Ž . European Journal of Pharmacology 342 1998 333–338 Chloroquine inhibits a -adrenergic action in hepatocytes 1B J. Adolfo Garcıa-Sainz ) , Artemio Mendoza-Mendoza ´ ´ Departimento de Bioenergetica, Instituto de Fisiologıa Celular, UniÕersidad Nacional Autonoma de Mexico, Apartado Postal 70-248, ´ ´ ´ 04510 Mexico, Mexico Received 26 June 1997; revised 13 October 1997; accepted 31 October 1997 Abstract Noradrenaline increased phosphorylase a activity through activation of a -adrenoceptors in rat hepatocytes. Such effect was 1B Ž . inhibited by chloroquine K f55 nM and only slightly reduced by high concentrations of primaquine. Chloroquine did not inhibit the i w 3 x activation of phosphorylase a induced by vasopressin or angiotensin II. Binding competition experiments using H prazosin showed that both chloroquine and primaquine interact with a -adrenoceptors, but only at very high concentrations. This indicates that the ability of 1B chloroquine to block the a -adrenergic action was not due to antagonism at the receptor level. Noradrenaline increased phosphatidyli- 1B nositol resynthesis and inositol trisphosphate production; these effects were inhibited by chloroquine and phorbol 12-myristate 13-acetate. Ž w w Ž . x Ž . . Staurosporine and Ro 31-8220 3- 1- 3- amidinothio propyl-1H-indol-3-yl -3- 1-methyl-1H-indol-3-yl maleimide , reduced the inhibitions induced by the active phorbol ester and the antimalarial drug on adrenergic-stimulated phosphatidylinositol resynthesis. Similarly, staurosporine blocked the inhibitory actions of chloroquine and phorbol 12-myristate 13-acetate on noradrenaline-stimulated inositol trisphosphate production. These data suggest the possibility that protein kinases, such as protein kinase C, could be involved in the actions of chloroquine. q 1998 Elsevier Science B.V. Keywords: a -Adrenoceptor; Hepatocyte; Chloroquine; Protein kinase C 1B 1. Introduction The natural adrenergic amines, adrenaline and nor- adrenaline, are among the main modulators of liver Ž . metabolism Hems and Whitton, 1980 , both a and b - 1 2 adrenoceptors seem to mediate such modulation. The rela- tive roles of these adrenoceptors and their densities in Ž hepatocytes vary considerably among species Sulakhe et . al., 1988 . In hepatocytes, from normal adult rats, a - 1 Ž adrenoceptors of the a subtype Han et al., 1987; 1B . Garcıa-Sainz et al., 1992; Garcıa-Sainz et al., 1994 are the ´ ´ ´ ´ main mediators of catecholamine actions. Activation of Ž a -adrenoceptors leads to phosphoinositide turnover hy- 1B drolysis of phosphatidylinositol 4,5-bisphosphate, with production of the second messengers, diacylglycerol and Ž . IP inositol 1,4,5-trisphosphate , and subsequent resynthe- 3 . 2q Ž sis of phosphoinositides and Ca signaling Garcıa-Sainz, ´ ´ ) Corresponding author. Tel.: q52-5-6225612; fax: q52-5-6225613; e-mail: agarcia@ifcsun1.ifisiol.unam.mx 1987; Garcıa-Sainz, 1993; Minneman and Esbenshade, ´ ´ . 1994; Graham et al., 1996 . Interestingly, activation of protein kinase C with active phorbol esters, such as phorbol 12-myristate 13-acetate Ž . PMA blocks immediately a -adrenergic actions, in cells 1 Ž such as hepatocytes Corvera and Garcıa-Sainz, 1984; ´ ´ Cooper et al., 1985; Lynch et al., 1985; Garcıa-Sainz et al., ´ ´ . 1985; Van de Werve et al., 1985; Corvera et al., 1986 , Ž smooth muscle cells Leeb-Lundberg et al., 1985, 1987; . Ž Bouvier et al., 1987 or fibroblasts Lattion et al., 1994; Diviani et al., 1996; Vazquez-Prado and Garcıa-Sainz, ´ ´ ´ . 1996 . This effect is associated to receptor phosphorylation Ž Leeb-Lundberg et al., 1985, 1987; Bouvier et al., 1987; . Lattion et al., 1994; Diviani et al., 1996 . This action of protein kinase C seems to be physiologically relevant in homologous and heterologous desensitization of the a - 1 Ž adrenergic action Garcıa-Sainz et al., 1986; Bouvier et al., ´ ´ . 1987; Cowlen and Toews, 1988; Diviani et al., 1996 . Although, other protein kinases also participate in these Ž processes Leeb-Lundberg et al., 1987; Lattion et al., . 1994 . 0014-2999r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved.