Effects of the hypoglycaemic drugs repaglinide and glibenclamide on ATP-sensitive potassium-channels and cytosolic calcium levels in ? TC3 cells and rat pancreatic beta cells

Gromada, Jesper; Dissing, Steen; Kofod, Hans; J, Frøkjaer-Jensen

doi:10.1007/bf00402171

Cited by 112 publications

(72 citation statements)

References 23 publications

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“…These estimates agree well with the values reported by Gromada et al [39] on the inhibition of the native channel in rat pancreatic beta cells in culture (IC 50 =0.089 and 0.047 nmol/l, respectively). The upper limit for repaglinide is, however, much lower than the value determined in metabolically poisoned Xenopus oocytes [24].…”

Section: Potency and Efficacysupporting

confidence: 92%

Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular KATP channels

et al. 2006

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Aims/hypothesis Sulfonylureas and glinides close beta cell ATP-sensitive K + (K ATP ) channels to increase insulin release; the concomitant closure of cardiovascular K ATP channels, however, leads to complications in patients with cardiac ischaemia. The insulinotrope repaglinide is successful in therapy, but has been reported to inhibit the recombinant K ATP channels of beta cells, cardiocytes and non-vascular smooth muscle cells with similar potencies, suggesting that the (patho-)physiological role of the cardiovascular K ATP channels may be overstated. We therefore re-examined repaglinide's potency at and affinity for the recombinant pancreatic, myocardial and vascular K ATP channels in comparison with glibenclamide. Results Repaglinide and glibenclamide, respectively, were ≥30 and ≥1,000 times more potent in closing the pancreatic than the cardiovascular channels and they did not lead to complete inhibition of the myocardial channel. Binding assays showed that the selectivity of glibenclamide was essentially based on high affinity for the pancreatic SUR, whereas binding of repaglinide to the SUR subtypes was rather non-selective. After coexpression with Kir6.x to form the assembled channels, however, the affinity of the pancreatic channel for repaglinide was increased 130-fold, an effect much larger than with the cardiovascular channels. This selective effect of coexpression depended on the piperidino substituent in repaglinide. Conclusions/interpretation Repaglinide and glibenclamide show higher potency and efficacy in inhibiting the pancreatic than the cardiovascular K ATP channels, thus supporting their clinical use.

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Section: Potency and Efficacysupporting

confidence: 92%

Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular KATP channels

et al. 2006

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“…Applying digital Ca 2ϩ imaging on single ␤-TC3 cells, it has been shown that repaglinide and GLY induce a concentration-dependent increase in intracellular free Ca 2ϩ concentration (40 channels because it is inhibited by verapamil. Based on studies of the heart and other tissues, it has been suggested that increases in cytosolic Ca 2ϩ concentration may lead to an increase in intramitochondrial free Ca 2ϩ and activation of several matrix dehydrogenases and increased turnover of the Krebs cycle (41).…”

Section: Fig 5 Effect Of High Glucose (A)mentioning

confidence: 99%

Differential Effects of Glucose and Glyburide on Energetics and Na+ Levels of βHC9 Cells

et al. 2003

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In the present study, noninvasive 31 P and 23 Na ؉ -nuclear magnetic resonance (NMR) technology and respirometry were used to compare the effect of high glucose (30 mmol/l) with the effect of the antidiabetic sulfonylurea (SU) compound glyburide (GLY) on energy metabolism, Na ؉ flux, insulin, and cAMP release of continuously superfused ␤-HC9 cells encapsulated in microscopic agarose beads. Both high glucose and GLY increased oxygen consumption in ␤-HC9 cells (15-30%) with a maximal effect at 8 mmol/l for glucose and at 250 nmol/l for GLY. At the same time, insulin release from ␤-cells increased by 15-and 25-fold with high glucose or GLY, respectively. The P-creatine (PCr) level was greatly increased and inorganic phosphate (P i ) was decreased with 30 mmol/l glucose in contrast to the decreased level of PCr and increased P i with GLY. ATP levels remained unchanged during both interventions. Studies on isolated mitochondria of ␤-HC9 cells showed that GLY added to mitochondria oxidizing glutamine or glutamate abolished the stimulation of respiration by ADP (state 3) meanwhile leaving state 3 respiration unchanged during oxidation of other substrates. Exposure of ␤-HC9 cells to 5 mmol/l glucose decreased intracellular Na ؉ levels monitored by 23 Na ؉ -NMR spectroscopy and 30 mmol/l glucose resulted in a further decrease in cytosolic Na ؉ . In contrast, Na ؉ increased when 1 mol/l GLY was added to the perfusate containing 5 mmol/l glucose. These data support the hypothesis that glucose activates the ␤-cell through a "push mechanism" due to substrate pressure enhancing fuel flux, energy production, and extrusion of Na ؉ from the cells in contrast to SU receptor (SUR)-1 inhibitors, which may modify intermediary and energy metabolism secondarily through a "pull mechanism" due to higher energy demand resulting from increased ion fluxes and the exocytotic work load. Diabetes 52:394 -402, 2003

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“…The phosphorylation reaction was started by adding 80 -120 nM PKG-I␣ for 15 min at 37°C and stopped by adding Laemmli buffer (3ϫ) containing 10% ␤-mercaptoethanol (36). The phosphorylated proteins were separated on SDS-PAGE, stained, destained, dried, and exposed to Kodak X-Omat film at Ϫ70°C.…”

mentioning

confidence: 99%

The Large Conductance, Voltage-dependent, and Calcium-sensitive K+ Channel, Hslo, Is a Target of cGMP-dependent Protein Kinase Phosphorylation in Vivo

Alioua¹,

Tanaka²,

Wallner³

et al. 1998

Journal of Biological Chemistry

165

129

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Native large conductance, voltage-dependent, and Ca 2؉ -sensitive K ؉ channels are activated by cGMP-dependent protein kinase. Two possible mechanisms of kinase action have been proposed: 1) direct phosphorylation of the channel and 2) indirect via PKG-dependent activation of a phosphatase. To scrutinize the first possibility, at the molecular level, we used the human poreforming ␣-subunit of the Ca 2؉ -sensitive K ؉ channel, Hslo, and the ␣-isoform of cGMP-dependent protein kinase I. In cell-attached patches of oocytes co-expressing the Hslo channel and the kinase, 8-Br-cGMP significantly increased the macroscopic currents. This increase in current was due to an increase in the channel voltage sensitivity by ϳ20 mV and was reversed by alkaline phosphatase treatment after patch excision. In inside-out patches, however, the effect of purified kinase was negative in 12 of 13 patches. In contrast, and consistent with the intact cell experiments, purified kinase applied to the cytoplasmic side of reconstituted channels increased their open probability. This stimulatory effect was absent when heat-denatured kinase was used. Biochemical experiments show that the purified kinase incorporates ␥-33 P into the immunopurified Hslo band of ϳ125 kDa. Furthermore, in vivo phosphorylation largely attenuates this labeling in back-phosphorylation experiments. These results demonstrate that the ␣-subunit of large conductance Ca 2؉ -sensitive K ؉ channels is substrate for G-I␣ kinase in vivo and support direct phosphorylation as a mechanism for PKG-I␣-induced activation of maxi-K channels.

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Effects of the hypoglycaemic drugs repaglinide and glibenclamide on ATP-sensitive potassium-channels and cytosolic calcium levels in ? TC3 cells and rat pancreatic beta cells

Cited by 112 publications

References 23 publications

Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular KATP channels

Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular KATP channels

Differential Effects of Glucose and Glyburide on Energetics and Na+ Levels of βHC9 Cells

The Large Conductance, Voltage-dependent, and Calcium-sensitive K+ Channel, Hslo, Is a Target of cGMP-dependent Protein Kinase Phosphorylation in Vivo

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