Altered responses of regenerating hepatocytes to norepinephrine and transforming growth factor type β

Norepinephrine (NE), acting through the α 1 ‐adrenergic receptor, modulates the response of rat hepatocytes in primary culture to transforming growth factor type β 1 (TGFβ) by increasing the amount of TGFβ required for a given degree of inhibition of epidermal growth factor (EGF)‐induced DNA synthesis (Houck et al., J. Cell. Physiol. 135 :551–555, 1988). This effect was also found in hepatocytes isolated from regenerating livers but was greatly magnified in cells isolated between 12 and 18 hr after two‐thirds partial hepatectomy (PHX). During this period of enhanced sensitivity, NE was equally potent in terms of dose but more efficacious in the regenerating hepatocytes. As it did in control hepatocytes (Cruise et al., Science 227 :749–751, 1985), the α 1 ‐adrenergic receptor mediated the activity of NE in regenerating hepatocytes. Vasopressin (VP) and angiotensin‐II (AG) also antagonized the effect of TGFβ and showed increased activity in regenerating hepatocytes but at only 50% or less of the maximal effect reached by NE. Regenerating hepatocytes isolated 24–72 hr after PHX exhibited decreased sensitivity to inhibition by TGFβ, with a nadir in 48‐hr‐regenerating cells. These findings suggest that NE may be involved in triggering the early phase of DNA synthesis during liver regeneration, with the subsequent acquisition of innate resistance to TGFβ responsible for continued proliferation at a time when TGFβ mRNA is known to be increasing in the liver (Braun et al., Proc. Natl. Acad. Sci. USA 85 :1539–1543, 1988). EGF induced increased DNA and protein synthesis in cultures of control hepatocytes; TGFβ inhibited the EGF‐induced DNA synthesis but had no effect on protein synthesis. This may be relevant to the latter stages of liver regeneration, when high levels of TGFβ mRNA are detected in liver and cellular hypertrophy predominates over hyperplasia.