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Modulation of the hepatic α 1 ‐adrenoceptor responsiveness by colchicine: dissociation of free cytosolic Ca 2+ ‐dependent and independent responses
Author(s) -
Butta Nora,
MartinRequero Angeles,
Urcelay Elena,
Parrilla Roberto,
Ayuso Matilde S.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15606.x
Subject(s) - glycogenolysis , colchicine , stimulation , endocrinology , medicine , receptor , biology , chemistry , biophysics , biochemistry , glycogen
1 . The cytoskeletal depolymerizing agent, colchicine, prevents the hepatic α 1 ‐adrenoceptor‐mediated stimulation of respiration, H + and Ca 2+ release to the effluent perfusate, intracellular alkalosis, and glycogenolysis. Unlike the other parameters, colchicine does not perturb the α 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 α 2 ‐adrenoceptor‐mediated effects indicates that its actions are α 1 ‐specific. 2 . Colchicine enhances the acute α 1 ‐adrenoceptor‐mediated intracellular Ca 2+ mobilization and prevents the activation of protein kinase C. This differential effect on the two branches of the α 1 ‐adrenoceptor signalling pathway is a distinctive feature of the colchicine action. 3 . The lack of effect of colchicine in altering the α 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 β‐lumicolchicine to prevent all the α 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 Ca 2+ in isolated hepatocytes and prevents the sustained decrease of Ca 2+ 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 α 1 ‐adrenoceptor signalling pathways. One is colchicine‐sensitive, independent of variations in free cytosolic Ca 2+ , and protein kinase C‐independent; the other one is colchicine‐insensitive, dependent on variations in free cytosolic Ca 2+ , and protein kinase C‐independent.