Hypocalcemia in sepsis: Analysis of the subcellular distribution of Ca²⁺ in septic rats and LPS/TNF-α-treated HUVECs

Introduction: Hypocalcemia has been widely recognized in sepsis patients. However, the cause of hypocalcemia in sepsis is still not clear, and little is known about the subcellular distribution of Ca²⁺ in tissues during sepsis. Methodology: We measured the dynamic change in Ca²⁺ levels in body fluid and subcellular compartments, including the cytosol, endoplasmic reticulum and mitochondria, in major organs of cecal ligation and puncture (CLP)-operated rats, as well as the subcellular Ca²⁺ flux in HUVECs which treated by endotoxin and cytokines. Results: In the model of CLP-induced sepsis, the blood and urinary Ca²⁺ concentrations decreased rapidly, while the Ca²⁺ concentration in ascites fluid increased. The Ca²⁺ concentrations in the cytosol, ER, and mitochondria were elevated nearly synchronously in major organs in our sepsis model. Moreover, the calcium overload in CLP-operated rats treated with calcium supplementation was more severe than that in the non-calcium-supplemented rats but was alleviated by treatment with the calcium channel blocker verapamil. Similar subcellular Ca²⁺ flux was found in vitro in HUVECs and was triggered by lipopolysaccharide (LPS)/TNF-α. Conclusions: Ca²⁺ influx from the blood into the intercellular space and Ca²⁺ release into ascites fluid may cause hypocalcemia in sepsis and that this process may be due to the synergistic effect of endotoxin and cytokines.