The role of triglyceride accumulation and of necrosis in the hemodynamic responses of the isolated perfused rat liver after administration of carbon tetrachloride

Abstract

Carbon tetrachloride (CCl 4) treatment in the rat results in an increase in hepatic vascular resistance in the subsequently perfused isolated liver. The effects of several agents, which protect against various effects of CCl 4, on the increased hepatic resistance to perfusate flow induced by this hepatotoxic substance are presented. β-TM-10 and promethazine do not block increases in hepatic triglyceride content and, likewise, do not abate the early (3-hour) hemodynamic changes. These agents do protect against necrosis and also protect against the late (12-hour) increase in resistance if the animals are allowed to become hypothermic. If normal body temperature is maintained, protection against both responses is lost. The administration of EDTA does not protect against either the early or late response. Female rats, which show greater accumulation of fat, exhibit a greater 3-hour hemodynamic response than do males. This effect is antagonized by prior ovariectomy and treatment with testosterone. The administration of ethionine to female rats, which causes accumulation of fat, produces a significant increase in hepatic resistance to perfusate flow. This effect can be ameliorated by concomitant administration of methionine. The administration of thioacetamide, which leads to necrosis but not triglyceride accumulation, is also capable of producing a marked increase in hepatic resistance. However, this increase is seen only at 24 hours. The data are consistent with the previously reported biphasis effect of CCl 4 on hepatic resistance to perfusate flow and indicate the involvement of triglyceride accumulation in the early (3-hour) change and necrosis in the later (12-hour) change in resistance.