An insulin-releasing property of imidazoline derivatives is not limited to compounds that block ?-adrenoceptors

Abstract

As we have demonstrated previously phentolamine stimulates the release of additional insulin from isolated mouse islets and raises plasma insulin levels in the whole rat. This effect was independent of the well known property of phentolamine to block alpha-adrenoceptors. In experiments on isolated pancreatic islets from mice we now demonstrate that tolazoline and antazoline which are chemically closely related to phentolamine, share its ability to potentiate insulin release. The following results were taken as evidence that this effect does not result from an alpha-adrenoceptor blocking action of imidazoline compounds. More than 10 times higher concentrations of phentolamine were required to liberate additional insulin from isolated islets than were effective in counteracting the inhibitory effect of clonidine on insulin release. The newly introduced alpha 2-adrenoceptor antagonist BDF 8933, which is an imidazoline derivative, stimulates insulin release as well, while the irreversible alpha-adrenoceptor blocking agent benextramine of different structure failed to do so, even when being present in concentrations blocking the alpha 2-adrenoceptor-mediated effects of clonidine. Antazoline shared the ability of phentolamine to stimulate insulin release despite having no or only very little alpha-adrenoceptor blocking activity. When used under our conditions, it almost entirely failed to alleviate the inhibition of insulin release induced by clonidine. We conclude that the response of the islet cells to imidazoline derivatives is not limited to those capable of blocking alpha-adrenoceptors. On the other hand, alpha-adrenoceptor blocking agents of different chemical structure fail to induce the release of additional insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Essential role of the imidazoline moiety in the insulinotropic effect but not the KATP channel-blocking effect of imidazolines; a comparison of the effects of efaroxan and its imidazole analogue, KU14R

“…The demonstration that the insulinotropic property of α-adrenoceptor ligands was not correlated with the α-antagonistic property but with the presence of an imidazoline moiety in the molecule [6,33] was the basis for the group name of insulinotropic imidazolines. This has led to the implicit assumption that these insulin secretagogues have a homogeneous pharmacological profile, which is not the case [2,3].…”

“…When it became clear that the insulinotropic property of this compound was not due to alpha-antagonism but was related to the presence of an imidazoline moiety [6,7], it was hypothesised that, like other tissues, beta cells express specific imidazoline binding sites [8][9][10]. A number of observations supported the view that these binding sites are receptors activating an intracellular signalling cascade, in particular that long-term exposure to imidazolines induces a homologous desensitisation and that enantiomers of efaroxan differ widely in their insulinotropic efficacy [11,12].…”

The imidazoline site involved in control of insulin secretion: characteristics that distinguish it from I1‐ and I2‐sites

“…Recent studies have shown that certain compounds which possess an imidazoline moeity within their structure, are able to enhance the rate of insulin secretion, both in vivo and in vitro (Ahren & Lundquist, 1985;Schulz & Hasselblatt, 1988;1989a;Chan et al, 1988;1991a). 86Rb+ efflux experiments and electrophysiological studies have provided evidence that this response is due to a reduction in potassium efflux through ATP-sensitive K+ channels in the islet P-cell plasma membrane, resulting in membrane depolarization (Chan & Morgan, 1990;Chan et al, 1991a,b;Dunne, 1991;Jonas et al, 1992).…”

Antagonism of the stimulatory effects of efaroxan and glibenclamide in rat pancreatic islets by the imidazoline, RX801080

“…It has now been established, however, that the primary determinant of this secretagogue activity is not a2-antagonism per se, but rather the possession of an imidazoline ring within the molecule. Thus, certain other imidazolines which are not a2-antagonists also have insulin secretagogue activity (Schulz & Hasselblatt 1989a); as does clonidine, which is an M2-adrenoceptor agonist (Schulz & Hasselblatt, 1989b;Plant et al, 1991).…”