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Targeting Phosphodiesterase-5 by Vardenafil Improves Vascular Graft Function.
- Source :
-
European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery [Eur J Vasc Endovasc Surg] 2018 Aug; Vol. 56 (2), pp. 256-263. Date of Electronic Publication: 2018 May 01. - Publication Year :
- 2018
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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.<br />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.<br />Results: Compared with the control, the saline group showed significantly attenuated endothelium dependent maximal relaxation (R <subscript>max</subscript> ) 2 h after reperfusion, which was significantly improved by vardenafil supplementation (R <subscript>max</subscript> 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).<br />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.<br /> (Copyright © 2018 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Actins metabolism
Animals
Aorta, Thoracic enzymology
Aorta, Thoracic physiopathology
Cold Ischemia
Cyclic GMP metabolism
Cytoprotection
DNA Damage drug effects
Intercellular Adhesion Molecule-1 metabolism
Male
Nitrosative Stress drug effects
Platelet Endothelial Cell Adhesion Molecule-1 metabolism
Rats, Inbred Lew
Reperfusion Injury enzymology
Reperfusion Injury physiopathology
Signal Transduction drug effects
Tyrosine analogs & derivatives
Tyrosine metabolism
Vascular Cell Adhesion Molecule-1 metabolism
Vascular System Injuries enzymology
Vascular System Injuries physiopathology
Warm Ischemia
Aorta, Thoracic drug effects
Aorta, Thoracic transplantation
Phosphodiesterase 5 Inhibitors pharmacology
Reperfusion Injury prevention & control
Tissue and Organ Harvesting adverse effects
Vardenafil Dihydrochloride pharmacology
Vascular System Injuries prevention & control
Vasodilator Agents pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1532-2165
- Volume :
- 56
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery
- Publication Type :
- Academic Journal
- Accession number :
- 29724533
- Full Text :
- https://doi.org/10.1016/j.ejvs.2018.03.025