Opposing effects of tenidap on the volume-regulated anion channel and K(ATP) channel activity in rat pancreatic beta-cells.

Leonard Best, Peter D Brown, Abdullah Sener, Willy J Malaisse

Schools of Medicine, University of Manchester, UK. Len.Best@cmft.nhs.uk

European journal of pharmacology 2010 Mar 10

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Tenidap (5-chloro-2-hydroxy-3-(thiophene-2-carbonyl)indole-1-carboxamide) is a non-steroidal anti-inflammatory and anti-rheumatic drug with several cellular actions including inhibition of anion transport processes. Since other anion transport inhibitors have been shown to inhibit activity of the volume-regulated anion channel (VRAC), the present study investigated the effects of tenidap on activity of this channel in pancreatic beta-cells. Membrane potential, VRAC currents and input conductance were recorded from single rat beta-cells in primary culture using perforated patch, conventional whole-cell and cell-attached configurations of the patch-clamp technique. Relative cell volume was measured using a video-imaging method. Tenidap (0.1mM) was found to rapidly hyperpolarise the beta-cell membrane potential and terminate glucose-induced electrical activity. This effect was associated with a pronounced outward current shift at a holding potential of -65mV. Tenidap was found to inhibit activity of the volume-regulated anion channel with IC(50) values of 31 and 43microM for outward and inward currents respectively. Tenidap also markedly increased beta-cell input conductance, representing an activation of the K(ATP) conductance. beta-cell regulatory volume decrease following hypotonically-induced cell swelling was sensitive to inhibition by 50microM tenidap. Tenidap is a potent inhibitor of the volume-regulated anion channel and K(ATP) channel activator in rat pancreatic beta-cells. These actions could at least in part explain the recently reported inhibitory actions of the drug on electrical and secretory activity in the beta-cell, and could also underlie other pharmacological actions of the drug. Copyright (c) 2009 Elsevier B.V. All rights reserved.

Citation

Leonard Best, Peter D Brown, Abdullah Sener, Willy J Malaisse. Opposing effects of tenidap on the volume-regulated anion channel and K(ATP) channel activity in rat pancreatic beta-cells. European journal of pharmacology. 2010 Mar 10;629(1-3):159-63