Extracellular magnesium deficiency induces contraction of arterial muscle:role of PI3-kinases and MAPK signaling pathways

The present study investigated the actions of extracellular Mg2+ ([Mg2+](o) ) deficiency on isolated rat aortae and rat aortic smooth muscle cells (RAS MC). Exposure of isolated, intact rat aortic rings to Mg2+-free or Mg2+-def icient medium (0.15-0.6 mM) produced endothelium-independent, concentration -dependent contractions: the lower the [Mg2+](o), the stronger the contract ion. Pre- or post-incubation of the vessels with low concentrations of U012 6, SB-203580, PD-98059, wortmannin, LY-294002, or a SH2 domain inhibitor pe ptide suppressed [Mg2+](o) deficiency-induced contractions significantly. T he concentrations of these antagonists required for half-maximal inhibition (IC50) were not very different from the inhibitory constants (K-i) for the se drugs. A variety of specific pharmacological antagonists of several know n endogenously-formed vasoconstrictors did not inhibit or attenuate the con tractions induced by low [Mg2+](o). Mg2+-free medium induced a 6- to 7-fold increase in intracellular Ca2+ ([Ca2+](i)) in RASMC. Pre- or post-treatmen t of the cells with U0126, SB-203580, PD-98059, wortmannin, LY-294002, or a SH2 domain inhibitor peptide markedly inhibited the increments in ([Ca2+]( i)) in RASMC induced by exposure to Mg2+-free medium. The present findings suggest that Mg2+-deficiency-induced contractions of rat aortae are associa ted with activation of several cellular signal pathways, such as mitogen-ac tivated protein kinase, phosphatidylinositol-3 (PI3) kinases, and SH2 domai n-containing proteins.