Benton, D.C.H.; (1995) The pharmacology of calcium and ATP-dependent potassium channels in erythrocytes and in smooth skeletal muscle. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Potassium channels are a diverse class of membrane proteins found in virtually all cells. The first part of this study concerns the pharmacology of the calcium activated potassium channel (KCa) found in mammalian erythrocytes. This channel is blocked by cetiedil, an anti-sickling agent, and the initial section of the thesis explores the structure activity relationship (SAR) of compounds related to cetiedil, investigates their mechanism of action and compares them with other blocking agents. This was studied by measuring the effects of the test compounds on the KCa -mediated net K+ loss which results from the application of A23187 to a suspension of rabbit erythrocytes. Qualitative differences between the action of the cetiedil analogues and another potent KCa blocker, clotrimazole, were observed, suggesting a different mechanism of channel block. The relative activity of the optical enantiomers of cetiedil, UCL 1348 and UCL 1349, as anti-muscarinic and calcium entry blocking agents were also examined. Finally, the ability of cetiedil and two of its analogues, UCL 1495 and UCL 1285, to inhibit levcromakalim stimulated 86Rb efflux from rat aorta was compared. The results indicate that the SAR for cetiedil at this site differs from that for in erythrocytes. In the second part the effects of K+ channel openers (KCO's) and metabolic inhibition on K+ channels in skeletal muscle were investigated. In the frog, cromakalim and levcromakalim increased 86Rb efflux and caused membrane hyperpolarisation associated with a decrease in input resistance. The effects of cromakalim were blocked by glibenclamide and tolbutamide. These findings are consistent with an action of cromakalim on ATP-sensitive potassium channels (KATP). Comparisons are made between this channel and the KCO sensitive K+ channel of smooth muscle. Levcromakalim was far less effective in mammalian skeletal muscle and possible reasons for the difference between frog and mammalian muscle are discussed. An incidental observation was that metabolic inhibition caused a large Ba2+ sensitive increase in 86Rb efflux from mouse soleus. However, only a small component was blocked by glibenclamide suggesting involvement of channels other than KATP.

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