Barbiturates inhibit ATP-K+ channels and voltage-activated currents in CRI-G1 insulin-secreting cells.
1. Patch-clamp recording techniques were used to examine the effects of barbiturates upon the ATP-K+ channel, and voltage-activated channels present in the plasma membrane of CRI-G1 insulin-secreting cells. 2. Thiopentone inhibited ATP-K+ channel activity when applied to cell-attached patches or the intracellular or extracellular surface of cell-free patches. Secobarbitone and pentobarbitone were also effective inhibitors of ATP-K+ channels in cell-free patches, whereas phenobarbitone was ineffective. 3. The diabetogenic agent, alloxan, which is structurally related to the barbiturates also produced an inhibition of ATP-K+ channel activity in outside-out patches. 4. Whole-cell ATP-K+ currents were used to quantify the effects of the barbiturates: concentration-inhibition curves for thiopentone, secobarbitone and pentobarbitone resulted in IC50 values of 62, 250 and 360 microM respectively. Phenobarbitone at a concentration of 1 mM was virtually ineffective. 5. Calculation of the apparent membrane concentrations for these drugs indicate that for a given degree of ATP-K+ channel inhibition a similar concentration of each barbiturate is present in the membrane. This suggests that hydrophobicity plays a primary role in their mechanism of action. The pH-dependence and additive nature of barbiturate block also indicates a membrane site of action. 6. Thiopentone, (100 microM) was also found to inhibit differentially voltage-activated whole-cell currents. The relative potency of thiopentone at this concentration was 0.64, 0.38 and 0.12 for inhibiting Ca2+, K+ and Na+ currents respectively when compared with its ability to inhibit the ATP-K+ channel.
Kozlowski
R Z
RZ
Department of Pharmacology, University of Cambridge.
Ashford
M L
ML
D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D001463:Barbiturates / Q000494:pharmacology*; D002478:Cells, Cultured; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007515:Islets of Langerhans / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D013874:Thiopental / Q000494:pharmacology
D001463:Barbiturates; D015221:Potassium Channels; D000255:Adenosine Triphosphate; D013874:Thiopental; D003981:Diazoxide