Prolonged treatment of vascular endothelial cells with pathologically high D-glucose amplifies autacoid-induced Ca2+ mobilization and thus formation of nitric oxide. This study investigated the Ca2+ source for the change in endothelial Ca2+ response on agonist stimulation. Pretreatment with high D-glucose (44 vs. 5 mM) enhanced release of intracellular Ca2+ by bradykinin as a result of a 2.0-fold increased formation of inositol 1,4,5-trisphosphate. High D-glucose also amplified Ca2+ influx (2.0-fold). In high D-glucose preincubated cells, stimulation with bradykinin significantly increased transplasmalemmal 45Ca2+ flux (3.2-fold) and caused a 2.0-fold increase in permeability to Mn2+, a surrogate for endothelial plasma membrane Ca2+ channels. A significant 2.0-fold increase occurred in the maximal slope, suggesting a higher rate of Mn2+ (Ca2+) influx. Ca2+ influx, stimulated by an inositol phosphate-independent depletion of intracellular Ca2+ stores with 2,5-di-(tert-butyl)-hydroquinone was also significantly increased 2.4-fold by high D-glucose, with no effect on intracellular Ca2+ release. D-glucose failed to modulate resting or stimulated cAMP levels. We suggest that prolonged exposure to pathologically high D-glucose increases formation of inositol polyphosphates, thus increasing Ca2+ release. Ca2+ entry is increased by amplification of unknown signal transduction mechanisms triggered by Ca2+ store depletion.
Intracellular Mechanisms Involved in D-Glucose–Mediated Amplification of Agonist-Induced Ca2+ Response and EDRF Formation in Vascular Endothelial Cells
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Thomas C Wascher, Hermann Toplak, Güunter J Krejs, Sabine Simecek, Walter R Kukovetz, Wolfgang F Graier; Intracellular Mechanisms Involved in D-Glucose–Mediated Amplification of Agonist-Induced Ca2+ Response and EDRF Formation in Vascular Endothelial Cells. Diabetes 1 August 1994; 43 (8): 984–991. https://doi.org/10.2337/diab.43.8.984
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