Modulation of the hepatic alpha sub(1)-adrenoceptor responsiveness by colchicine: Dissociation of free cytosolic Ca super(2+)-dependent and independent responses

The cytoskeletal depolymerizing agent, colchicine, prevents the hepatic alpha sub(1)-adrenoceptor-mediated stimulation of respiration, H super(+) and Ca super(2+) release to the effluent perfusate, intracellular alkalosis, and glycogenolysis. Unlike the other parameters, colchicine does not perturb the alpha sub(1)-agonist-induced stimulation of gluconeogenesis or phosphorylase `a' activation, and enhances the increase in portal pressure response. The lack of effect of colchicine on the hepatic alpha sub(2)-adrenoceptor-mediated effects indicates that its actions are alpha sub(1)-specific. Colchicine enhances the acute alpha sub(1)-adrenoceptor-mediated intracellular Ca super(2+) mobilization and prevents the activation of protein kinase C. This differential effect on the two branches of the alpha sub(1)-adrenoceptor signalling pathway is a distinctive feature of the colchicine action. The lack of effect of colchicine in altering the alpha sub(1)-adrenoceptor ligand binding affinity suggests that it might interact with some receptor-coupled regulatory element(s). The acuteness of the colchicine effect and the ability of its isomer beta -lumicolchicine to prevent all the alpha sub(1)-adrenoceptor-mediated responses but the increase in vascular resistance, indicate that its action cannot be merely ascribed to its effects in depolymerizing tubulin. Colchicine perturbs the hepatic responses to vasoactive peptides. It enhances the vasopressin-induced rise of cytosolic free Ca super(2+) in isolated hepatocytes and prevents the sustained decrease of Ca super(2+) in the effluent perfusate. It also inhibits the stimulation of glycogenolysis, without altering the stimulation of gluconeogenesis. It is concluded that there are at least two major alpha sub(1)-adrenoceptor signalling pathways. One is colchicine-sensitive, independent of variations in free cytosolic Ca super(2+), and protein kinase C-dependent; the other one is colchicine-insensitive, dependent on variations in free cytosolic Ca super(2+), and protein kinase C-independent.