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The imidazoline site involved in control of insulin secretion: characteristics that distinguish it from I 1 ‐ and I 2 ‐sites
Author(s) -
Chan Susan L.F.,
Brown Colin. A.,
Scarpello Kay E.,
Morgan Noel G.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb13191.x
Subject(s) - imidazoline receptor , idazoxan , moxonidine , rilmenidine , endocrinology , medicine , chemistry , secretagogue , insulin , agonist , phentolamine , receptor , biology , prazosin , antagonist
1 The nature of the binding site mediating the insulin secretagogue activity of certain imidazoline compounds remains unclear and the pharmacology of the I 1 ‐ and I 2 ‐imidazoline sites, described in many tissues, does not correlate with the observed responses to imidazolines in islets. In the present paper, we describe further results which support the concept that the islet imidazoline site may represent a novel subtype of imidazoline receptor. 2 Culture of rat isolated islets in the presence of imidazoline secretagogues (either efaroxan or phentolamine) resulted in loss of responsiveness on subsequent re‐exposure to these agents. However, culture of islets with either idazoxan or UK 14,304 (imidazoline ligands that do not stimulate insulin secretion) did not lead to any loss of response when the islets were subsequently exposed to efaroxan. By contrast, islets cultured with UK 14,304 (a potent α 2 ‐adrenoceptor agonist), displayed loss of sensitivity to noradrenaline, consistent with down‐regulation of α 2 ‐adrenoceptors. 3 In order to characterize the imidazoline site further, radioligand binding studies were performed in membranes from RINm5F insulinoma cells using [ 3 H]‐RX821002, an imidazoline insulin secretagogue that does not interact significantly with imidazoline sites in other tissues. [ 3 H]‐RX821002 labelled α 2 ‐adrenoceptors with high affinity (2.01 ± 0.7 nM) but also labelled a second, non‐adrenoceptor site with much lower affinity. 4 Under conditions of α 2 ‐adrenoceptor blockade (in the presence of adrenaline), efaroxan displaced [ 3 H]‐RX821002 binding to the low affinity site, in a dose‐dependent manner. Competition studies employing additional imidazoline compounds of varying secretagogue activity revealed that the pharmacological profile of the low affinity site correlates well with that observed in secretion experiments. 5 The results obtained from the down‐regulation experiments with isolated islets and from the radioligand binding studies suggest that the low affinity [ 3 H]‐RX821002 binding site may represent the functional receptor responsible for the secretagogue activity of imidazoline compounds in the endocrine pancreas and that it has a pharmacological profile distinct from those of I 1 ‐ and I 2 ‐sites.