Mode of Action of Sulfonylureas

Panten, U.; Schwanstecher, Mathias; Schwanstecher, Christina

doi:10.1007/978-3-662-09127-2_6

Cited by 11 publications

(25 citation statements)

References 169 publications

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“…Most importantly, the benzoic acid analogues of the sulphonylureas did not interact with these sites. This is in contrast to the observations in B-cells (or cell lines) and in vascular smooth muscle where these compounds show a potency comparable to long chain sulphonylureas both on a functional level and in binding studies (B cell: reviews Ashcroft and Ashcroft 1992;Panten et al 1996; in rat aorta: Quast et al 1993;Quast 1996b). However, the K i values for glibenclamide and tolbutamide determined here are in excellent agreement with those determined for inhibition of the K ATP channels in the A6 cell, an amphibian tubular cell line (Broillet and Horisberger 1993).…”

Section: High Affinity Glibenclamide Sitescontrasting

confidence: 49%

“…Binding studies with sulphonylureas have shown the existence of high and low affinity binding sites for these drugs in membrane preparations from many tissues including pancreatic B-cells (or related cell lines), brain, heart, skeletal and smooth muscle (for review see Ashcroft and Ashcroft 1992;Panten et al 1996). K ATP channel openers do not interact in a meaningful manner with sulphonylurea binding sites in membranes prepared from smooth muscle (Zini et al 1991) and heart (Gopalakrishnan et al 1991); in the presence of MgATP, however, 3 H-glibenclamide binding in membranes from insulin secreting cells and brain cortex is inhibited by high concentrations of the openers pinacidil and diazoxide, but not cromakalim (Niki and Ashcroft 1991;Schwanstecher et al 1991Schwanstecher et al , 1992a.…”

Section: Introductionmentioning

confidence: 99%

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Sulphonylurea binding in rat isolated glomeruli: pharmacological characterization and dependence on cell metabolism and cytoskeleton

Metzger

Löffler

Quast

1997

Naunyn-Schmiedeberg's Arch Pharmacol

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The kidney is endowed with ATP-sensitive K+ channels (KATP channels) both at the vascular and at the epithelial level. In this study we have characterized the binding of the sulphonylurea glibenclamide, the most widely used blocker of KATP channels, in rat isolated glomeruli. In metabolically intact glomeruli, 3H-glibenclamide labelled two different binding components with affinities of 47 +/- 12 nM and 10 +/- 1 microM and estimated binding capacities of 1.2 +/- 0.1 and 501 +/- 11 pmol/mg protein, respectively. 3H-glibenclamide binding was inhibited differentially by other sulphonylureas (tolbutamide, glibornuride, gliquidone and glipizide) and benzoic acid analogues such as meglitinide, AZ-DF 265 and UL-DF 9. Sulphonylureas interacted with the high affinity component and, in some cases, also with the low affinity component whereas the benzoic acid derivatives inhibited exclusively low affinity glibenclamide binding. Severe metabolic stress affected both components of glibenclamide binding by shifting high affinity binding to the right and reducing the capacity of the low affinity component. Disruption of the cytoskeletal actin filaments by cytochalasin B and D mimicked the effect of metabolic stress on the high affinity component but left the low affinity component unchanged. In crude membranes, the affinity of the first component was again reduced and a major loss of the low affinity sites was observed. The data show that the two binding components of glibenclamide binding in rat isolated glomeruli have very different properties. The high affinity component is not recognized by the benzoic acid derivatives; its affinity is modulated by cell metabolism and the actin component of the cytoskeleton. The low affinity sites are, in their majority, cytosolic. The function and cellular localization of the high affinity sites are under further study.

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Section: High Affinity Glibenclamide Sitescontrasting

confidence: 49%

Section: Introductionmentioning

confidence: 99%

Sulphonylurea binding in rat isolated glomeruli: pharmacological characterization and dependence on cell metabolism and cytoskeleton

Metzger

Löffler

Quast

1997

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Due to their specificity for the sulfonylurea receptor in humans, glibenclamide and KCOs have been developed for clinical use in patients (see, e.g., Demolombe and Escande, 1996;Lawson, 1996;Lazdunski, 1996;Panten et al, 1996;Luzi and Pozza, 1997). Essentially, the hypoglycemic effect of glibenclamide results in the inhibition of the sulfonylurea receptor, leading to the stimulation of insulin secretion.…”

Section: Pharmacological Specificity Of Abc Protein Modulatorsmentioning

confidence: 99%

ATP Binding Cassette Modulators Control Abscisic Acid–Regulated Slow Anion Channels in Guard Cells

1999

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In animal cells, ATP binding cassette (ABC) proteins are a large family of transporters that includes the sulfonylurea receptor and the cystic fibrosis transmembrane conductance regulator (CFTR). These two ABC proteins possess an ion channel activity and bind specific sulfonylureas, such as glibenclamide, but homologs have not been identified in plant cells. We recently have shown that there is an ABC protein in guard cells that is involved in the control of stomatal movements and guard cell outward K ؉ current. Because the CFTR, a chloride channel, is sensitive to glibenclamide and able to interact with K ؉ channels, we investigated its presence in guard cells. Potent CFTR inhibitors, such as glibenclamide and diphenylamine-2-carboxylic acid, triggered stomatal opening in darkness. The guard cell protoplast slow anion current that was recorded using the whole-cell patch-clamp technique was inhibited rapidly by glibenclamide in a dose-dependent manner; the concentration producing half-maximum inhibition was at 3 M. Potassium channel openers, which bind to and act through the sulfonylurea receptor in animal cells, completely suppressed the stomatal opening induced by glibenclamide and recovered the glibenclamide-inhibited slow anion current. Abscisic acid is known to regulate slow anion channels and in our study was able to relieve glibenclamide inhibition of slow anion current. Moreover, in epidermal strip bioassays, the stomatal closure triggered by Ca 2 ؉ or abscisic acid was reversed by glibenclamide. These results suggest that the slow anion channel is an ABC protein or is tightly controlled by such a protein that interacts with the abscisic acid signal transduction pathway in guard cells. INTRODUCTIONThe ATP binding cassette (ABC) superfamily is probably the largest and most diverse family of proteins that mediate ATP-dependent transfer of solutes across membranes in species ranging from Escherichia coli to humans (Higgins, 1992). These proteins have become of fundamental interest due to their involvement in numerous pathologies, such as cystic fibrosis, diabetes, or multidrug resistance (Demolombe and Escande, 1996). Among them, both the cystic fibrosis transmembrane conductance regulator (CFTR) and the sulfonylurea receptor (SUR) exhibit either an ion channel activity and/or regulate heterologous channels (Higgins, 1995).The CFTR constitutes a chloride channel inhibited by diphenylamine-2-carboxylic acid (DPC; McCarty et al., 1993), which can control K ϩ channels (Valverde et al., 1995; McNicholas et al., 1996; Ishida-Takahashi et al., 1998). The SUR is tightly associated with an inward-rectifying potassium channel (Inagaki et al., 1995) to form the ATP-sensitive K ϩ channel. These channels and the CFTR are both receptors for sulfonylureas (Schmid-Antomarchi et al., 1987;Schultz et al., 1996) and are blocked by glibenclamide in numerous tissues (Sheppard and Welsh, 1992; Gopalakrishnan et al., 1993). The SUR is also the receptor for K ϩ channel openers (KCOs;Schwanstecher et al., 1998), such as crom...

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“…IGF‐2–secreting tumors can also secrete “big” IGF‐2, a biologically active precursor of IGF‐2 . Antidiabetic medications, such as sulfonylureas, increase endogenous IGF‐1, which, in turn, lowers blood glucose levels . In addition, IGF‐1 and IGF‐2 possess glucose‐lowering potential, but this is not observed until IGF‐1 and/or IGF‐2 levels are elevated due to their low potency compared to insulin .…”

Section: Discussionmentioning

confidence: 99%

Severe Hypoglycemia Caused by Lenalidomide

2017

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Lenalidomide is commonly used for multiple myeloma as either induction or maintenance therapy. The agent is associated with a host of adverse effects, but hypoglycemia has only been reported in one phase I trial in patients with solid tumors. We describe a 74-year-old woman who experienced grade 3 hypoglycemia (blood glucose level 35 mg/dl) likely related to lenalidomide. Her medical history was significant for refractory myeloma and type 2 diabetes mellitus. Lenalidomide was started as maintenance therapy following autologous bone marrow transplantation. Approximately 3 years later, she developed refractory hypoglycemia necessitating hospital admission despite stopping antihyperglycemic agents 4 weeks prior to admission. Lenalidomide was withheld during her admission and restarted 2 days prior to discharge. Work-up for causes of persistent hypoglycemia was negative, and her glucose levels improved over her 26-day hospitalization. She was readmitted approximately one month later for hypoglycemia, and lenalidomide was permanently discontinued. Again, work-up for causes of hypoglycemia was negative, and her glucose levels stabilized over her hospitalization. After discontinuation of lenalidomide, hypoglycemia did not recur, and within 1 year the patient required reinitiation of antihyperglycemic medications to control her glucose levels. Given the resolution of hypoglycemia with lenalidomide discontinuation and return of hyperglycemia after restarting the agent, it is likely that lenalidomide was the cause of the patient's hypoglycemia. Use of the Naranjo adverse drug reaction probability scale indicated a definite relationship (score of 9) between the patient's development of grade 3 hypoglycemia and lenalidomide therapy. Although this adverse drug reaction had been previously reported with lenalidomide during phase I trials in patients with solid tumors, only grade 1 or 2 hypoglycemia was reported in three patients. To our knowledge, this is the first reported case of grade 3 hypoglycemia caused by lenalidomide. KEY WORDS lenalidomide, hypoglycemia, multiple myeloma.

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Mode of Action of Sulfonylureas

Cited by 11 publications

References 169 publications

Sulphonylurea binding in rat isolated glomeruli: pharmacological characterization and dependence on cell metabolism and cytoskeleton

Sulphonylurea binding in rat isolated glomeruli: pharmacological characterization and dependence on cell metabolism and cytoskeleton

ATP Binding Cassette Modulators Control Abscisic Acid–Regulated Slow Anion Channels in Guard Cells

Severe Hypoglycemia Caused by Lenalidomide

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