Effector systems involved in the insulin secretory responses to efaroxan and RX871024 in rat islets of Langerhans

Mourtada, Mirna; Smith, Stephen A.; Morgan, Noel G.

doi:10.1016/s0014-2999(98)00245-3

Cited by 13 publications

(21 citation statements)

References 26 publications

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“…This mechanism cannot account for the effects of efaroxan on insulin secretion, since the imidazoline does not alter islet cAMP levels ( Fig. 8; [14]) and its secretory effects are not impaired by inhibitors of protein kinase A (12). Furthermore, in permeabilized islets, any endogenous cAMP would be lost from the cells very rapidly by dilution into the incubation medium.…”

Section: K Atp Channel-independent Effects Of Efaroxanmentioning

confidence: 97%

“…Because efaroxan can potentiate Ca 2+ -induced insulin secretion by a mechanism that is independent of membrane potential, we investigated whether the actions of the imidazoline are mediated via a pathway that is also used by other potentiators of secretion. Previous work has shown that protein kinase C is not required for the secretory actions of imidazolines (7,12), and thus we explored the possible involvement of a protein kinase A-dependent mechanism.…”

Section: K Atp Channel-independent Effects Of Efaroxanmentioning

confidence: 99%

“…midazoline reagents, such as efaroxan (1)(2)(3)(4)(5), phentolamine (6)(7)(8), and RX871024 (9)(10)(11)(12)(13)(14), can stimulate insulin secretion both in vivo and in vitro, and a number of structurally related compounds are currently under development as novel oral antihyperglycemic agents. Despite this, the mechanism of action of imidazoline insulinsecretagogues has not been fully established, and their principal molecular target has not been defined at the level of the ␤-cell.…”

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confidence: 99%

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Characterization of a KATP Channel—Independent Pathway Involved in Potentiation of Insulin Secretion by Efaroxan

2001

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Efaroxan, like several other imidazoline reagents, elicits a glucose-dependent increase in insulin secretion from pancreatic ␤-cells. This response has been attributed to efaroxan-mediated blockade of K ATP channels, with the subsequent gating of voltage-sensitive calcium channels. However, increasing evidence suggests that, at best, this mechanism can account for only part of the secretory response to the imidazoline. In support of this, we now show that efaroxan can induce functional changes in the secretory pathway of pancreatic ␤-cells that are independent of K ATP channel blockade. In particular, efaroxan was found to promote a sustained sensitization of glucose-induced insulin release that persisted after removal of the drug and to potentiate Ca 2+ -induced insulin secretion from electropermeabilized islets. To investigate the mechanisms involved, we studied the effects of the efaroxan antagonist KU14R. This agent is known to selectively inhibit insulin secretion induced by efaroxan, without altering the secretory response to glucose or KCl. Surprisingly, however, KU14R markedly impaired the potentiation of insulin secretion mediated by agents that raise cAMP, including the adenylate cyclase activator, forskolin, and the phosphodiesterase inhibitor isobutylmethyl xanthine (IBMX). These effects were not accompanied by any reduction in cAMP levels, suggesting an antagonistic action of KU14R at a more distal point in the pathway of potentiation. In accord with our previous work, islets that were exposed to efaroxan for 24 h became selectively desensitized to this agent, but they still responded normally to glucose. Unexpectedly, however, the ability of either forskolin or IBMX to potentiate glucose-induced insulin secretion was severely impaired in these islets. By contrast, the elevation of cAMP was unaffected by culture of islets with efaroxan. Taken together, the data suggest that, in addition to effects on the K ATP channel, imidazolines also interact with a more distal component that is crucial to the potentiation of insulin secretion. This component is not required for Ca 2+ -dependent secretion per se but is essential to the mechanism by which cAMP potentiates insulin release. Overall, the results indicate that the actions of efaroxan at this distal site may be more important for control of insulin secretion than its effects on the K ATP channel. Diabetes 50:340-347, 2001

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Section: K Atp Channel-independent Effects Of Efaroxanmentioning

confidence: 97%

Section: K Atp Channel-independent Effects Of Efaroxanmentioning

confidence: 99%

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confidence: 99%

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Characterization of a KATP Channel—Independent Pathway Involved in Potentiation of Insulin Secretion by Efaroxan

2001

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“…Idazoxan works only at very high concentration. Comparing Efaroxan with RX871024, the latter shows a lower activity at low glucose concentration in stimulating the secretion of insulin, but exhibits a higher activity at high glucose concentration; so RX871024 shows higher potential as an antidiabetic drug [28,29]. The order of the four imidazolines in stimulating the secretion of insulin and the inhibitory activity of K ATP channel is the same.…”

Section: The Relationship Of the Function And Binding Modementioning

confidence: 98%

Docking and molecular dynamics studies on the interaction of four imidazoline derivatives with potassium ion channel (Kir6.2)

Zhang

Wang

Ling

et al. 2010

Molecular Simulation

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Kir6.2, a key component of the ATP-sensitive potassium channel (K ATP ), can directly interact with imidazoline derivativesa kind of potential antidiabetic drug. This paper explores the interaction of Kir6.2 with four imidazoline derivatives by using AutoDock and Gromacs programs. The docking results reveal that the binding sites of the four imidazolines are different from each other: Idazoxan lies in a polar active pocket formed by residues H177, G299 and R301; while RX871024 is situated in a hydrophobic pocket composed of residues F168, M169 and I296; as for Efaroxan and Clonidine, residues H175, R177, K67 and W68 constitute the binding pocket. Based on the docking results, the four imidazoline/Kir6.2 complexes with explicit water and infinite lipid bilayer membrane were constructed to perform molecular dynamics (MD) simulation. The results of MD calculation are as follows: dioleoyl phosphatidyl choline bilayer membrane stabilised the structure of these complexes through polar and nonpolar interaction; Idazoxan and RX871024 are stably combined with Kir6.2 in their docking sites; Efaroxan has a minor change in contrast to the docking result; whereas Clonidine has an obvious change compared to docking conformation. The binding sites and interaction modes of these imidazolines with Kir6.2 may provide theoretical support in the pharmacological study of imidazoline drugs.

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“…Email: kulikov@bsu.edu.ru (Mourtada et al, 1998). At present, to solve such problems is to use a prospective direction imidazoline receptor agonists (Brigand et al, 1999 A third pharmacologically distinct entity, the I 3 subtype, is found in the pancreas and is involved in regulation of insulin secretion.…”

Section: * Corresponding Authormentioning

confidence: 99%

Pharmacokinetics of a new imidazoline receptor agonist in rat plasma after intragastric and intravenous administration

2017

J App Pharma Sci

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3-(1h-benzimidazol-2-yl)-1,2,2-trimethylcyclopentancarboxylic acid (C7070) is a novel synthetic imidazoline receptor agonist -potential antidiabetic agent. This study aimed to obtain the pharmacokinetic profiles in rats. Additionally, an HPLC MS/MS method was developed and validated to quantify C7070 in rat plasma. The pharmacokinetic profiles of intragastric and intravenous administration routes at singles doses of 50 mg/kg, were studied in rats. The elimination half-life of intravenously administered C7070 was approximately 154.1 min. The maximum plasma level of C7070 was reached approximately 170 min (2.8 h) after intragastric administration, with a Cmax value of 17.6 μg/mL and an AUC (o-t) value of 6964 μg*min -1 /mL; the oral bioavailability was approximately 18%.

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Effector systems involved in the insulin secretory responses to efaroxan and RX871024 in rat islets of Langerhans

Cited by 13 publications

References 26 publications

Characterization of a KATP Channel—Independent Pathway Involved in Potentiation of Insulin Secretion by Efaroxan

Characterization of a KATP Channel—Independent Pathway Involved in Potentiation of Insulin Secretion by Efaroxan

Docking and molecular dynamics studies on the interaction of four imidazoline derivatives with potassium ion channel (Kir6.2)

Pharmacokinetics of a new imidazoline receptor agonist in rat plasma after intragastric and intravenous administration

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