Targeting Phosphodiesterase-5 by Vardenafil Improves Vascular Graft Function

Gábor Veres, Martin Hagenhoff, Harald Schmidt, T. Radovits, Sivakkanan Loganathan, Yang Bai, Sevil Korkmaz-Icöz, Paige Brlecic, Alex Ali Sayour, Matthias Karck, G. Szabó

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4 Citations (Scopus)

Abstract

Objectives: Ischaemia reperfusion (IR) injury occurs during vascular graft harvesting and implantation during vascular/cardiac surgery. Elevated intracellular cyclic guanosine monophosphate (cGMP) levels contribute to an effective endothelial protection in different pathophysiological conditions. The hypothesis that the phosphodiesterase-5 inhibitor vardenafil would protect vascular grafts against IR injury by upregulating the nitric oxide–cGMP pathway in the vessel wall of the bypass graft was investigated. Methods: Lewis rats (n = 6–7/group) were divided into Group 1, control; Group 2, donor rats received intravenous saline; Group 3, received intravenous vardenafil (30 μg/kg) 2 h before explantation. Whereas aortic arches of Group 1 were immediately mounted in an organ bath, aortic segments of Groups 2 and 3 were stored for 2 h in saline and transplanted into the abdominal aorta of the recipient. Two hours after transplantation, the implanted grafts were harvested. Endothelium dependent and independent vasorelaxations were investigated. TUNEL, CD-31, ICAM-1, VCAM-1, α-SMA, nitrotyrosine, dihydroethidium and cGMP immunochemistry were also performed. Results: Compared with the control, the saline group showed significantly attenuated endothelium dependent maximal relaxation (Rmax) 2 h after reperfusion, which was significantly improved by vardenafil supplementation (Rmax control, 91 ± 2%; saline 22 ± 2% vs. vardenafil 39 ± 4%, p <.001). Vardenafil pre-treatment significantly reduced DNA fragmentation (control 9 ± 1%, saline 66 ± 8% vs. vardenafil 13 ± 1%, p <.001), nitro-oxidative stress (control 0.8 ± 0.3, saline 7.6 ± 1.3 vs. vardenafil 3.8 ± 1, p =.036), reactive oxygen species level (vardenafil 36 ± 4, control 34 ± 2 vs. saline 43 ± 2, p =.049), prevented vascular smooth muscle cell damage (control 8.5 ± 0.7, saline 4.3 ± 0.6 vs. vardenafil 6.7 ± 0.6, p =.013), decreased ICAM-1 (control 4.1 ± 0.5, saline 7.0 ± 0.9 vs. vardenafil 4.4 ± 0.6, p =.031), and VCAM-1 score (control 4.4 ± 0.4, saline 7.3 ± 1.0 vs. vardenafil 5.2 ± 0.4, p =.046) and increased cGMP score in the aortic wall (control 11.2 ± 0.8, saline 6.5 ± 0.8 vs. vardenafil 8.9 ± 0.6, p =.016). The marker for endothelial integrity (CD-31) was also higher in the vardenafil group (control 74 ± 4%, saline 22 ± 2% vs. vardenafil 40 ± 3%, p =.008). Conclusions: The results support the view that impairment of intracellular cGMP signalling plays a role in the pathogenesis of the endothelial dysfunction of an arterial graft after bypass surgery, which can effectively be prevented by vardenafil. Its clinical use as preconditioning drug could be a novel approach in vascular/cardiac surgery.

Original languageEnglish
JournalEuropean Journal of Vascular and Endovascular Surgery
DOIs
Publication statusAccepted/In press - Jan 1 2018

Keywords

  • cGMP
  • Endothelial dysfunction
  • Graft
  • Ischaemia reperfusion injury
  • Vardenafil

ASJC Scopus subject areas

  • Surgery
  • Cardiology and Cardiovascular Medicine

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    Veres, G., Hagenhoff, M., Schmidt, H., Radovits, T., Loganathan, S., Bai, Y., Korkmaz-Icöz, S., Brlecic, P., Sayour, A. A., Karck, M., & Szabó, G. (Accepted/In press). Targeting Phosphodiesterase-5 by Vardenafil Improves Vascular Graft Function. European Journal of Vascular and Endovascular Surgery. https://doi.org/10.1016/j.ejvs.2018.03.025