Vardenafil and cilostazol can improve vascular reactivity in rats with diabetes mellitus and rheumatoid arthritis co-morbidity

Research Abstract

Endothelial dysfunction and vascular reactivity defects secondary to metabolic and immunological disorderscarry risk of serious cardiovascular complications. Here, the effects of the phosphodiesterase (PDE) inhibitorsvardenafil and cilostazol were examined against rheumatoid arthritis (RA)/diabetes mellitus (DM)-co-morbidity-induced endothelial dysfunction and vascular reactivity defects. After setting of RA/DM-co-morbidity model,rats were divided into a normal control group, an RA/DM-co-morbidity group, and two treatment groups re-ceiving oral vardenafil (10 mg/kg/day) and cilostazol (30 mg/kg/day) for 21 days after RA/DM-co-morbidityinduction. Aorta was isolated for biochemical estimations of the pro-inflammatory vasoconstrictor moleculesangiotensin-II (Ang-II) and endothelin-1 (ET-1), the adhesion molecules P-selectin and vascular cell adhesionmolecule-1 (VCAM-1), the energy sensor adenosine-5′-monophosphate-activated protein kinase (AMPK), and thevasodilator anti-inflammatory molecule vasoactive intestinal peptide (VIP) using enzyme-linked immunosorbentassay (ELISA) and western blot analysis. Immunohistochemical estimations of endothelial nitric oxide synthase(eNOS) and matrix metalloproteinase (MMP)-2 were performed coupled with histopathological examinationusing routine hematoxylin and eosin (H&E) and special Masson trichrome staining. Thein vitrostudy wasconducted using aortic strips where cumulative concentration response curves were done for the endothelium-dependent relaxing factor acetylcholine and the endothelium-independent relaxing factor sodium nitroprussideafter submaximal contraction with phenylephrine. Vardenafil and cilostazol significantly improved endothelialintegrity biomarkersin vivosupported with histopathologicalfindings in addition to improved vasorelaxationinvitro. Apart from their known PDE inhibition, up-regulation of vascular AMPK and eNOS coupled with down-regulation of Ang-II, ET-1, P-selectin, VCAM-1 and MMP-2 may explain vardenafil and cilostazol protectiveeffect against RA/DM-co-morbidity-induced endothelial dysfunction and vascular reactivity defects.

Research Keywords

VardenafilCilostazolEndothelial dysfunctionVascular reactivityRheumatoid arthritisDiabetes mellitus