Opposing effects of tenidap on the volume-regulated anion channel and K(ATP) channel activity in rat pancreatic beta-cells.
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.
Best
Leonard
L
Schools of Medicine, University of Manchester, UK. Len.Best@cmft.nhs.uk
Brown
Peter D
PD
Sener
Abdullah
A
Malaisse
Willy J
WJ
D000818:Animals; D048429:Cell Size / Q000187:drug effects; D004553:Electric Conductivity; D005260:Female; D007211:Indoles / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D054086:KATP Channels / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D000078183:Oxindoles; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism*
D007211:Indoles; D054086:KATP Channels; D000078183:Oxindoles; D050994:Voltage-Dependent Anion Channels; C062866:tenidap