Novel Actions of the Potassium Channel Modulator SDZ PCO 400 on ATP-Regulated Potassium Channels in Insulin Secreting Cells
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Potassium channel openers are a novel group of compounds that have potent effects upon a number of tissues. In general, their actions are most pronounced in smooth muscle cells, where they may prove to be an important group of agents effective against a number of pathophysiological disorders such as angina, hypertension, genitourinary dysfunction, asthma, etc. (for reviews see references 1 and 2). Despite the fact that diazoxide was the first synthetic compound shown to be directly capable of opening potassium ion channels(3, 4), prominent interest in the K+ channel modulators was only stimulated when the physiological and pharmacological effects of cromakalim (BRL 34915) were first described(5,6). Since then, cromakalim, and its active enantiomer levcromakalim, have become widely accepted as the ‘prototypical molecule,’ although there are several other structures capable of modulating K+ channels e.g. pinacidil, nicorandil, RP 49356, BPDZ44, etc.(1,2,7), see Table 1. Through the activation of K+ channels, these compounds elicit a marked hyperpolarisation of the cell membrane potential, leading to the inhibition of voltage-gated calcium channels and a subsequent lowering of the free intracellular calcium ion concentration ([Ca2+ i]). The principal site of action of the K+ channel activators is the ATP-gated potassium (K+ATP) channel. As has been well documented, this group of K+ channels play an important role in the regulation of insulin secretion from the β-cells of the pancreatic islets of Langerhans (for reviews see 8–11). Glucose-induced closure of K+ ATP channels initiates a depolarisation of the membrane, and the opening of voltage-gated Ca2+ channels(12).
KeywordsPotassium Channel Channel Modulator Cell Membrane Potential RINm5F Cell Potassium Channel Opener
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- 21.Pirotte, B., De Tullio, P., Lebrun, P., Antoine, M.-H., Masereel, B., Schynts, M., Dupont, L., Herchuelz, A., and Delarge, J., 1993, 3-Alkylamino-4H-pyrido[4,3-e][1,2,4]thiadiazine 1,1-dioxides as powerful inhibitors of insulin release from pancreatic B cells, J. Med. Chem. 36: 3211.PubMedCrossRefGoogle Scholar
- 22.Kane, C., Harding, E.A., Antoine, M.-H., Lebrun, P., Pirotte, B., James, R.F.L., Johnson, P.R.V., Lindley, K.J., and Dunne, M.J., 1995, Activation of potassium channels in human and rodent β-cells by BPDZ-44 and BPDZ-62 — mechanisms of action and effect in human neonatal nesidioblastosis, Diabetologia 38: A24.CrossRefGoogle Scholar
- 23.Evans, J.M., Hadley, M.S., and Stemp, G., 1992, Potassium channel activators, Structure-activity relationships. In: Potassium Channel Modulators, by A.H. Weston and T.C. Hamilton, pp 341–368. Blackwell, UK.Google Scholar
- 27.Dunne, M.J., Yule, D.I., Gallacher, D.V., and Petersen, O.H., 1990b, A comparative study of the effects of cromakalim BRL 34915., and diazoxide on membrane potential, [Ca2+]i and ATP-sensitive potassium currents in insulin-secreting cells, J. Membr. Biol., 114: 54–61.Google Scholar