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Purpose: Metformin is the only oral anti-hyperglycemic drug that has been shown to reduce overall mortality, yet the full spectrum of its effects is not fully elucidated. This study was designed to assess the vasoprotective effects of metformin by evaluating its inhibition of vascular contractility in response to serotonin, which is released during vascular injury.
Methods: The aortas from wistar rats (250-300g) were denuded of endothelium using polyethylene tubing. The aortas were then cut into 2-mm rings, mounted onto a myograph, and placed in an oxygenated Kreb’s buffer. After a two-hour equilibration period, samples were treated with 80 mM potassium chloride to assess viability, and then exposed to 100 µM acetylcholine to confirm endothelial denudation. Subsequently, the effects of increasing concentrations of metformin (10 µM - 3 mM) or 1 mM AICAR (an AMP-kinase activator) on serotonin-induced smooth muscle contractility were determined.
Results: At 3 mM concentration, metformin treatment resulted in significant inhibition of serotonin-induced contraction (p<0.05). Metformin reduced both the sensitivity (EC50) and the maximal contractile response (Emax) to serotonin. Notably, the inhibitory effect of 3 mM metformin on the contractile response was similar to that observed with 1 mM AICAR group. AICAR was used as a positive control since the effects of metformin are associated with AMP-kinase activation, as revealed by western blot analysis. Furthermore, the inhibitory effect of 3 mM metformin on serotonin-induced contractility was sustained, even after the withdrawal of metformin from Kreb’s buffer and sequential washing. The persistent decrease in serotonin-induced contractility with 3 mM metformin may be due to tissue accumulation. Metformin at 10 µM and 1 mM concentrations did not significantly affect serotonin-induced contractility.
Conclusion: Metformin reduced serotonin-induced contraction, indicating it may have a stabilizing effect on vascular smooth muscle. This stabilizing effect could partially contribute to the reduction in mortality associated with metformin use.