Selective effects of portal blood diversion and glucagon on rat hepatocyte rates of S-phase entry and deoxyribonucleic acid synthesis.

Hepatocyte growth transition constants were measured during liver regeneration induced by 70% hepatectomy in portacaval shunted rats and in pair-fed sham-operated controls. Portal blood diversion 48 h before 70% hepatectomy coordinately reduced DNA synthetic and mitotic responses 60-70%. Both responses reflected preferential changes in overall rates of S- and M-phase entry (S delta and M delta, respectively); marked differences were not seen between experimental or control DNA synthesis and mitotic onset times (St = approximately 12 h; and Mt = approximately 20 h, for each group). Proliferative defects were manifested progressively across the liver lobule, from portal (approximately 44% of control) to midzonal (approximately 20%) to central areas (approximately 5%). In addition, radioautography and studies of [3H]thymidine uptake into nuclear DNA showed that in shunted rats, average DNA synthesis rates per hepatocyte fell 44-86% between 16-30 h. RIAs of glucagon and insulin in portal and aortic plasma obtained from 0-72 h showed overall reductions of 37-41% in hepatic hormone gradients of shunted rats. The greatest decreases occurred 8-24 h after 70% hepatectomy. Early (0-2 h) or late prereplicative (8-10 h) administration of insulin (0.02-1 mg kg-1) failed to restore [3H]thymidine uptake rates at 22-24 h to normal levels. However, exogenous glucagon (20 micrograms kg-1) given at 8-10 h increased these rates to 50% of control values. Higher doses (0.2-1 mg glucagon kg-1) were inhibitory. By contrast, no effects on DNA synthesis were found when glucagon was injected between 0-2 h. These findings suggest that hepatocyte growth transition constants are modulated selectively by different mitogens. Glucagon may control S delta and average hepatocellular DNA synthesis rates apart from other endocrine factors that regulate St.