Liver cell adenylate cyclase and β-adrenergic receptors. Increased β-adrenergic receptor number and responsiveness in the hypothyroid rat

β-Adrenergic stimulation of adenylate cyclase activity and β-adrenergic receptor status were assessed in whole homogenates and various subcellular fractions of isolated hepatocytes obtained from hypothyroid or euthyroid rats. Hypothyroid rat hepatocytes were previously shown to display a potentiated β-adrenergic stimulation of cyclic AMP accumulation and activation of glycogen phosphorylase and the basis for this enhanced cyclic AMP response was investigated in the present study. Hepatocyte protein and the protein content of the various subcellular fractions derived from the hepatocytes were not affected by hypothyroidism. Stimulation of adenylate cyclase activity over basal in response to a maximal concentration of (-)-isoproterenol was 3-fold greater in homogenates prepared from hypothyroid as compared to euthyroid rat hepatocytes, although the stimulation in response to maximal concentration of glucagon was unaltered. The activities and recoveries of fluoride-stimulated adenylate cyclase of 5'-nucleotidase of homogenates and subcellular fractions were unaffected in the hypothyroid state. Cyclic AMP phosphodiesterase activity measured in homogenates at 0.125 and 1.025 μM substrate was likewise unaltered by hypothyroidism. Specific binding of [¹²⁵I] iodohydroxybenzylpindolol was increased in homogenate, particulate, and purified membrane fractions obtained from hypothyroid, as compared to euthyroid, rat hepatocytes. The maximum binding capacity of purified hepatocyte membranes was increased 2-to 3-fold in the hypothyroid state. Specific binding of ¹²⁵I-glucagon to these membranes, in contrast, was found to be only 35% greater in hypothyroid as compared to euthyroid preparations. No change in the affinity of these [¹²⁵I] iodohydroxybenzylpindolol binding sites (K(d) ~ 0.2 nM) of purified membranes was noted in the hypothyroid state. The affinity of these sites for either (-)-propranolol (K(d), 2 to 4 nM) or (-)-isoproterenol (K(d)~ 15 nM), as assessed by binding inhibition studies, was unaltered in the hypothyroid state. The increased β-adrenergic response of the cyclase and increased number of [¹²⁵I]iodohydroxybenzylpindolol binding sites observed in preparations obtained from hypothyroid as compared to euthyroid rat hepatocytes were reversed by the administration of triiodothyronine to hypothyroid rats in vivo. This increase in the number of hepatocyte [¹²⁵I]iodohydroxybenzylpindolol binding sites (putative β-adrenergic receptors) appears to be the major factor responsible for the enhanced β-adrenergic stimulation of both adenylate cyclase activity and cyclic AMP accumulation by hepatocytes observed in the hypothyroid state. Thus, thyroid hormones appear to have the opposite effect on both β-adrenergic action, and β-adrenergic receptor number in the liver as compared to the heart.