Pleiotropic Activity of Metformin and Its Sulfonamide Derivatives on Vascular and Platelet Haemostasis

摘要

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.