MODULATION OF CL- SECRETION IN RAT DISTAL COLON BY GENISTEIN, A PROTEIN-TYROSINE KINASE INHIBITOR

Authors
Citation
M. Diener et F. Hug, MODULATION OF CL- SECRETION IN RAT DISTAL COLON BY GENISTEIN, A PROTEIN-TYROSINE KINASE INHIBITOR, European journal of pharmacology, 299(1-3), 1996, pp. 161-170
Citations number
27
Categorie Soggetti
Pharmacology & Pharmacy
ISSN journal
00142999
Volume
299
Issue
1-3
Year of publication
1996
Pages
161 - 170
Database
ISI
SICI code
0014-2999(1996)299:1-3<161:MOCSIR>2.0.ZU;2-9
Abstract
The protein tyrosine kinase inhibitor, genistein, caused an increase o f short-circuit current (Isc) across the rat distal colon in forskolin -pretreated tissues, suggesting a synergistic interaction of the drug with cAMP-dependent secretion. In the absence of forskolin, genistein had a dual effect on Isc, it increased Isc in tissues with a low basel ine, but decreased Isc in tissues with a high baseline Isc. The secret ory effect of genistein was dependent on the presence of Cl- and was b locked by inhibitors of Cl- secretion like bumetanide, an inhibitor of the Na+-K+-Cl- cotransporter, or 5-nitro-2-(3-phenylpropylamino)-benz oate (NPPB), a Cl- channel blocker. Unidirectional flux measurements r evealed that genistein inhibited Na+ and Cl- absorption and induced ne t Cl- secretion. The protein tyrosine phosphatase inhibitor vanadate s uppressed the secretory effect of genistein. In contrast, genistein ca used an inhibition of carbachol-induced, i.e. Ca2+-mediated secretion. Whole-cell patch-clamp experiments confirmed the synergistic effect o f genistein on cAMP-induced Cl- currents. In the presence of forskolin , genistein caused a depolarization concomitant with an increase in me mbrane inward current. In addition, genistein caused an inhibition of a basal K+ conductance and inhibited the Ca2+-dependent K+ conductance stimulated by carbachol. These results suggest a complex role of the protein tyrosine kinase pathway in the control of colonic Cl- secretio n, an antagonistic action on the cAMP pathway and a synergistic action on the Ca2+ pathway as revealed by the opposing effects of genistein. The physiological importance of this regulation remains to be clarifi ed.