Imidazole antimycotics affect the activity of various ion channels and insulin secretion in mouse pancreatic B-cells.
In the present paper the effects of antimycotics with imidazole structure on the activity of various ion currents of mouse pancreatic B-cells and insulin secretion from isolated islets have been studied. Clotrimazole (0.1-10 microM, bath solution without albumin) reversibly inhibited the whole-cell K + ATP current studied with the patch-clamp technique and concomitantly depolarized the membrane potential. Two other structurally related compounds, econazole and ketoconazole, exhibited similar effects on the whole-cell K + ATP current. Clotrimazole also inhibited the current through single K + ATP channels measured in the inside-out configuration. According to these results it seems unlikely that a cytoplasmic factor is involved in the action of clotrimazole on K + ATP currents. Clotrimazole (10 microM) also reduced the current through voltage-dependent Ca2+ and K+ channels and altered inactivation kinetics. Moreover, clotrimazole reversibly abolished a recently described inward current which is induced by hypotonic cell swelling. The results show that clotrimazole altered the activity of all ion currents in B-cells investigated in this study. Clotrimazole (3-100 microM, solution with albumin) irreversibly inhibited insulin secretion from isolated islets. With econazole and ketoconazole similar effects on hormone release were observed. The changes in the activity and kinetics of voltage-dependent Ca2+ and K+ currents are likely to contribute to the observed inhibition of insulin secretion. However, we cannot entirely rule out that imidazole antimycotics also interfere with a step in stimulus-secretion coupling distal to changes in membrane potential.
Welker
S
S
Universität Tübingen, Abteilung Pharmakologie, Germany.
Drews
G
G
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D003022:Clotrimazole / Q000494:pharmacology; D046508:Culture Techniques; D004464:Econazole / Q000494:pharmacology; D004594:Electrophysiology; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D051379:Mice; D018408:Patch-Clamp Techniques
D000935:Antifungal Agents; D007093:Imidazoles; D007328:Insulin; D007473:Ion Channels; D004464:Econazole; D003022:Clotrimazole; D007654:Ketoconazole