Calcium Behavior in Endotoxin‐Poisoned Mice: Especially Calcium Accumulation in Mitochondria

Abstract

A possible role of intracellular Ca2+ and participation of calmodulin in cellular metabolism in endotoxin‐poisoned mice were investigated. The levels of calcium in liver cytosol and liver mitochondria fractions in poisoned mice were markedly higher 18–48 hr after endotoxin injection than in the control mice. On the other hand, the levels of serum calcium in the poisoned mice were about 20% lower at 18 hr than in the controls. The serum calcium levels in mice injected with 50 and 100 μg of endotoxin showed no dose‐response effect, but a dose‐response effect was observed at a dose of 200–400 μg. The serum Ca2+ levels in endotoxin‐tolerant mice were similar to those in the control mice. The levels in mice injected with glucocorticoid‐antagonizing factor mice were about 14% lower at 3 hr than in the controls. The mice fed a vitamin D3‐ and calcium‐free diet showed a higher mortality rate in the early stage (12–18 hr) of endotoxication than that of the mice fed a normal diet.The lipid peroxide levels and Ca2+‐ATPase activity in the liver mitochondria fraction in endotoxin‐poisoned mice showed a higher level than those of the control mice. There was little or no difference in the levels of serum glucose between the mice injected with calmodulin antagonist (trifluoperazine, TFP) plus endotoxin and those given endotoxin alone. However, the liver glycogen levels in TFP plus endotoxin‐treated mice were markedly higher than that in mice given endotoxin alone. Furthermore, calcium antagonist (verapamil) plus endotoxin‐treated mice had about a 40% higher survival rate after 72 hr than those given endotoxin alone.The findings suggest that there is a possibility of participation of the Ca2+‐calmodulin system in carbohydrate metabolic disorders during endotoxemia and that the changes in intracellular Ca2+ may result in various metabolic disorders.

Histochemical alteration of Ca++ ATPase in liver of rats treated with endotoxin.

“…Serum and liver MDA increased after endotoxin injection. Sakaguchi (8) reported that the lipid peroxidation level and Ca ++ ATPase activity in the liver mitochondria fraction showed a higher level than those of control animals after endotoxin treatment.…”

“…Hepatic cellular Ca++ regulation appears to be affected during shock, and calcium ions are a possible candidate for an intracellular mediator in a variety of biochemical reactions during endotoxemia (8,11). The increase in cytosolic calcium produced by endotoxin could be due to altered movement of Ca++ between extracytosolic and cytoplasmic compartments, such as mitochondria, endoplasmic reticulum, and plasma membranae (10).…”

Participation of Calcium Ion on Depletion Mechanism of Liver Glycogen by Purified Glucocorticoid Antagonizing Factor Released in Blood during Endotoxemia

“…Recently, several studies have implicated endotoxin-mediated alterations in transmembrane Ca2+ movements and cellular Ca2+ homeostasis (3,9,17,18,(24)(25)(26). We reported (20,22) previously that there is a possibility of participation of the Ca2+ regulation in carbohydrate metabolic disorders and free radical formation during endotoxemia. It is well known that Ca2+ has an important role in glycogen metabolism, and especially it has been proposed as an additional candidate for an intracellular mediator of protein kinase of glycogen phosphorylase in liver.…”

Preventive Effects of a Chinese Herb Medicine (Sho‐saiko‐to) against Lethality after Recombinant Human Tumor Necrosis Factor Administration in Mice

“…Cytokines, in turn, may induce many of the responses associated with gram-negative bacterial sepsis or endotoxemia in animals (12). Although, until now, we have done various studies to prevent the shock syndromes after endotoxin administration (17,19), sufficient preventive effect could not be found in lethality to the endotoxemic animals. Tumor necrosis factor (TNF) was discovered in 1975, in the serum of BCGprimed and endotoxin-treated animals, as a polypeptide that induces hemorrhagic necrosis of tumors in recipient animals (5).…”

“…TNF and cachectin have severally been reported to cause a shock syndrome similar to endotoxin shock, and it has been suggested that TNF may be the major mediator of endotoxin shock (3,10). From a series in our study on metabolic response in endotoxemia (1,(15)(16)(17)(18)(19)(20), we paid attention to the pharmacological response of Kampo-Sho-saiko-to (14) in order to improve endotoxin shock. The present study was initially carried out to observe the effects of Sho-saiko-to on the lethal and antitumor activities of rhTNF in mice.…”