METFORMIN ATTENUATES AGONIST-STIMULATED CALCIUM TRANSIENTS IN VASCULAR SMOOTH-MUSCLE CELLS

Metformin, an antidiabetic agent that increases insulin sensitivity, has been shown to lower blood pressure. However, the mechanism of action of metformin in vascular smooth muscle (VSM) cell is not fully understood. We have tested the hypothesis that metformin produces vascular changes by direct interaction with VSM cells by investigating its effect on platelet-derived growth factor (PDGF)- and angiotensin II (ANG II)-stimulated intracellular calcium concentration ([Ca2+](i)) and VSM cell proliferation in response to PDGF in cultured cells. VSM cells were cultured from rat thoracic aorta and [Ca2+](i) was estimated in single cells by image analysis. Treatment of VSM cells with 1 or 2 mu g/ml metformin significantly decreased (p < 0.05) PDGF- or ANG II-stimulated [Ca2+](i). Treatment of VSM cells with 1, 2, 5, or 10 mu g/ml metformin had no significant effect on PDGF-stimulated [H-3]-thymidine incorporation. However, metformin at pharmacological doses of 20 and 50 mu g/ml significantly reduced (p < 0.05) PDGF-stimulated thymidine incorporation. We conclude that metformin mediates its vascular effects by attenuating agonist-stimulated [Ca2+](i).