Role of the NO/cGMP Pathway in Postoperative Vasodilation in Perforator Flaps

Abstract

Background The nitric oxide (NO)/cyclic guanylyl monophosphate (cGMP) pathway is one of the most important regulators of tissue perfusion. Here, we sought to elucidate the protective effects of the NO/cGMP pathway on the microcirculation of axial pattern skin flaps.

Material and Methods Overall 40 rats were divided into four groups (n = 10 each): group A, sildenafil was administered orally at 10 mg/kg daily; group B, sildenafil citrate (10 mg/kg, oral) and nitro-amino-methyl-L-arginine (L-NAME, intraperitoneal injection), a nitric oxide synthase inhibitor, were administered daily; group C, L-NAME was administered alone; and group D, no drugs were administered. After surgery, the surviving flap area was calculated as a percentage of total flap dimensions using the paper template technique. Angiography and imaging were performed to compare the macrovascular changes of the choke zones in the flaps. Histological examinations were performed to compare the differences in microvascular changes between the two choke zones.

Results A significant improvement of flap survival area and a significant dilation of vessels in both choke zones were found after administration of sildenafil. We also found that the postoperative vasodilation of choke vessels could be altered by inhibition of NO synthase (NOS). Moreover, the vasodilatory effect prolonged by the phosphodiesterase 5 inhibitor sildenafil was attenuated after administration of L-NAME. L-NAME significantly reversed the protection afforded by sildenafil.

Conclusions Targeting the NO/cGMP pathway can dilate vessels along the axis of the flap, including the choke vessels, thus augmenting flap viability. Therefore, targeting of this pathway may have therapeutic applications.

Keywords

nitric oxide - cGMP - three-territory skin flap - choke vessels - rat model

• References

• 1 Morris SF, Taylor GI. The time sequence of the delay phenomenon: when is a surgical delay effective? An experimental study. Plast Reconstr Surg 1995; 95 (3) 526-533
• 2 Kerrigan CL, Daniel RK. Critical ischemia time and the failing skin flap. Plast Reconstr Surg 1982; 69 (6) 986-989
• 3 Braithwaite F. Preliminary observations on the vascular channels in tube pedicles. Br J Plast Surg 1950; 3 (1) 40-46
• 4 McGregor IA, Morgan G. Axial and random pattern flaps. Br J Plast Surg 1973; 26 (3) 202-213
• 5 Taylor GI, Palmer JH. The vascular territories (angiosomes) of the body: experimental study and clinical applications. Br J Plast Surg 1987; 40 (2) 113-141
• 6 Miyamoto S, Minabe T, Harii K. Effect of recipient arterial blood inflow on free flap survival area. Plast Reconstr Surg 2008; 121 (2) 505-513
• 7 Moncada S, Higgs EA. Nitric oxide and the vascular endothelium. Handbook Exp Pharmacol 2006; 176 (176 Pt 1) 213-254
• 8 Brock G. Sildenafil citrate (Viagra). Drugs Today (Barc) 2000; 36 (2-3) 125-134
• 9 Lim PH, Moorthy P, Benton KG. The clinical safety of viagra. Ann N Y Acad Sci 2002; 962: 378-388
• 10 Ayyildiz A, Uysal A, Koçer U , et al. Effect of sildenafil citrate on viability of flaps: an experimental study in rats. Scand J Plast Reconstr Surg Hand Surg 2005; 39 (4) 204-208
• 11 Ulusoy MG, Uysal A, Koçer U , et al. Improved flap viability with site-specific delivery of sildenafil citrate using fibrin glue. Ann Plast Surg 2005; 55 (3) 292-296
• 12 Hart K, Baur D, Hodam J , et al. Short- and long-term effects of sildenafil on skin flap survival in rats. Laryngoscope 2006; 116 (4) 522-528
• 13 Gravvanis A, Papalois A, Delikonstantinou I , et al. Changes in arterial blood flow of free flaps after the administration of sildenafil in swine. Microsurgery 2011; 31 (6) 465-471
• 14 Gribbe O, Samuelson UE, Wiklund NP. Effects of nitric oxide synthase inhibition on blood flow and survival in experimental skin flaps. J Plast Reconstr Aesthet Surg 2007; 60 (3) 287-293
• 15 McDonald WS, Lo Jr TP, Thurmond M , et al. Role of nitric oxide in skin flap delay. Plast Reconstr Surg 2004; 113 (3) 927-931
• 16 Xiao-Xiao T, Sen-Min W, Ding-Sheng L. Effects of vinpocetine on random skin flap survival in rats. J Reconstr Microsurg 2013; 29 (6) 393-398
• 17 Chen ZG, Persons B, Lin L, Lineaweaver WC, Zhang F. Vascular endothelial growth factor upregulates inducible nitric oxide synthase expression in the muscle flap ischemia model in the rat. J Reconstr Microsurg 2009; 25 (4) 219-225
• 18 Freeman B. Free radical chemistry of nitric oxide. Looking at the dark side. Chest 1994; 105 (3) , Suppl) 79S-84S
• 19 Dawson DA. Nitric oxide and focal cerebral ischemia: multiplicity of actions and diverse outcome. Cerebrovasc Brain Metab Rev 1994; 6 (4) 299-324
• 20 Crow JP, Beckman JS. The role of peroxynitrite in nitric oxide-mediated toxicity. Curr Top Microbiol Immunol 1995; 196: 57-73
• 21 Radomski MW, Moncada S. The biological and pharmacological role of nitric oxide in platelet function. Adv Exp Med Biol 1993; 344: 251-264
• 22 Freund PR, Brengelmann GL, Rowell LB, Engrav L, Heimbach DM. Vasomotor control in healed grafted skin in humans. J Appl Physiol 1981; 51 (1) 168-171