• cardiovascular diseases
• hybrid drug
• hydrogen sulfide
• metformin
• type 2 diabetes mellitus

More than 500 million people worldwide live with Type 2 diabetes mellitus (T2DM) and metformin represents the first line therapy for this disease. Notably, cardiovascular diseases (CVDs) are one of the most common complications in patients with T2DM. In the last decade, several studies have demonstrated the vasoprotective properties of H2S. From these bases a new hybrid molecule was synthetized combining metformin with a H2S-donor moiety represented by an isothiocyanate. The aim of this research is to evaluate the H2S-derived vasoprotective properties of metformin-isothiocyanate (Met-ITC) compared to the native molecule Metformin (Met).
Methods
The ability of Met-ITC to release H2S inside HAECs and HASMCs cell lines was firstly tested. Cell viability, ROS production and β-galactosidase activity against oxidative stress caused by hydrogen peroxide, homocysteine, and high concentrations of glucose were evaluated after preincubation of Met-ITC or Met on HAECs and HASMCs. Met-ITC hyperpolarizing properties were tested on HASMC before evaluating its direct vasorelaxing properties on endothelium‐intact and -denuded rat aortic rings. The inhibition of NA‐induced vasoconstriction was also evaluated by pre-incubating the endothelium‐denuded aortic rings with Met-ITC/Met before the cumulative addition of NA.
Results
Met-ITC is able to release H2S in a concentration-dependent manner inside vascular cell lines and exhibited antioxidant and anti-ageing properties against H2O2-, homocysteine- and hyperglycemic-induced damage. It also exerted a concentration dependent hyperpolarization on HASMC cellular membrane. It exhibited a significantly stronger vasodilation of rat aortic rings compared to Met and the vasodilation was strongly inhibited by the pre-incubation of XE-991 or L-NAME. Moreover, the pre-incubation of Met-ITC induced a significantly higher concentration‐dependent inhibition of NA-evoked‐vasoconstriction compared to Met at 300µM.
Conclusions
Met-ITC is a H2S-donor hybrid drug able to maintain the anti-diabetic properties of Met while enhancing its vasoprotective profile. In particular, the vasorelaxation and endothelial protective properties can help the diabetic patient in the treatment of the endothelial dysfunction, one of the main causes of vascular complications.