Abstract
As type 2 diabetes mellitus (T2DM) predisposes patients to endothelial cell injury and dysfunction, improvement of vascular function should be an important target for therapy. The aim of this study was to evaluate the effects of metformin, its sulfenamide and sulfonamide derivatives on selected parameters of endothelial and smooth muscle cell function, and platelet activity. Metformin was not found to significantly affect the viability of human umbilical vein endothelial cells (HUVECs) or aortal smooth muscle cells (AoSMC); however, it decreased cell migration by approximately 21.8% in wound healing assays after 24 h stimulation (wound closure 32.5 µm versus 41.5 µm for control). Metformin reduced platelet aggregation manifested by 19.0% decrease in maximum of aggregation (Amax), and 20% reduction in initial platelet aggregation velocity (v0). Furthermore, metformin decreased spontaneous platelet adhesion by 27.7% and ADP-induced adhesion to fibrinogen by 29.6% in comparison to control. Metformin sulfenamide with an n-butyl alkyl chain (compound 1) appeared to exert the most unfavourable effects on AoSMC cell viability (IC50 = 0.902 ± 0.015 μmol/mL), while 4-nitrobenzenesulfonamide (compound 3) and 2-nitrobenzenesulfonamide (compound 4) derivatives of metformin did not affect AoSMC and HUVEC viability at concentrations up to 2.0 μmol/mL. These compounds were also found to significantly reduce migration of smooth muscle cells by approximately 81.0%. Furthermore, sulfonamides 3 and 4 decreased the initial velocity of platelet aggregation by 11.8% and 20.6%, respectively, and ADP-induced platelet adhesion to fibrinogen by 76.3% and 65.6%. Metformin and its p- and o-nitro-benzenesulfonamide derivatives 3, 4 appear to exert beneficial effects on some parameters of vascular and platelet haemostasis.
Highlights
The associations between type 2 diabetes mellitus (T2DM) and concomitantly occurring haemostasis disturbances, including thrombosis and the activation of blood coagulation are widely known [1]
Considering the variedeffects multi-directional derivatives plasma on haemostasis, this paper presents the effects metformin, its selected effects ofon metformin the cardiovascular system and coagulation, andof beneficial effectsand of metformin sulfenamide and derivatives on the viability of of human umbilical endothelial derivatives onsulfonamide plasma haemostasis, this(Figure paper 1)
Maximum aggregation (Amax) was of metformin obtained in T-TAS experiments [34] may be attributed to its anti-aggregatory properties, decreased; these changes were not of statistical significance. These results suggest that the expressed as decreased initial velocity of aggregation (p < 0.01) and reduced maximum aggregation anti-thrombotic effects of metformin obtained in T-TAS experiments [34] may be attributed to its anti(Amax, NS)
Summary
The associations between T2DM and concomitantly occurring haemostasis disturbances, including thrombosis and the activation of blood coagulation are widely known [1]. Divide the characteristic haemostatic abnormalities in T2DM into those occurring in stages of coagulation: thrombus formation, impaired fibrinolysis, endothelial dysfunction and platelet hyperreactivity. It was reported that platelets in diabetes subjects are characterized by hyperreactivity, increased adhesiveness, exaggerated aggregation and changed metabolism [3]. T2DM patients can present a pro-coagulation state following increased activity of coagulation factors such as fibrinogen, vWF, or factor FVII [1]. In T2DM patients, increased fibrin levels and thrombin generation have been reported [3]. Vascular endothelial dysfunction can induce a pro-coagulant state in diabetes subjects, and can lead to the pathogenesis and clinical expression of atherosclerosis [4]
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