Large concentrations of local anesthetics administered intrathecally increased glutamate concentrations in the cerebrospinal fluid. The margin of safety may be smallest with lidocaine.

Membrane type 1-matrix metalloproteinase (MT1-MMP) plays a key role in endothelial cell migration, matrix remodeling, and angiogenesis. Previous studies demonstrated that a mechanical force, cyclic strain, increases MT1-MMP expression by displacing Sp1 with increased Egr-1 expression and binding to the promoter site. However, the effect of shear stress (SS) on MT1-MMP expression is poorly understood. Although Egr-1 mRNA transcription and protein was induced (7.6-fold) in response to SS (n ‫؍‬ 5, 0 -8 h, p < 0.05), SS decreased MT1-MMP mRNA transcription and protein levels in a time-dependent fashion (10, 50, and 90% reduction at 1, 4, and 8 h, respectively; n ‫؍‬ 5, p < 0.05). Egr-1 protein was increased after SS and cyclic strain, but Sp1 was serine-phosphorylated only after SS. SS increased Sp1 DNA binding (3.8-, 5.8-, and 2.4-fold increase at 1, 4, and 8 h, respectively; n ‫؍‬ 5, p < 0.05) that was inhibitable by calf intestinal phosphatase. Thus, SS inhibits MT1-MMP expression despite Egr-1 up-regulation by inducing the serine phosphorylation of Sp1, which in turn increases its binding affinity for its site on the MT1-MMP promoter, reducing the ability of Egr-1 to displace it. These data illustrate the complex control of microvascular endothelial cell MT1-MMP expression in response to distinct environmental stimuli (cyclic strain versus shear stress), consisting of both the modulation of specific transcription factor expression (Egr-1) as well as transcription factor post-translational modification (serine phosphorylation of Sp1).Angiogenesis is critical for different physiologic and pathologic processes including wound healing, tissue remodeling, chronic inflammatory disease, and tumorigenesis (1-3). Angiogenesis requires endothelial cells (EC) 1 to coordinate multiple functions including reduction of intercellular adhesion, degradation of subendothelial matrix, migration, proliferation, and formation of new capillary tubes (4). The matrix metalloproteinases (MMPs) are a family of structurally related zinc endopeptidases capable of proteolysis of numerous components of the extracellular matrix (5). Production and activation of MMPs correlate strongly with migration and invasion in endothelium (6, 7). Membrane type-1 matrix metalloproteinase (MT1-MMP, MMP-14), one of the members of the family of matrix-bound MMPs by a C-terminal transmembrane domain, is identified as a physiological activator of pro-MMP-2 on the cell surface as well as a functional enzyme that degrades a number of extracellular matrix components (8, 9). It is not surprising that MT1-MMP has been shown to be a key regulator of angiogenesis (10, 11).MT1-MMP mRNA and protein levels are expressed at low levels in most noninvasive cells but are up-regulated during EC migration and matrix remodeling, and this up-regulation correlates with MMP-2 activation (11). The up-regulation of MT1-MMP mRNA and protein occurs in microvascular EC cultured in a three-dimensional collagen type-I matrix as a consequence of increased production and promoter bindi...

SMC directly respond to oscillatory SS by increasing DNA synthesis, proliferation, and activation of the PI3K-Akt signal transduction pathway. These results suggest a mechanism of SMC survival and proliferation in response to endothelial-denuding arterial injury.