Opposing effects of tenidap on the volume-regulated anion channel and K ATP channel activity in rat pancreatic β-cells

Abstract

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 β-cells. Membrane potential, VRAC currents and input conductance were recorded from single rat β-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 (0.1 mM) was found to rapidly hyperpolarise the β-cell membrane potential and terminate glucose-induced electrical activity. This effect was associated with a pronounced outward current shift at a holding potential of − 65 mV. Tenidap was found to inhibit activity of the volume-regulated anion channel with IC 50 values of 31 and 43 µM for outward and inward currents respectively. Tenidap also markedly increased β-cell input conductance, representing an activation of the K ATP conductance. β-cell regulatory volume decrease following hypotonically-induced cell swelling was sensitive to inhibition by 50 µM tenidap. Tenidap is a potent inhibitor of the volume-regulated anion channel and K ATP channel activator in rat pancreatic β-cells. These actions could at least in part explain the recently reported inhibitory actions of the drug on electrical and secretory activity in the β-cell, and could also underlie other pharmacological actions of the drug.