Protective effect of various calcium antagonists against an experimentally induced calcium overload in isolated hepatocytes.
The effect of the hepatotoxic substance diamidinothionaphthene (98/202) on cytosolic, mitochondrial and extra-mitochondrial calcium distribution was measured in isolated rat hepatocytes. The drastic disturbance of the intracellular calcium homeostasis caused by this substance (increase of the cytosolic and mitochondrial calcium contents and depletion of extra-mitochondrial calcium stores, which at last lead to cell death) gave rise to an investigation of the possible cytoprotective effect of calcium antagonists of various chemical classes: verapamil, diltiazem, and nifedipine on isolated hepatocytes. Our results show that all three calcium antagonists prevented cell death caused by 98/202. The 98/202-induced increase of cytosolic and mitochondrial calcium content was inhibited by all three calcium antagonists. However, only verapamil was able to inhibit the depletion of extra-mitochondrial calcium stores. Since 98/202-induced cell death occurs only in the presence of extracellular calcium, it is concluded that calcium antagonists are also able to inhibit the influx of extracellular calcium in liver cells, which leads to a calcium overload of the cytosol and mitochondria. The various ways of interfering with the calcium homeostasis of liver cells qualifies the hepatotoxic substance 98/202 as a suitable in vitro hepatotoxicity model for testing the hepatoprotective effect of different calcium antagonists.
Sippel
H
H
Dept of Pharmacology and Toxicology, University of Erlangen-Nürnberg, Germany.
Stauffert
I
I
Estler
C J
CJ
D000578:Amidines / Q000037:antagonists & inhibitors*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002470:Cell Survival; D002478:Cells, Cultured / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects; D010762:Phosphorylase a / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012430:Ruthenium Red
D000578:Amidines; D002121:Calcium Channel Blockers; D012430:Ruthenium Red; C016880:98-202; D010762:Phosphorylase a; D002118:Calcium