Predominance of beta-adrenergic over alpha-adrenergic receptor functions involved in phosphorylase activation in liver cells of cholestatic rats.
Hepatocytes isolated from normal and cholestatic rats responded to adrenergic agonists and antagonists in a quite different manner. Much greater activation of glycogen phosphorylase was caused by phenylephrine, an alpha-agonist, than by isoproterenol, a beta-agonist, in normal rat hepatocytes, and vice versa in the cholestatic rat cells. Epinephrine activation of phosphorylase was antagonized more efficiently by phenoxybenzamine, an alpha-antagonist, than by propranolol, a beta-antagonist, in normal rats, whereas it was antagonized totally by propranolol but only partially by phenoxybenzamine in cholestatic rat hepatocytes. The number of alpha-adrenergic receptors, measured by [3H]prazosin binding to membranes, as well as alpha-receptor-mediated increases in 32Pi incorporation into phosphatidylinositol and in 45Ca efflux, were reduced in hepatocytes after induction of cholestasis. The reduction of these parameters of alpha-receptor-linked functions was associated with the reciprocal increase in the number of beta-receptors and enhancement of beta-receptor-mediated accumulation of cyclic AMP in cholestatic rat hepatocytes. The affinity of epinephrine for beta-receptors was higher in cholestatic rat cells than in normal rat cells; this difference in affinity was abolished by the addition of guanylylimidodiphosphate, indicating that induction of cholestasis rendered hepatic beta-receptors more tightly coupled to the GTP-binding protein. Thus, the cascade reactions arising from beta-receptors are predominant over those from alpha-receptors, eventually leading to glycogen breakdown in cholestatic rat hepatocytes, principally because of not only the elevated beta to alpha ratio of the membrane receptor density but also the tight coupling of beta-receptors to the adenylate cyclase system via the guanine nucleotide regulatory protein.
D000818:Animals; D002478:Cells, Cultured; D002779:Cholestasis / Q000201:enzymology*; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004837:Epinephrine / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D008297:Male; D006005:Phosphorylases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D013565:Sympatholytics / Q000494:pharmacology; D013566:Sympathomimetics / Q000494:pharmacology; D014667:Vasopressins / Q000494:pharmacology
D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D013565:Sympatholytics; D013566:Sympathomimetics; D014667:Vasopressins; D000242:Cyclic AMP; D006005:Phosphorylases; D004837:Epinephrine