Age-associated alterations in hepatic beta-adrenergic receptor/adenylate cyclase complex.

The effect of age on catecholamine regulation of hepatic glycogenolysis and on hepatic adenylate cyclase was studied in male rats up to 24 mo of age. Epinephrine and norepinephrine stimulated glycogenolysis in isolated hepatocytes at all age groups studied. Isoproterenol, however, stimulated glycogenolysis only at 24 mo. In isolated liver membranes, usual activators of adenylate cyclase increased the activity of the enzyme considerably more in membranes from 24-mo-old rats than in membranes from either 3- or 21-mo-old rats. The Mn2+-dependent activity of the cyclase was increased by 2.9-fold in 3-mo-old animals and approximately 5.7-fold in 24-mo-old rats, indicating a substantial age-dependent increase in the intrinsic activity of the catalytic unit. The density of the beta-adrenergic receptor, as measured by the binding of [125I]-iodocyanopindolol to plasma membranes, was 5-8 fmol/mg protein in rats aged 3-12 mo but increased to 19 fmol/mg protein in 24-mo-old rats. Computer-aided analysis of isoproterenol competition of the binding indicated a small age-dependent increase (from 30% at 3 mo to 43% at 24 mo) in the proportion of beta-receptors in the high-affinity state. These observations suggest that beta-receptor-mediated hepatic glycogenolysis in the aged rat is predicated upon increases in the density of beta-receptors as well as increased intrinsic activity of the catalytic unit of adenylate cyclase.