Modulation of early [[Ca.sup.2+]].sub.i] rise in metabolically inhibited endothelial cells by xestospongin C

Schafer, M., D. Bahde, B. Bosche, Y. Ladilov, C. Schafer, H. M. Piper, and T. Noll. Modulation of early [[Ca.sup.2+]].sub.i] rise in metabolically inhibited endothelial cells by xestospongin C. Am J Physiol Heart Circ Physiol 280: H1002-H1010, 2001.--When energy metabolism is disrupted, endothelial cells lose [Ca.sup.2+] from endoplasmic reticulum (ER) and the cytosolic [Ca.sup.2+] concentration ([[Ca.sup.2+]].sub.i]) increases. The importance of glycolytic energy production and the mechanism of [Ca.sup.2+] loss from the ER were analyzed. Endothelial cells from porcine aorta in culture and in situ were used as models. 2-Deoxy-D-glucose (2-DG, 10 mM), an inhibitor of glycolysis, caused an increase in [[Ca.sup.2+]].sub.i] (measured with fura 2) within 1 min when total cellular ATP contents were not yet affected. Stimulation of oxidative energy production with pyruvate (5 mM) did not attenuate this 2-DG-induced rise of [[Ca.sup.2+]].sub.i], while this maneuver preserved cellular ATP contents. The inhibitor of ER-[Ca.sup.2+]-ATPase, thapsigargin (10 nM), augmented the 2-DG-induced rise of [[Ca.sup.2+]].sub.i]. Xestospongin C (3 [micro]M), an inhibitor of D-myo-inositol 3-phosphate [Ins(3)P]-sensitive ER-[Ca.sup.2+] release, abolished the rise. The results demonstrate that the ER of endothelial cells is very sensitive to glycolytic metabolic inhibition. When this occurs, the ER [Ca.sup.2+] store is discharged by opening of the Ins(3)P-sensitive release channel. Xestospongin C can effectively suppress the early [[Ca.sup.2+]].sub.i] rise in metabolically inhibited endothelial cells. D-myo-inositol 3-phosphate-sensitive [Ca.sup.2+] release; ischemia; hypoxia; cytosolic [Ca.sup.2+] concentration