Carbon tetrachloride,
chloroform,
dimethylnitrosamine,
thioacetamide or
acetaminophen was each administered to rats in a single hepatotoxic dose.
Nifedipine,
verapamil or
chlorpromazine was administered in association with the hepatotoxic agents to determine if
calcium channel blocking agents would prevent an increase in liver cell
calcium associated with hepatotoxicity and to determine if these agents would protect against the development of centrilobular
necrosis. Following a latent period different for each toxic agent, a 4- to 18-fold increase in liver cell
calcium content had occurred by 24 hr. The
calcium increase and the centrilobular
necrosis (mean histologic score) were correlated. A relatively high
calcium to
necrosis ratio was obtained with
dimethylnitrosamine,
thioacetamide and
acetaminophen. A lesser
calcium to
necrosis ratio was obtained with
chloroform and
carbon tetrachloride, the two toxic agents that destroyed the intracellular
calcium sequestration activity of the liver endoplasmic reticulum.
Nifedipine or
chlorpromazine, administered prior to and 7 hr after the toxic agent, completely prevented the centrilobular
necrosis caused by
thioacetamide,
carbon tetrachloride and
acetaminophen; almost completely prevented
necrosis with
dimethylnitrosamine; and provided partial protection against
chloroform toxicity. Two doses of
verapamil provided partial protection against
necrosis when
carbon tetrachloride was the toxic agent and provided almost complete protection with
dimethylnitrosamine. A reduction in liver cell
calcium was associated with the protective action of the three
calcium channel blocking agents. These findings are compared with earlier studies of the protective effects of
calcium channel blocking agents in cardiac
ischemia.