title: Treatment with Sildenafil and Donepezil Improves Angiogenesis in Experimentally Induced Critical Limb Ischemia.
abstract: Objectives. In this study, we aimed to demonstrate the role of sildenafil (an antagonist of phosphodiesterase type 5 (PDE-5)) and donepezil (a specific and reversible inhibitor of acetylcholinesterase (Ach)) in increasing ischemia-induced angiogenesis.Method. Critical limb ischemia was induced by ligation of the common femoral artery followed by ligation of the common iliac artery. The operated animals were divided into 3 groups: receiving sildenafil, receiving donepezil, and surgery alone; the contralateral lower limb was used as a negative control. The results were controlled based on clinical score and Doppler ultrasound. Gastrocnemius muscle samples were taken from all animals, both from the ischemic and nonischemic limb and were used for histopathological and immunohistochemical examination for the evaluation of the number of nuclei/field, endothelial cells (CD31), dividing cells (Ki-67), and vascular endothelial growth factor (VEGFR-3).Results. An increasing tendency of the number of nuclei/field with time was observed both in the case of sildenafil and donepezil treatment. The formation of new capillaries (the angiogenesis process) was more strongly influenced by donepezil treatment compared to sildenafil or no treatment. This treatment significantly influenced the capillary/fiber ratio, which was increased compared to untreated ligated animals. Sildenafil treatment led to a gradual increase in the number of dividing cells, which was significantly compared to the negative control group and compared to the ligation control group. The same effect (increase in the number of Ki-67 positive cells) was more obvious in the case of donepezil treatment.Conclusion. Donepezil treatment has a better effect in ligation-induced ischemia compared to sildenafil, promoting angiogenesis in the first place, and also arteriogenesis.
authors.affiliation: Department of Surgery, Surgical Clinic II, "Iuliu Haţieganu" University of Medicine and Pharmacy Cluj-Napoca, 4-6 Clinicilor, 400006 Cluj-Napoca, Romania.
authors.forename: Ioana M
authors.initials: IM
authors.lastname: Constantinescu
authors.affiliation: University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, 3-5 Mănăştur, 400372 Cluj-Napoca, Romania.
authors.forename: Pompei
authors.initials: P
authors.lastname: Bolfa
authors.affiliation: Department of Sugery, Surgical Clinic IV, "Iuliu Haţieganu" University of Medicine and Pharmacy Cluj-Napoca, 16-18-20 Republicii, 400015 Cluj-Napoca, Romania.
authors.forename: Dan
authors.identifier: 0000-0001-9699-8888
authors.initials: D
authors.lastname: Constantinescu
authors.affiliation: Department of Surgery, Surgical Clinic II, "Iuliu Haţieganu" University of Medicine and Pharmacy Cluj-Napoca, 4-6 Clinicilor, 400006 Cluj-Napoca, Romania.
authors.forename: Aurel I
authors.initials: AI
authors.lastname: Mironiuc
authors.affiliation: Department of Medical Education, "Iuliu Haţieganu" University of Medicine and Pharmacy Cluj-Napoca, 23 Marinescu, 400337 Cluj-Napoca, Romania.
authors.forename: Claudia D
authors.identifier: 0000-0003-1207-988X
authors.initials: CD
authors.lastname: Gherman
mesh_terms: D000818:Animals; D002196:Capillaries / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D000077265:Donepezil; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology*; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use*; D007511:Ischemia / Q000188:drug therapy*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D017208:Rats, Wistar; D000068677:Sildenafil Citrate / Q000494:pharmacology / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D007189:Indans; D010880:Piperidines; D042461:Vascular Endothelial Growth Factor A; D000077265:Donepezil; D000068677:Sildenafil Citrate