Comparative Effects of Efaroxan and b‐Carbolines on the Secretory Activity of Rodent and Human b Cells

Abstract

The pancreatic beta-cell expresses an imidazoline-binding site that is involved in the regulation of insulin secretion. This site is pharmacologically atypical in comparison with the I(1) and I(2) sites described in other tissues, and it has been classified as I(3). The structural requirements for binding of ligands to the I(3) site have not been fully defined, although a range of synthetic I(3) ligands have been characterized in functional terms. Evidence has been presented that an endogenous I(3) ligand may exist, because extracts of brain contain an active principle that stimulates insulin secretion in a manner consistent with the involvement of I(3) sites. The active component has not been identified but has been equated with the long-sought clonidine displacing substance (CDS) that is proposed as the endogenous ligand for imidazoline-binding sites. Recent evidence has indicated that one active component of CDS may be a beta-carboline, but it is not known whether beta-carbolines can stimulate insulin secretion. Thus, we have studied the effects of beta-carbolines on insulin secretion and cytosolic Ca(2+) levels in rodent and human islet cells. The results reveal that harmane, pinoline, and norharmane cause a dose- and glucose-dependent increase in insulin secretion but show that this response differs in a number of ways from that elicited by the well-characterized I(3)-agonist, efaroxan. Thus, beta-carbolines represent a new class of insulin secretagogues, although it remains unclear whether their action is mediated solely by I(3) sites in the beta cell.

Activation of imidazoline‐I3 receptors ameliorates pancreatic damage

“…Thus, although agmantine belongs to a non‐selective agonist of imidazoline receptors, administration agmantine to β‐cells will assure its action via activation of I3 receptors in the main. The first described insulinotropic action of I3 imidazolines was the closure of ATP‐sensitive potassium channels (K ATP ), which leads to depolarization, calcium influx and release of insulin . The existence of distinct I3 binding proteins has also been suggested on the basis of pharmacological experiments, which demonstrated that although the I3 agonist, efaroxan, and the β‐carboline, harmane, directly elevate cytosolic Ca 2+ and increase insulin secretion, these responses display different characteristics .…”

“…The first described insulinotropic action of I3 imidazolines was the closure of ATP-sensitive potassium channels (K ATP ), which leads to depolarization, calcium influx and release of insulin. 21 The existence of distinct I3 binding proteins has also been suggested on the basis of pharmacological experiments, which demonstrated that although the I3 agonist, efaroxan, and the b-carboline, harmane, directly elevate cytosolic Ca 2+ and increase insulin secretion, these responses display different characteristics. 10 In the present study, KU14R, a specific antagonist against the imidazoline I3 receptor, could inhibit the agmatine-induced cell protective effect, suggesting that agmatine functions through the imidazoline I3 receptor.…”

Endogenous β‐Carbolines as Clonidine‐Displacing Substances

“…43 The I 3 site is associated with potentiation of insulin secretion, and harmane has been shown to induce insulin secretion. 44 Furthermore, Harmane induces a hypotensive response when injected into the rostrolateral ventrolateral medulla of rats, an effect which is antagonized by the mixed I 1 -α 2 AR antagonist efaroxan. 36…”

Imidazoline receptors agonists: possible mechanisms of endothelioprotection

“…Since the addition of an activator of K + -ATP-dependent diazoxin channels prevents insulinolysis, it is considered that I 3 R performs its function through regulation of K + and Ca 2+ concentrations of Langerhans cells. Later, β-carboline Harmane was found as its selective agonist (Morgan et al 2003).…”