Advertisement

Novel Actions of the Potassium Channel Modulator SDZ PCO 400 on ATP-Regulated Potassium Channels in Insulin Secreting Cells

SDZ PCO 400 and β-Cells
  • E. A. Harding
  • M. J. Dunne
Chapter
  • 117 Downloads
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 426)

Abstract

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).

Keywords

Potassium Channel Channel Modulator Cell Membrane Potential RINm5F Cell Potassium Channel Opener 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Cook, N.S., 1988, The pharmacology of potassium channels and their therapeutic potential. Trends Pharmacol. Sci. 9:21–28.PubMedCrossRefGoogle Scholar
  2. 2.
    Quast, U., and Cook, NS, 1989, Moving together, K+ channel openers and ATP-sensitive K+ channels, Trends in Pharmacol. Sci. 10: 431–435.CrossRefGoogle Scholar
  3. 3.
    Trube, G., Rorsman, P., and Ohno-Shosaku, T., 1986, Opposite effects of tolbutamide and diazoxide on the ATP-dependent K+ channel in mouse pancreatic β-cells, Pflugers Arch. 407: 493–499.PubMedCrossRefGoogle Scholar
  4. 4.
    Dunne, M.J., Ilott, M.C., and Petersen, O.H., 1987, Interactions of diazoxide, tolbutamide and ATP4− on nucleotide-dependent K+ channels in an insulin-secreting cell line, J. Membr. Biol. 99: 215–224.PubMedCrossRefGoogle Scholar
  5. 5.
    Hamilton, T.C., Weir, S.W., and Weston, A.H., 1986, Comparison of the effects of BRL 34915 and verapamil on electrical and mechanical activity in rat portal vein, Br. J. Pharmacol. 88: 103–111.PubMedCrossRefGoogle Scholar
  6. 6.
    Weir, S.W., and Weston, A.H., 1986, The effects of BRL34915 and nicorandil on electrical and mechanical activity and on 86Rb+ efflux in rat blood vessels, Br. J. Pharmacol. 88: 113–120.PubMedCrossRefGoogle Scholar
  7. 7.
    Edwards, G., and Weston, A.H., 1990, Structure-activity relationships of K+ channel openers, Trends Pharmacol. Sci. 11:417–423.PubMedCrossRefGoogle Scholar
  8. 8.
    Petersen, O.H., and Findlay, I., 1987, Electrophysiology of the pancreas, Physiol. Rev. 67: 1054–1116.PubMedGoogle Scholar
  9. 9.
    Ashcroft F.M., and Rorsman P., 1989, Electrophysiology of the pancreatic β-cell, Prog. Biophys. Mol. Biol. 54: 87–143.PubMedCrossRefGoogle Scholar
  10. 10.
    Dunne, M.J., and Petersen, O.H., 1991, Potassium selective ion channels in insulin-secreting cells, physiology, pharmacology and their role in stimulus-secretion coupling, Biochim. Biophys. Acta 1071: 67–82.PubMedCrossRefGoogle Scholar
  11. 11.
    Lebrun, P., Antoine M.-H., and Herchuelz, A., 1992, Mini review: K+ channel openers and insulin release, Life Sciences 51: 795.PubMedCrossRefGoogle Scholar
  12. 12.
    Ashcroft, F.M., Harrison, D.E., and Ashcroft, S.J.H., 1984, Glucose induces closure of single potassium channels in isolated rat pancreatic β-cells, Nature 312: 446–448.PubMedCrossRefGoogle Scholar
  13. 13.
    Henquin, J.C., and Meissner, H.P., 1982, Opposite effects of tolbutamide and diazoxide on 86Rb fluxes and membrane potential in mouse pancreatic B-cells, Biochemical Pharmacology 31: 1407–1413.PubMedCrossRefGoogle Scholar
  14. 14.
    Dunne, M.J., Aspinall, R.J., and Petersen, O.H., 1990a, Cromakalim (BRL 34915) opens ATP-sensitive potassium channels in insulin-secreting cells, Br. J. Pharmacol. 99: 169–175.PubMedCrossRefGoogle Scholar
  15. 15.
    Dunne, M.J., 1989, Protein phosphorylation is required for diazoxide to open ATP-sensitive potassium channels in insulin (RINm5F) secreting cells, FEBS Lett. 250: 262–266.PubMedCrossRefGoogle Scholar
  16. 16.
    Dunne, M.J., 1990, Effects of pinacidil, RP 49356 and nicorandil on ATP-sensitive potassium channels in insulin-secreting cells, Br. J. Pharmacol. 99: 487–492.PubMedCrossRefGoogle Scholar
  17. 17.
    Kozlowski, R.Z., Hales, C.N., and Ashford, M.L.J., 1989, Dual effects of diazoxide on ATP-K+ currents recorded from an insulin-secreting cell line. Br. J. Pharmacol. 97: 1039–1050.PubMedCrossRefGoogle Scholar
  18. 18.
    Kozlowski, R.Z., and Ashford, M.L.J., 1992, Nucleotide-dependent activation of K+ ATP channels by diazoxide in CRI-GI insulin-secreting cells. Br. J. Pharmacol. 107: 34–43.PubMedCrossRefGoogle Scholar
  19. 19.
    Harding, E.A., Jaggar, J.H., Ayton, B.J., and Dunne, M.J. 1993, Properties of diazoxide and cromakalim-induced activation of potassium channels in insulin-secreting cells; Effects of GTP, Exp. Physiol. 78: 25–34.PubMedGoogle Scholar
  20. 20.
    Jaggar, J.H., Harding, E.A., Ayton, B.J., and Dunne, M.J., 1993, Interaction of diazoxide and cromakalim with ATP-regulated potassium channels in insulin-secreting cells, J. Mol. Endocrinol 10: 59–70.PubMedCrossRefGoogle Scholar
  21. 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. 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. 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
  24. 24.
    Chapman, I.D., Kristersson, A., Meathelin, G., Schaemblin, E., Mazzoni, L., Boubekeur, K., Murphy, N., and Morley, J., 1992, Effects of a potassium channel activator (SDZ PCO 400) on guinea pig and human pulmonary airways, Br. J. Pharmacol. 106: 423–429.PubMedCrossRefGoogle Scholar
  25. 25.
    Small, R.C., Berry, J.L., Foster, R.W., Blarer, S., and Quast, U., 1992, Analysis of the relaxant action of SDZ PCO 400 in airway smooth muscle from ox and guinea pig, Eur. J. Pharmacol. 219: 81–88.PubMedCrossRefGoogle Scholar
  26. 26.
    Sutton, R., Peters, M., McShane, P., Gray, D.W.R., and Morris, P.J., 1986, Isolation of pancreatic islets by ductal injection of collaginase, Transplantation 42: 689–691.PubMedCrossRefGoogle Scholar
  27. 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
  28. 28.
    Sturgess, N., Ashford, M.L.J., Cook, D.L., and Hales, C.N., 1985, The sulphonylurea receptor may be an ATP-sensitive potassium channel, Lancet 8453: 474–475.CrossRefGoogle Scholar
  29. 29.
    Dunne, M.J. 1991, Block of ATP-regulated potassium channels by phentolamine and other a-adrenoceptor antagonists, Br. J. Pharmacol. 103: 1847–1850.PubMedCrossRefGoogle Scholar
  30. 30.
    Quast, U., 1993, Do the K+ channel openers relax smooth muscle by opening K+ channels? Trends in Pharmacol Sci., 14:332–337.CrossRefGoogle Scholar
  31. 31.
    Fozard, J.R., Menninger, K., Cook, N.S., Blarer, S., and Quast, U., 1990, The cardiovascular effects of SDZ PCO-400 in vivo, Br. J. Pharmacol. 99: 77P.CrossRefGoogle Scholar
  32. 32.
    Faivre, J.-J., and Findlay, I., 1989, Effects of tolbutamide, glibenclamide and diazoxide upon action potentials recorded from rat ventricular muscle, Biochim. Biophys. Acta 984: 1–5.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • E. A. Harding
    • 1
  • M. J. Dunne
    • 1
  1. 1.Cell Biology Research Group, Department of Biomedical ScienceThe UniversitySheffieldUK

Personalised recommendations