Modulation of early [Ca2+](i) rise in metabolically inhibited endothelial cells by xestospongin C

When energy metabolism is disrupted, endothelial cells lose Ca2+ from endop lasmic reticulum (ER) and the cytosolic Ca2+ concentration ([Ca2+](i)) incr eases. The importance of glycolytic energy production and the mechanism of Ca2+ loss from the ER were analyzed. Endothelial cells from porcine aorta i n culture and in situ were used as models. 2-Deoxy-D-glucose (2-DG, 10 mM), an inhibitor of glycolysis, caused an increase in [Ca2+](i) (measured with fura 2) within 1 min when total cellular ATP contents were not yet affecte d. Stimulation of oxidative energy production with pyruvate (5 mM) did not attenuate this 2-DG-induced rise of [Ca2+](i), while this maneuver preserve d cellular ATP contents. The inhibitor of ER-Ca2+-ATPase, thapsigargin (10 nM), augmented the 2-DG-induced rise of [Ca2+](i). Xestospongin C (3 mM), a n inhibitor of D-myo-inositol 3-phosphate [Ins(3)P]-sensitive ER-Ca2+ relea se, abolished the rise. The results demonstrate that the ER of endothelial cells is very sensitive to glycolytic metabolic inhibition. When this occur s, the ER Ca2+ store is discharged by opening of the Ins(3)P-sensitive rele ase channel. Xestospongin C can effectively suppress the early [Ca2+](i) ri se in metabolically inhibited endothelial cells.