Addition of vardenafil into storage solution protects the endothelium in a hypoxia- reoxygenation model

Abstract

WHAT THIS PAPER ADDS During bypass surgery, preservation of vascular grafts in preservation solutions (saline or Custodiol) causes endothelial dysfunction, leading to an enhanced rate of complications and unfavourable early and late outcome (e.g., early graft thrombosis, vasospasm, restenosis, and occlusion). Additionally, there are unavoidable situations in vascular or transplantation surgery in which a long ischaemic period is necessary and therefore current storage protocols need further improvement. We proved in our model that vardenafil-enriched solution efficiently preserved the endothelium after long-term cold ischaemic storage and warm reperfusion, and could be a new therapeutic option for an optimal preservation of vascular grafts.Objective: Based upon the well known protective effect of intracellular cyclic guanosine monophosphate (cGMP) accumulation, we tested the hypothesis that storage solution enriched with optimal concentration of the phosphodiestherase-5 inhibitor vardenafil could provide better protection of vascular grafts against reperfusion injury after long-term cold ischaemic storage. Methods: Isolated thoracic aorta obtained from rats underwent 24-h cold ischaemic preservation in physiological saline or vardenafil (10 À11 M)-supplemented saline solution. Reperfusion injury was simulated by hypochlorite (200 mM) exposure for 30 minutes. Endothelium-dependent vasorelaxation was assessed, and histopathological and molecularebiological examination of the aortic tissue were performed. Results: Compared with the control group, the saline group showed significantly attenuated endotheliumdependent maximal relaxation (R max ) to acetylcholine after hypoxia-reoxygenation, which was significantly improved by vardenafil supplementation (R max control: 98 AE 1%; saline: 48 AE 6%; vardenafil: 75 AE 4%; p < .05).Vardenafil treatment significantly reduced DNA strand breaks (control: 10.6 AE 6.2%; saline: 72.5 AE 4.0%; vardenafil: 14.2 AE 5.2%; p < .05) and increased cGMP score in the aortic wall (control: 8.2 AE 0.6; saline: 4.5 AE 0.3; vardenafil: 6.7 AE 0.6; p < .05). Conclusions: Our results support the view that impairment of intracellular cGMP signalling plays a role in the pathogenesis of the endothelial dysfunction induced by cold storage warm reperfusion, which can be effectively reversed by pharmacological phosphodiesterase-5 inhibition. Ó