A potent diazoxide analogue activating ATP-sensitive K + channels and inhibiting insulin release

Lebrun, Philippe; Arkhammar, Per; Antoine, Marie-Hélène; Nguyễn, Quỳnh Anh; Hansen, John Bondo; Pirotte, Bernard

doi:10.1007/s001250051370

Cited by 62 publications

(130 citation statements)

References 30 publications

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“…Indeed, in 45 Ca-loaded pancreatic islets, the increment in 45 Ca FOR evoked by high K + again results from the stimulation of a 40 Ca/ 45 Ca exchange process [12,22].…”

Section: Discussionmentioning

confidence: 96%

“…Incidentally, the effects of imipramine on the cationic responses to glucose and KCl depolarisation are reminiscent of those evoked by Cd 2+ or verapamil, two calcium channel blockers known to interact with the L-type Ca 2+ channels [12,22,23,24].…”

Section: Discussionmentioning

confidence: 99%

“…Experiments were performed with pancreatic islets isolated by the collagenase method from fed female Wistar albino rats (180-220 g, Charles River Laboratories, Brussels, Belgium) [11,12]. Laboratory animal care was approved by the Ethics Committee of the Université Libre de Bruxelles (Free University of Brussels).…”

Section: Measurement Of Insulin Secretion From Incubated Pancreatic Imentioning

confidence: 99%

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Tricyclic antidepressant imipramine reduces the insulin secretory rate in islet cells of Wistar albino rats through a calcium antagonistic action

et al. 2004

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Aims/hypothesis. Treatments with antidepressants have been associated with modifications in glucose homeostasis. The aim of this study was to assess the effect of imipramine, a tricyclic antidepressant, on insulinsecreting cells. Methods. Insulin radioimmunoassay, radioisotopic, fluorimetric and patch-clamp methods were used to characterise the effects of imipramine on ionic and secretory events in pancreatic islet cells from Wistar albino rats. Results. Imipramine induced a dose-dependent decrease in glucose-stimulated insulin output (IC 50 =5.2 µmol/l). It also provoked a concentration-dependent reduction in 45 Ca outflow from islets perifused in the presence of 16.7 mmol/l glucose. Moreover, imipramine inhibited the increase in 45 Ca outflow mediated by K + depolarisation. Patch-clamp recordings further revealed that imipramine provoked a marked and reversible decrease of the inward Ca 2+ current. In single islet cells, imipramine counteracted the rise in [Ca 2+ ] i evoked by glucose or high K + concentrations. Conclusions/interpretation. These data indicate that imipramine dose-dependently reduces the insulin secretory rate from rat pancreatic beta cells. Such an effect appears to be mediated by the inhibition of voltage-sensitive Ca 2+ channels with subsequent reduction in Ca 2+ entry. Thus, it is possible that some adverse effects of imipramine are related, at least in part, to its capacity to behave as a Ca 2+ entry blocker.

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“…Indeed, in 45 Ca-loaded pancreatic islets, the increment in 45 Ca FOR evoked by high K + again results from the stimulation of a 40 Ca/ 45 Ca exchange process [12,22].…”

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Measurement Of Insulin Secretion From Incubated Pancreatic Imentioning

confidence: 99%

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Tricyclic antidepressant imipramine reduces the insulin secretory rate in islet cells of Wistar albino rats through a calcium antagonistic action

et al. 2004

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“…Diazoxide, BPDZ 73 (7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide), 15 NNC 55-0118 (6-chloro-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide), 16 and NNC 55-0462 (6-chloro-3-(1-methylcyclobutyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide) 16 were synthesized in house and kept as 100-mM stock solutions in dry DMSO. Tolbutamide, FCCP (carbonyl cyanide p-[trifluoromethoxy] phenylhydrazone), oligomycin, and antimycin were from Sigma.…”

Section: Methodsmentioning

confidence: 99%

Establishment and Application of in Vitro Membrane Potential Assays in Cell Lines with Endogenous or Recombinant Expression of ATP-Sensitive Potassium Channels (Kir6.2/SUR1) Using a Fluorescent Probe Kit

Arkhammar¹,

Wahl²,

Gerlach³

et al. 2004

SLAS Discovery

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The flow of current through the adenosine triphosphate (ATP)-sensitive potassium channel (K ATP ) of the isoform Kir6.2/ SUR1 regulates the resting membrane potential in the pancreatic β-cell. In combination with the cellular glucose metabolism, it is an important minute-to-minute regulator of insulin secretion and whole-body glucose homeostasis. The same K ATP isoform is further reported to be present in glucagon-secreting α-cells, intestinal L-cells, and glucose-responsive neurons in the hypothalamus. All in all, this makes Kir6.2/SUR1 an interesting drug target. Using a commercially available fluorescent membrane potential probe kit and a conventional 96-well fluorescence plate reader, the authors have developed and established qualitative membrane potential assays used to screen for potassium channel closers (KCCs) and openers (KCOs) in insulin-and glucagon-secreting cell lines as well as in cells with recombinant expression of the human Kir6.2/ SUR1 channel complex. Both glucose-and KCC-induced depolarization could be demonstrated. The magnitudes of these responses and KCO-induced repolarization at high glucose displayed some variation between the different cell lines but a similar rank order of test compounds. Some cell types required the presence of a KCC, such as tolbutamide, to display significant effects of KCOs. The authors find that robust and reliable functional in vitro assays compatible with medium-throughput screening and high-throughput screening can be developed as a base for finding new, more potent, and isoform-selective

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“…Discussion 7-Chloro-3-isopropylamino-4f/-1,2,4-benzothiadiazine 1,1 -dioxide, namely BPDZ73, was revealed to be one of the most potent and tissue-selective pancreatic B-cells ATP sensitive potassium channel opener [1,2]. Some crystallographic structures of related compounds have been determined such as 7-iodo-3-isopropylamino-4/M ,2,4-benzothiadiazine 1,1-dioxide (BPDZ69) [3] which is less powerful and less sensitive at the level of the pancreatic tissue.…”

Section: Source Of Materialsmentioning

confidence: 99%

Crystal structure of 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide, C10H12ClN3O2S

Dupont¹,

Pirotte²,

Tullio³

2005

Zeitschrift Für Kristallographie - New Crystal Structures

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A potent diazoxide analogue activating ATP-sensitive K + channels and inhibiting insulin release

Cited by 62 publications

References 30 publications

Tricyclic antidepressant imipramine reduces the insulin secretory rate in islet cells of Wistar albino rats through a calcium antagonistic action

Tricyclic antidepressant imipramine reduces the insulin secretory rate in islet cells of Wistar albino rats through a calcium antagonistic action

Establishment and Application of in Vitro Membrane Potential Assays in Cell Lines with Endogenous or Recombinant Expression of ATP-Sensitive Potassium Channels (Kir6.2/SUR1) Using a Fluorescent Probe Kit

Crystal structure of 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide, C10H12ClN3O2S

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