Health  Vol.2 No.2 , February 2010
Comparative effects of idazoxan, efaroxan, and BU 224 on insulin secretion in the rabbit: Not only interaction with pancreatic imidazoline I2 binding sites
Abstract: The nature of the binding site(s) involved in the insulin secretory activity of imidazoline compo- unds remains unclear. An imidazoline I2 binding site (I2BS) has been neglected since the classic I2 ligand, idazoxan, does not release insulin. Using the rabbit as an appropriate model for the study of this type of binding sites, we have tried to re-evaluate the effects of idazoxan, the selective I2 compound BU 224, and efaroxan on insulin secretion. Mimicking efaroxan, idazoxan and BU 224 potentiated insulin release from perifused islets in the presence of 8 mM glucose. In static incubation, insulin secretion induced by idazoxan and BU 224 exhibited both dose and glucose dependencies. ATP-sensitive K+ (KATP) channel blockade, though at a different site from the SUR1 receptor, with subsequent Ca2+ entry, mediates the insulin releasing effect of the three ligands. However, additional MAO independent intracellular steps in stimulus- secretion coupling linked to PKA and PKC activation are only involved in the effect of BU 224. Therefore, both an I2 related binding site at the channel level shared by the three ligands and a putative I3-intracellularly located binding site stimulated by BU 224 would be mediating insulin release by these compounds. In vivo experiments reassess the abilities of idazoxan and BU 224 to enhance glucose-induced insulin secretion and to elicit a modest blood glucose lowering response.
Cite this paper: nullGarcía-Barrado, M. , Pastor, M. , Iglesias-Osma, M. , Carpéné, C. and Moratinos, J. (2010) Comparative effects of idazoxan, efaroxan, and BU 224 on insulin secretion in the rabbit: Not only interaction with pancreatic imidazoline I2 binding sites. Health, 2, 112-123. doi: 10.4236/health.2010.22018.

[1]   [1] Chan, S.L., Brown, C.A., and Morgan, N.G. (1993) Stimulation of insulin secretion by the imidazoline alpha 2-adrenoceptor antagonist efaroxan is mediated by a novel, stereoselective, binding site. Eur J Pharmacol, 230(3), 375-8.

[2]   [2] Schulz, A. and Hasselblatt, A. (1989) An insulin-releasing property of imidazoline derivatives is not limited to compounds that block alpha-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol, 340, 321-7.

[3]   [3] Berdeu, D., Puech, R., Ribes, G., Loubatieres-Mariani, M.M., and Bertrand, G. (1997) Antazoline increases insu-lin secretion and improves glucose tolerance in rats and dogs. Eur J Pharmacol, 324, 233.

[4]   [4] Pele-Tounian, A., Chan, S.L., Rondu, F., Le Bihan, G., Giroix, M.H., Lamouri, A., Touboul, E., Pfeiffer, B., Manechez, D., Renard, P., Guardiola-Lemaitre, B., God-froid, J.J., Penicaud, L., Morgan N.G., and Ktorza A. (1999) Effect of the new imidazoline derivative S-22068 (PMS 847) on insulin secretion in vitro and glucose turnover in vivo in rats. Eur J Pharmacol, 377, 81-87.

[5]   [5] Wang, X., Rondu, F., Lamouri, A., Dokhan, R., Marc, S., Touboul, E., Pfeiffer, B., Manechez D., Renard, P., Guar-diola-Lemaitre, B., Godfroid, J.J., Ktorza, A., and Peni-caud, L. (1996) Effect of S-21663 (PMS 812), an imida-zoline derivative, on glucose tolerance and insulin secre-tion in a rat model of type II diabetes. J Pharmacol Exp Ther, 278, 82-89.

[6]   [6] Williams, C.A., Shih, M.F., and Taberner, P.V. (2000) Effect of acute and sub-chronic administration of the imidazoline compound S22068 on in vivo glucose and insulin responses in normal lean CBA/Ca mice. Gen. Pharmacol., 34, 183-91.

[7]   [7] Efendic, S., Efanov, A.M., Berggren, P.O., and Zaitsev, S.V. (2002) Two generations of insulinotropic imidazoline compounds. Diabetes, 51 (3), S448-S547.

[8]   [8] Efanov, A.M., Zaitsev, S.V., Mest, H.J., Raap, A., Appel-skog, I.B., Larsson, O., Berggren, P.O., and Efendic, S. (2001) The novel imidazoline compound BL11282 po-tentiates glucose-induced insulin secretion in pancreatic beta-cells in the absence of modulation of KATP channel activity. Diabetes, 50, 797-802.

[9]   [9] Proks, P. and Ashcroft, F.M. (1997) Phentolamine block of KATP channels is mediated by Kir6.2. Proc Natl Acad Sci USA, 94, 1716-20.

[10]   [10] Morgan, N.G., Chan, S.L., Mourtada, M., Monks, L.K., and Ramsden, C.A. (1999) Imidazolines and pancreatic hormone secretion. Ann N Y Acad Sci, 881, 217-28.

[11]   [11] Farret, A., Lugo-Garcia, L., Galtier, F., Gross, R., and Petit, P. (2005) Pharmacological interventions that di-rectly stimulate or modulate insulin secretion from pan-creatic beta-cell: Implications for the treatment of type 2 diabetes. Fundam Clin Pharmacol, 19, 647-656.

[12]   [12] Mourtada, M., Smith, S.A., and Morgan, N.G. (1998) Effector systems involved in the insulin secretory re-sponses to efaroxan and RX871024 in rat islets of Langerhans. Eur J Pharmacol, 350, 251-8.

[13]   [13] Rustenbeck, I., Leupolt, L., Kowalewski, R., and Hassel-blatt, A. (1999) Heterogeneous characteristics of imida-zoline-induced insulin secretion. Naunyn Schmiedebergs Arch Pharmacol, 359, 235-42.

[14]   [14] Mourtada, M., Brown, C.A., Smith, S.A., Piercy, V., Chan, S.L., and Morgan, N.G. (1997) Interactions between imi-dazoline compounds and sulphonylureas in the regulation of insulin secretion. Br J Pharmacol, 121, 799-805.

[15]   [15] Berdeu, D., Gross, R., Puech, R., Loubatieres-Mariani, M.M., and Bertrand, G. (1995) Evidence for two different imidazoline sites on pancreatic B cells and vascular bed in rat. Eur J Pharmacol, 275, 91-8.

[16]   [16] Zaitsev, S.V., Efanov, A.M., Raap, A., Efanova, I.B., Schloos, J., Steckel-Hamann, B., Larsson, O., Ostenson, C.G., Berggren, P.O., Mest, H.J., and Efendic, S. (1999) Different modes of action of the imidazoline compound RX871024 in pancreatic beta-cells: Blocking of K+ channels, mobilization of Ca2+ from endoplasmic reticu-lum, and interaction with exocytotic machinery. Ann N Y Acad Sci, 881, 241-52.

[17]   [17] Boronat, M.A., Olmos, G., Miller, D.D., Patil, P.N., and Garcia-Sevilla, J.A. (1998) Isothiocyanatobenzyl imida-zoline is an alkylating agent for I2-imidazoline binding sites in rat and rabbit tissues. Naunyn Schmiedebergs Arch Pharmacol, 357, 351-57.

[18]   [18] Chan, S.L., Brown, C.A., Scarpello, K.E., and Morgan, N.G. (1994) The imidazoline site involved in control of insulin secretion: Characteristics that distinguish it from I1- and I2-sites. Br J Pharmacol, 112, 1065-70.

[19]   [19] Le Brigand, L., Virsolvy, A., Manechez, D., Godfroid, J.J., Guardiola-Lemaitre, B., Gribble, F.M., Ashcroft, F.M., and Bataille, D. (1999) In vitro mechanism of action on insulin release of S-22068: A new putative antidiabetic compound. Br J Pharmacol, 128, 1021-6.

[20]   [20] Cooper, E.J., Hudson, A.L., Parker, C.A., and Morgan, N.G. (2003) Effects of the beta-carbolines, harmane and pinoline: On insulin secretion from isolated human islets of Langerhans. Eur J Pharmacol, 482, 189-96.

[21]   [21] Mayer, G. and Taberner, P.V. (2002) Effects of the imi-dazoline ligands efaroxan and KU14R on blood glucose homeostasis in the mouse. Eur J Pharmacol, 454, 95-102.

[22]   [22] Ernsberger, P. (1992) Heterogeneity of imidazoline bind-ing sites: Proposed I1 and I2 subtypes. Fund Clin Phar-macol., 6(1), 55S.

[23]   [23] Coupry, I., Podevin, R.A., Dausse, J.P., and Parini, A. (1987) Evidence for imidazoline binding sites in baso-lateral membranes from rabbit kidney. Biochem Biophys Res Commun, 147, 55-60.

[24]   [24] Hudson, A.L, Husbands, S., Lewis, J.W., and Nutt, D.J. (1994) Affinity and selectivity of BU224 and BU239 for rabbit brain non-adrenoceptor idazoxan binding sites (I2-sites). Br J Pharmacol, 112, (Proceedings Suppl), 320.

[25]   [25] Jou, S.B., Liu, I.M., and Cheng, J.T. (2004) Activation of imidazoline receptor by agmatine to lower plasma glucose in streptozotocin-induced diabetic rats. Neurosci Lett, 358, 111-4.

[26]   [26] MacInnes, N. and Handley, S.L. (2002) Characterization of the discriminable stimulus produced by 2-BFI: Effects of imidazoline I(2)-site ligands, MAOIs, beta-carbolines, agmatine, and ibogaine. Br J Pharmacol, 135, 1227-34.

[27]   [27] Nutt, D.J., French, N., Handley, S., Hudson, A., Husbands, S., Jackson, H., Jordan, S., Lalies, M.D., Lewis, J., Lione, L., et al. (1995) Functional studies of specific imidazoline-2 receptor ligands. Ann N Y Acad Sci, 763, 125-39.

[28]   [28] García-Barrado, M.J., Sancho, C., Iglesias-Osma, M.C., and Moratinos, J. (2001) Effects of verapamil and el-godipine on isoprenaline-induced metabolic responses in rabbits. Eur J Pharmacol., 415, 105-115.

[29]   [29] Moratinos, J., Carpene, C., De Pablos, I., and Reverte, M. (1988) Role of alpha 1- and alpha 2-adrenoceptors in catecholamine-induced hyperglycaemia, lipolysis and insulin secretion in conscious fasted rabbits. Br J Phar-macol, 94, 299-310.

[30]   [30] Chan, S.L., Dunne, M.J., Stillings M.R., and Morgan, N.G. (1991) The alpha 2-adrenoceptor antagonist efaroxan modulates K+ATP channels in insulin-secreting cells. Eur J Pharmacol, 204, 41-8.

[31]   [31] Gembal, M., Gilon, P., and Henquin, J.C. (1992) Evidence that glucose can control insulin release independently from its action on ATP-sensitive K+ channels in mouse B cells. J Clin Invest, 89, 1288-95.

[32]   [32] Cuchillo-Ibanez, I., Lejen, T., Albillos, A., Rose, S.D., Olivares, R., Villarroya, M., et al. (2004) Mitochondrial calcium sequestration and protein kinase C cooperate in the regulation of cortical F-actin disassembly and secre-tion in bovine chromaffin cells. J Physiol, 560, 63-76.

[33]   [33] Henquin, J.C. (2004) Pathways in beta-cell stimulus- secretion coupling as targets for therapeutic insulin se-cretagogues. Diabetes, 53 (3), S48-S58.

[34]   [34] Zaitsev, S.V., Efanov, A.M., Efanova, I.B., Larsson, O., Ostenson, C.G., Gold, G., Berggren, P.O., and Efendic, S. (1996) Imidazoline compounds stimulate insulin release by inhibition of KATP channels and interaction with the exocytotic machinery. Diabetes, 45, 1610-1618.

[35]   [35] Serban, D.N., Serban, I.L., and Nechifor, M. (2004) Ida-zoxan effects upon contractile activity in the rat aorta are related to alpha adrenoceptors and L-type channels. Fundan Clin Pharmacol, 18, 635-41.

[36]   [36] Malaisse, W.J. and Moratinos, J. (1986) Are pancreatic beta-cells equipped with alpha-1 adrenoceptors? IRCS Med Sci, 1194-1195.

[37]   [37] Ugedo, L., Pineda, J., Ruiz-Ortega, J.A., and Martin-Ruiz, R. (1998) Stimulation of locus coeruleus neurons by non-I1/I2-type imidazoline receptors: An in vivo and in vitro electrophysiological study. Br J Pharmacol, 125, 1685-1694.

[38]   [38] Efanov, A.M., Zaitsev, S.V., Efanova, I.B., Zhu, S., Os-tenson, C.G., Berggren, .PO., and Efendic, S. (1998) Signalling and sites of interaction for RX-871024 and sulfonylurea in the stimulation of insulin release. Am J Physiol, 274, E751-E757.

[39]   [39] Mourtada, M., Chan, S.L., Smith, S.A., and Morgan, N.G. (1999) Multiple effector pathways regulate the insulin secretory response to the imidazoline RX871024 in iso-lated rat pancreatic islets. Br J Pharmacol, 127, 1279- 1287.

[40]   [40] Chan, S.L., Mourtada, M., and Morgan, N.G. (2001) Characterization of a KATP channel-independent pathway involved in potentiation of insulin secretion by efaroxan. Diabetes, 50, 340-347.

[41]   [41] Bleck, C., Wienbergen, A., and Rustenbeck, I. (2005) Essential role of the imidazoline moiety in the insulino-tropic effect but not the KATP channel-blocking effect of imidazolines: A comparison of the effects of efaroxan and its imidazole analogue, KU14R. Diabetologia, 48, 2567-75.

[42]   [42] Bour, S., Iglesias-Osma, M.C., Marti, L., Duro, P., Gar-cia-Barrado, M.J., Pastor, M.F., Prevot, D., Visentin, V., Valet, P., Moratinos, J., and Carpene, C. (2006) The imi-dazoline I2-site ligands BU 224 and 2-BFI inhibit MAO-A and MAO-B activities, hydrogen peroxide production, and lipolysis in rodent and human adipocytes. Eur J Pharmacol, 552, 20-30.

[43]   [43] Iglesias-Osma, M.C., Garcia-Barrado, M.J., Visentin, V., Pastor-Mansilla, M.F., Bour, S., Prevot, D., Valet, P., Moratinos, J., and Carpene, C. (2004) Benzylamine ex-hibits insulin-like effects on glucose disposal, glucose transport, and fat cell lipolysis in rabbits and diabetic mice. J Pharmacol Exp Ther, 309, 1020-1028.

[44]   [44] Kimura, A., Tyacke, R.J., Minchin, M.C., Nutt, D.J., and Hudson, A.L. (2003) Identification of an I(2) binding protein from rabbit brain. Ann N Y Acad Sci, 1009, 364-366.

[45]   [45] Paterson, L.M., Robinson, E.S., Nutt, D.J., and Hudson, A.L. (2003) In vivo estimation of imidazoline(2) binding site turnover. Ann N Y Acad Sci, 1009, 367-370.

[46]   [46] Dickinson, K., North, T.J., and Jones, R.B. (1999) BTS 67 582 may mediate insulin secretion via the putative pancre-atic islet imidazoline receptor. Br J Pharmacol, 126, 133.

[47]   [47] Page, T.B.C.J. (1997) Glucose-lowering effect of BTS 67 582. Br J Pharmacol, 122, 1464-8.

[48]   [48] Tesson, F., Limon-Boulez, I., Urban, P., Puype, M., Vandekerckhove, J., Coupry, I., Pompon, D., and Parini, A. (1995) Localization of I2-imidazoline binding sites on monoamine oxidases. J Biol Chem, 270, 9856-61.

[49]   [49] Marti, L., Morin, N., Enrique-Tarancon, G., Prevot, D., Lafontan, M., Testar, X., Zorzano, A., and Carpene, C. (1998) Tyramine and vanadate synergistically stimulate glucose transport in rat adipocytes by amine oxidase- dependent generation of hydrogen peroxide. J Pharmacol Exp Ther, 285, 342-9.

[50]   [50] Portillo, M., Reverte, M., Langin, D., Senard, J.M., Tran, M.A., Berlan, M., and Montastruc, J.L. (1991) Effect of a 7-day treatment with idazoxan and its 2-methoxy deriva-tive RX 821002 [correction of RX 821001] on alpha 2-adrenoceptors and non-adrenoceptor idazoxan binding sites in rabbits. Br J Pharmacol, 104, 190-194.