Stimulatory and inhibitory effects of catecholamines on DNA synthesis in primary rat hepatocyte cultures: role of alpha 1- and beta-adrenergic mechanisms.
Previous studies suggest that catecholamines may be involved in the regulation of liver growth. Considerable evidence implicates alpha 1-adrenergic mechanisms in the initiation of hepatocyte proliferation, while the role of beta-adrenoceptors is less clear. We have examined further the adrenergic regulation of hepatocyte DNA synthesis, using primary monolayer cultures. In hepatocytes 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 beta-adrenergic agonist isoproterenol and the alpha-adrenergic agonist phenylephrine also stimulated the DNA synthesis, but were less efficient than epinephrine and norepinephrine. Experiments with the alpha 1-receptor blocker prazosine and the beta-receptor blocker timolol showed that the stimulatory effect of norepinephrine consisted of both an alpha 1- and a beta-adrenergic component. The alpha 1-component was most prominent in terms of maximal response at high concentrations of the agonist, but the beta-component contributed significantly and predominated at low concentrations (less than 0.1 microM) of norepinephrine. At later stages (about 40 h) of culturing norepinephrine strongly but reversibly inhibited the cells, acting at a point late in the G1 phase. This inhibition was mimicked by isoproterenol and abolished by timolol but was unaffected by prazosine, suggesting a beta-adrenoceptor-mediated effect. The results confirm the alpha 1-adrenoceptor-mediated stimulatory effect, but also show that beta-adrenoceptors may contribute to the growth stimulation by catecholamines. Furthermore, catecholamines, via beta-adrenoceptors and cyclic AMP, inhibit the G1-S transition, and may thus play a role in the termination of hepatic proliferation.
Refsnes
M
M
Department of Pharmacology, Faculty of Medicine, University of Oslo, Norway.
Thoresen
G H
GH
Sandnes
D
D
Dajani
O F
OF
Dajani
L
L
Christoffersen
T
T
D000818:Animals; D002395:Catecholamines / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D004247:DNA / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D016193:G1 Phase / Q000502:physiology; D007328:Insulin / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008099:Liver / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D016196:S Phase / Q000502:physiology; D013997:Time Factors; D013999:Timolol / Q000494:pharmacology
D002395:Catecholamines; D007328:Insulin; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D010656:Phenylephrine; D004815:Epidermal Growth Factor; D013999:Timolol; D004247:DNA; D000242:Cyclic AMP; D007545:Isoproterenol; D009638:Norepinephrine; D011224:Prazosin; D004837:Epinephrine