ORIGINAL ARTICLE

JOP. J. Pancreas (Online) 2003; 4(3):117-124.

Effects of the Imidazoline Binding Site Ligands, Idazoxan and Efaroxan, on the Viability of Insulin-Secreting BRIN-BD11 Cells

Hongwei Gao1, Mirna Mourtada1, Noel G Morgan1,2

1Cellular Pharmacology Group, School of Life Sciences, Keele University. Staffs, United Kingdom. 2Institute of Biomedical and Clinical Science, Peninsula Medical School. Plymouth, United Kingdom

Context Certain imidazoline drugs stimulate insulin secretion acutely but their longer term effects on the viability of pancreatic beta-cells are less well characterised. Indeed, some reports have suggested that imidazolines can be toxic to beta-cells while others have reported protective effects against other cytotoxic agents.

Objective In order to address these discrepancies, the effects of two structurally related imidazolines, efaroxan and idazoxan, on the viability of clonal BRIN-BD11 beta-cells, were compared.

Design and main outcome measures BRIN-BD11 cells were exposed to test reagents and their viability monitored by measuring cellular reducing ability and DNA fragmentation. Nitric oxide was measured indirectly via medium nitrite formation.

Results Efaroxan (up to 100 m M) did not directly affect BRIN-BD11 cell viability in the absence of other agents and it did not protect these cells against the cytotoxic effects of interleukin-1beta. Indeed, analysis of DNA fragmentation in BRIN-BD11 cells revealed that efaroxan enhanced the level of damage caused by interleukin-1beta. Idazoxan caused a time- and dose-dependent loss of BRIN-BD11 cell viability in the absence of other ligands. This was associated with marked DNA degradation but was not associated with formation of nitric oxide. The effects of idazoxan were insensitive to blockade of alpha2-adrenoceptors or 5-HT1A (5-hydroxytryptamine; serotonin) receptors.

Conclusions The results confirm that idazoxan is cytotoxic to beta-cells but show that efaroxan is better tolerated. However, since efaroxan enhanced the cytotoxic effects of interleukin-1beta, it appears that this imidazoline may sensitise BRIN-BD11 cells to the damaging effects of certain cytokines.

Full text: HTML format   PDF format
  Look up who cited this article

References

  1. Morgan NG, Chan SL. Imidazoline binding sites in the endocrine pancreas: can they fulfil their potential as targets for the development of new insulin secretagogues? Curr Pharm Des 2001; 7:1413-31. [More details]

  2. Bousquet P, Dontenwill M, Greney H, Feldman J. Imidazoline receptors in cardiovascular and metabolic diseases. J Cardiovasc Pharmacol 2000; 35(Suppl 4):S21-5. [More details]

  3. Evans AJ, Krentz AJ. Recent developments and emerging therapies for type 2 diabetes mellitus. Drugs R D 1999, 2:75-94. [More details]

  4. Eglen RM, Hudson AL, Kendall DA, Nutt DJ, Morgan NG, Wilson VG, Dillon MP. 'Seeing through a glass darkly': casting light on imidazoline 'I' sites. Trends Pharmacol Sci 1998; 19:381-90. [More details]

  5. Morgan NG, Chan SL, Mourtada M, Monks LK, Ramsden CA. Imidazolines and pancreatic hormone secretion. Ann N Y Acad Sci 1999; 881:217-28. [More details]

  6. Chan SL, Morgan NG. Stimulation of insulin secretion by efaroxan may involve interaction with potassium channels. Eur J Pharmacol 1990; 176:97-101. [More details]

  7. Dunne MJ. Block of ATP-regulated potassium channels by phentolamine and other alpha-adrenoceptor antagonists. Br J Pharmacol 1991; 103:1847-50. [More details]

  8. Jonas JC, Plant TD, Henquin JC. Imidazoline antagonists of alpha 2-adrenoceptors increase insulin release in vitro by inhibiting ATP-sensitive K+ channels in pancreatic beta-cells. Br J Pharmacol 1992; 107:8-14. [More details]

  9. Rustenbeck I, Kopp M, Ratzka P, Leupolt L, Hasselblatt A. Imidazolines and the pancreatic B-cell. Actions and binding sites. Ann N Y Acad Sci 1999; 881:229-40. [More details]

  10. Proks P, Ashcroft FM. Phentolamine block of KATP channels is mediated by Kir6.2. Proc Natl Acad Sci U S A 1997; 94:11716-20. [More details]

  11. Mukai E, Ishida H, Horie M, Noma A, Seino Y, Takano M. The antiarrhythmic agent cibenzoline inhibits KATP channels by binding to Kir6.2. Biochem Biophys Res Commun 1998; 251:477-81. [More details]

  12. Zaitsev SV, Efanov AM, Efanova IB, Larsson O, Ostenson CG, Gold G, et al. Imidazoline compounds stimulate insulin release by inhibition of KATP channels and interaction with the exocytotic machinery. Diabetes 1996; 45:1610-8. [More details]

  13. Chan SLF, Mourtada M, Morgan NG. Characterization of a KATP channel-independent pathway involved in potentiation of insulin secretion by efaroxan. Diabetes 2001; 50:340-7. [More details]

  14. Efanov AM, Zaitsev SV, Mest HJ, Raap A, Appelskog IB, Larsson O, et al. The novel imidazoline compound BL11282 potentiates glucose-induced insulin secretion in pancreatic beta-cells in the absence of modulation of KATP channel activity. Diabetes 2001; 50:797-802. [More details]

  15. Gothert M, Molderings GJ, Reis DJ. Imidazoline receptors and their endogenous ligands: current concepts and therapeutic potential. Ann N Y Acad Sci 1999; 881:1-454. [More details]

  16. Chan SL, Brown CA, Scarpello KE, Morgan NG. The imidazoline site involved in control of insulin secretion: characteristics that distinguish it from I1- and I2-sites. Br J Pharmacol 1994; 112:1065-70. [More details]

  17. Chan SL, Monks LK, Gao H, Deaville P and Morgan NG Identification of the monomeric G-protein, Rhes, as an efaroxan-regulated protein in the pancreatic beta-cell. Br J Pharmacol 2002; 136:31-6. [More details]

  18. Mourtada M, Elliott J, Smith SA, Morgan NG. Effects of imidazoline binding site ligands on the growth and viability of clonal pancreatic beta-cells. Naunyn Schmiedebergs Arch Pharmacol 2000; 361:146-54. [More details]

  19. Zaitsev SV, Appelskog IB, Kapelioukh IL, Yang SN, Kohler M, Efendic S, Berggren PO. Imidazoline compounds protect against interleukin 1beta-induced beta-cell apoptosis. Diabetes 2001; 50(Suppl 1):S70-6. [More details]

  20. Rustenbeck I, Winkler M, Jorns A. Desensitization of insulin secretory response to imidazolines, tolbutamide and quinine. I. Secretory and morphological studies. Biochem Pharmacol 2001; 62:1685-94. [More details]

  21. Papaccio G, Nicoletti F, Pisanti FA, Galdieri M, Bendtzen K. An imidazoline compound completely counteracts interleukin-1beta toxic effects to rat pancreatic islet beta-cells. Mol Med 2002; 8:536-45. [More details]

  22. Eizirik DL, Mandrup-Poulsen T. A choice of death - the signal transduction of immune-mediated beta cell apoptosis. Diabetologia 2001, 44:2115-33. [More details]

  23. McClenaghan NH, Ball AJ, Flatt PR. Specific desensitization of sulfonylurea- but not imidazoline-induced insulin release after prolonged tolbutamide exposure. Biochem Pharmacol 2001; 61:527-36. [More details]

  24. Llado J, Esteban S, Garcia-Sevilla J. The alfa 2-adrenoceptor antagonist idazoxan is an agonist at 5-HT1A autoreceptors modulating serotonin synthesis in the rat brain in vivo. Neurosci Lett 1996; 218:111-4. [More details]

  25. Rustenbeck I, Kopp M, Polzin C, Hasselblatt A. No evidence for PKC activation in stimulation of insulin secretion by phentolamine. Naunyn Schmiedebergs Arch Pharmacol 1998; 358:390-3. [More details]

  26. Olmos G, Kulkarni RN, Haque M, MacDermot J. Imidazolines stimulate release of insulin from RIN-5AH cells independently from imidazoline I1 and I2 receptors. Eur J Pharmacol 1994; 262:41-8. [More details]

Keywords Apoptosis; Biological Phenomena, Cell Phenomena, and Immunity; Cell Death; Cell Physiology; Chemicals and Drugs Category; Dioxanes; Dioxins; Growth Substances; Heterocyclic Compounds; Heterocyclic Compounds, 1-Ring; Idazoxan; Imidazoles; Interleukin-1

Correspondence Noel G Morgan: noel.morgan@pms.ac.uk