reconstr Aesthet Surg 2007;60:563-8.
  • 27 Gurlek A, Celik M, Parlakpinar H, Aydogan H, Bay-Karabulut A. The protective effect of melatonin on ischemia-reperfusion injury in the groin (inferior epigastric) flap model in rats. J Pineal Res 2006;40:312-7.
  • 28 Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124-36.
  • 29 Glazier SS, O′Rourke DM, Graham DI, Welsh FA. Induction of ischemic tolerance following brief focal ischemia in rat brain. J Cereb Blood Flow Metab 1994;14:545-53.
  • 30 Pang CY, Yang RZ, Zhong A, Xu N, Boyd B, Forrest CR. Acute ischaemic preconditioning protects against skeletal muscle infarction in the pig. Cardiovasc Res 1995;29:782-8.
  • 31 Domenech RJ, Sánchez G, Donoso P, Parra V, Macho P. Effect of tachycardia on myocardial sarcoplasmic reticulum and Ca2+ dynamics: A mechanism for preconditioning? J Mol Cell Cardiol 2003;35:1429-37.
  • 32 Vegh A, Szekeres L, Parratt J. Preconditioning of the ischaemic myocardium; involvement of the L-arginine nitric oxide pathway. Br J Pharmacol 1992;107:648-52.
  • 33 Gattullo D, Linden RJ, Losano G, Pagliaro P, Westerhof N. Ischaemic preconditioning changes the pattern of coronary reactive hyperaemia in the goat: Role of adenosine and nitric oxide. Cardiovasc Res 1999;42:57-64.
  • 34 Kinnunen I, Laurikainen E, Schrey A, Laippala P, Aitasalo K. Effect of hypothermia on blood-flow responses in pedicled groin flaps in rats. Br J Plast Surg 2002;55:657-63.
  • 35 Uzunov P, Weiss B. Separation of multiple molecular forms of cyclic adenosine-3′,5′- monophosphate phosphodiesterase in rat cerebellum by polyacrylamide gel electrophoresis. Biochim Biophys Acta 1972;284:220-6.
  • 36 Gresser U, Gleiter CH. Erectile dysfunction: Comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil: Review of the literature. Eur J Med Res 2002;7:435-46.
  • 37 Lepore JJ, Maroo A, Pereira NL, Ginns LC, Dec GW, Zapol WM, et al. Effect of sildenafil on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension. Am J Cardiol 2002;90:677-80.
  • 38 Dunkern TR, Hatzelmann A. The effect of Sildenafil on human platelet secretory function is controlled by a complex interplay between phosphodiesterases 2, 3 and 5. Cell Signal 2005;17:331-9.
  • 39 Gori T, Sicuro S, Dragoni S, Donati G, Forconi S, Parker JD. Sildenafil prevents endothelial dysfunction induced by ischemia and reperfusion via opening of adenosine triphosphate-sensitive potassium channels: A human in vivo study. Circulation 2005;111:742-6.
  • 40 Vlachopoulos C, Tsekoura D, Alexopoulos N, Panagiotakos D, Aznaouridis K, Stefanadis C. Type 5 phosphodiesterase inhibition by sildenafil abrogates acute smoking-induced endothelial dysfunction. Am J Hypertens 2004;17:1040-4.
  • 41 Cunningham AV, Smith KH. Anterior ischemic optic neuropathy associated with viagra. J Neuroophthalmol 2001;21:22-5.
  • 42 Gorkin L, Hvidsten K, Sobel RE, Siegel R. Sildenafil citrate use and the incidence of nonarteritic anterior ischemic optic neuropathy. Int J Clin Pract 2006;60:500-3.
  • 43 Arnavaz A, Aurich A, Weissenborn K, Hartmann U, Emrich HM, Schneider U. Effect of sildenafil (Viagra) on cerebral blood flow velocity: A pilot study. Psychiatry Res 2003;122:207-9.
  • 44 Oh M, Chang H, Minn KW. The effects of tadalafil on axial-pattern skin flap survival in rats. Dermatol Surg 2008;34:626-30.
  • 45 Ayyildiz A, Uysal A, Koçer U, Karaaslan O, Huri E, Germiyanoglu C, et al. Effect of sildenafil citrate on viability of flaps: An experimental study in rats. Scand J Plast Reconstr Surg Hand Surg 2005;39:204-8.
  • 46 Brewer MB, Stump AL, Holton LH, Janes LE, Silverman RP, Singh DP. Effects of systemic tadalafil on skin flap survival in rats. Eplasty 2012;12:e45.
  • 47 Askar I, Oktay MF, Gurlek A, Bac B. Protective effects of some antineoplastic agents on ischemia-reperfusion injury in epigastric island skin flaps. Microsurgery 2006;26:193-9.