1 The cytoskeletal depolymerizing agent, colchicine, prevents the hepatic alpha(1)-adrenoceptor-mediated stimulation of respiration, H+ and Ca2+ release to the effluent perfusate, intracellular alkalosis, and glycogenolysis. Unlike the other parameters, colchicine does not perturb the alpha(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(2)-adrenoceptor-mediated effects indicates that its actions are alpha(1)-specific. 2 Colchicine enhances the acute alpha(1)-adrenoceptor-mediated intracellular Ca2+ mobilization and prevents the activation of protein kinase C. This differential effect on the two branches of the a(1)-adrenoceptor signalling pathway is a distinctive feature of the colchicine action. 3 The lack of effect of colchicine in altering the alpha(1)-adrenoceptor ligand binding affinity suggests that it might interact with some receptor-coupled regulatory element(s). 4 The acuteness of the colchicine effect and the ability of its isomer beta-lumicolchicine to prevent all the alpha(1)-adrenoceptor-mediated responses but the increase in vascular resistance, indicate that its action cannot be merely ascribed to its effects in depolymerizing tubulin. 5 Colchicine perturbs the hepatic responses to vasoactive peptides. It enhances the vasopressin-induced rise of cytosolic free Ca2+ in isolated hepatocytes and prevents the sustained decrease of Ca2+ in the effluent perfusate. It also inhibits the stimulation of glycogenolysis, without altering the stimulation of gluconeogenesis. 6 It is concluded that there are at least two major alpha(1)-adrenoceptor signalling pathways. One is colchicine-sensitive, independent of variations in free cytosolic Ca2+, and protein kinase C-dependent; the other one is colchicine-insensitive, dependent on variations in free cytosolic Ca2+, and protein kinase C-independent.
