Box 1057 Blindern, N-0316 Oslo 3, Norway Previous studies suggest that catecholamines may be involved in the regulation of liver growth. Considerable evidence implicates a,-adrenergic mechanisms in the initiation of hepatocyte proliferation, while the role of P-adrenoceptors is less clear. We have examined further the adrenergic regulation of hepatocyte DNA synthesis, using primary monolayer cultures. In hepatocytcs that were also treated with epidermal growth factor and insulin, epinephrine or norepinephrine added early after the seeding strongly accelerated the rate of S phase entry. The P-adrenergic agonist isoproterenol and the a-adrenergic agonist phenylephrine also stimulated the DNA synthesis, but were less efficient than epinephrine and norepinephrine. Experiments with the a,-receptor blocker prazosine and thc (J-receptor blocker timolol showed that the stimulatory effect of norepinephrine consisted of both an a ,and a (J-adrenergic component. The a,-component was most prominent in terms of maximal response at high concentrations of the agonist, but the p-component contributed significantly and predominated at low concentrations (< 0.1 KM) of norepinephrine. At later stages (about 40 h) of culturing norepinephrine strongly but reversibly inhibited the cells, acting at a point late in the G, phase. This inhibition was mimicked by isoproterenol and abolished by timolol but was unaffected by prazosine, suggesting a (J-adrenoceptor-mediated effect.
The results confirm the a,-adrenoceptor-mediated stimulatory effect, but also show that p-adrenoceptors may contribute to the growth stimulation by catecholamines. Furthermore, catecholamines, via P-adrenoceptors and cyclic AMP, inhibit the G,-S transition, and may thus play a role in the termination of hepatic proliferation. o 1992 WiIey-Liss, Inc.