Metformin Improves Endothelial Function and Reduces Blood Pressure in Diabetic Spontaneously Hypertensive Rats Independent from Glycemia Control: Comparison to Vildagliptin

Abstract

Metformin confers vascular benefits beyond glycemia control, possibly via pleiotropic effects on endothelial function. In type-1-diabetes-mellitus (T1DM-)patients metformin improved flow-mediated dilation but also increased prostaglandin(PG)-F2α, a known endothelial-contracting factor. To explain this paradoxical finding we hypothesized that metformin increased endothelial-vasodilator mediators (e.g. NO and EDHF) to an even larger extent. Spontaneously-hypertensive-rats (SHR) display impaired endothelium-dependent relaxation (EDR) involving contractile PGs. EDR was studied in isolated SHR aortas and the involvement of PGs, NO and EDHF assessed. 12-week metformin 300 mg/kg/day improved EDR by up-regulation of NO and particularly EDHF; it also reduced blood pressure and increased plasma sulphide levels (a proxy for H2S, a possible mediator of EDHF). These effects persisted in SHR with streptozotocin (STZ)-induced T1DM. Vildagliptin (10 mg/kg/day), targeting the incretin axis by increasing GLP-1, also reduced blood pressure and improved EDR in SHR aortas, mainly via the inhibition of contractile PGs, but not in STZ-SHR. Neither metformin nor vildagliptin altered blood glucose or HbA1c. In conclusion, metformin reduced blood pressure and improved EDR in SHR aorta via up-regulation of NO and particularly EDHF, an effect that was independent from glycemia control and maintained during T1DM. A comparison to vildagliptin did not support effects of metformin mediated by GLP-1.

Vascular endothelial growth factor as a marker of endothelial dysfunction in poly- and comorbidity: focus on hypertension, type 2 diabetes mellitus and subclinical hypothyroidism

“…Lower values of VEGF-A in a combination of hypertension with T2DM versus isolated AH may be explained by the fact that in the present study, all patients with T2DM at the time of inclusion received Metformin. At present, there are numerous data, including those obtained in randomized trials, concerning the beneficial effects of Metformin on the function of endothelium [14]. Thus, Wu S et al (2014) demonstrated that the use of Metformin over a period of 12 months resulted in a significant improvement in endothelium function [15].…”

Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an Endothelial Disease? A Comprehensive Evaluation of Clinical and Basic Evidence

“…Even the antimalaric agents chloroquine and hydroxychloroquine, initially proposed as a therapy for COVID-19 based on anecdotal data [229,236], have been shown to improve endothelial function [237,238]. If our theory is correct [239], other drugs that might be effective in treating COVID-19 patients through their beneficial effects on endothelial cells include α1 adrenergic receptor blockers (e.g., doxazosin) [240], modulators of Sigma receptors [241][242][243], metformin [244], indomethacin [245], and endothelin receptor antagonists (e.g., bosentan) [246]. However, data from randomized trials confirming the actual efficacy of these drugs are not (yet) available.…”

Endothelial function and dysfunction: Impact of metformin

“…Metformin raises the tissue concentration of hydrogen sulphide (H 2 S), which is an atheroprotective gasotransmitter (Hamidi Shishavan, et al, 2017;Xu, Liu, & Liu, 2014). H 2 S functions as a vasculoprotective factor by sulfhydrating potassium channels and acting as an EDHF (Félétou M. , 2011).…”