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Circulation. Arrhythmia and... Sep 2023Hypoxia-ischemia predisposes to atrial arrhythmia. Atrial ATP-sensitive potassium channel (K) modulation during hypoxia has not been explored. We investigated the...
BACKGROUND
Hypoxia-ischemia predisposes to atrial arrhythmia. Atrial ATP-sensitive potassium channel (K) modulation during hypoxia has not been explored. We investigated the effects of hypoxia on atrial electrophysiology in mice with global deletion of K pore-forming subunits.
METHODS
Whole heart K RNA expression was probed. Whole-cell K current and action potentials were recorded in isolated wild-type (WT), Kir6.1 global knockout (6.1-gKO), and Kir6.2 global knockout (6.2-gKO) murine atrial myocytes. Langendorff-perfused hearts were assessed for atrial effective refractory period (ERP), conduction velocity, wavefront path length (WFPL), and arrhymogenicity under normoxia/hypoxia using a microelectrode array and programmed electrical stimulation. Heart histology was assessed.
RESULTS
Expression patterns were essentially identical for all K subunit RNA across human heart, whereas in mouse, Kir6.1 and SUR2 (sulphonylurea receptor subunit) were higher in ventricle than atrium, and Kir6.2 and SUR1 were higher in atrium. Compared with WT, 6.2-gKO atrial myocytes had reduced tolbutamide-sensitive current and action potentials were more depolarized with slower upstroke and reduced peak amplitude. Action potential duration was prolonged in 6.1-gKO atrial myocytes, absent of changes in other ion channel gene expression or atrial myocyte hypertrophy. In Langendorff-perfused hearts, baseline atrial ERP was prolonged and conduction velocity reduced in both K knockout mice compared with WT, without histological fibrosis. Compared with baseline, hypoxia led to conduction velocity slowing, stable ERP, and WFPL shortening in WT and 6.1-gKO hearts, whereas WFPL was stable in 6.2-gKO hearts due to ERP prolongation with conduction velocity slowing. Tolbutamide reversed hypoxia-induced WFPL shortening in WT and 6.1-gKO hearts through ERP prolongation. Atrial tachyarrhythmias inducible with programmed electrical stimulation during hypoxia in WT and 6.1-gKO mice correlated with WFPL shortening. Spontaneous arrhythmia was not seen.
CONCLUSIONS
K block/absence leads to cellular and tissue level atrial electrophysiological modification. Kir6.2 global knockout prevents hypoxia-induced atrial WFPL shortening and atrial arrhythmogenicity to programmed electrical stimulation. This mechanism could be explored translationally to treat ischemically driven atrial arrhythmia.
Topics: Humans; Animals; Mice; KATP Channels; Atrial Fibrillation; Tolbutamide; Tachycardia; Heart Atria; Hypoxia; Adenosine Triphosphate
PubMed: 37646176
DOI: 10.1161/CIRCEP.123.011870 -
Canadian Medical Association Journal Jun 1971
Topics: Canada; Diabetes Mellitus; Government Agencies; Humans; Tolbutamide; Voluntary Health Agencies
PubMed: 5580750
DOI: No ID Found -
Diabetes Research and Clinical Practice Jul 1996The classical sulphonylurea derivatives like glibenclamide and tolbutamide are widely prescribed in non-insulin dependent diabetes mellitus in order to stimulate insulin... (Review)
Review
The classical sulphonylurea derivatives like glibenclamide and tolbutamide are widely prescribed in non-insulin dependent diabetes mellitus in order to stimulate insulin secretion. The insulinotropic effect of these agents is based on the closure of adenosine-5'-triphosphate (ATP)-sensitive potassium channels (KATP-channels) in the beta-cells of the pancreas. Interestingly, the cardiovascular system also shares these KATP-channels. The open state probability of these channels is regulated by the intracellular concentration of ATP. During ischaemia, the KATP-channels are thought to open by a fall in the cytosolic ATP concentration. The increase in the extracellular adenosine concentration, and the release of endothelium-derived hyperpolarizing factor (EDHF) during ischaemia may further contribute to the opening of cardiovascular KATP-channels. Sulphonylurea derivatives like glibenclamide and tolbutamide have been reported to block the opening of KATP-channels in several types of tissues including myocardial and vascular smooth muscle cells. Since the opening of KATP-channels is regarded as an endogenous cardioprotective mechanism, the blocking effect of sulphonylurea derivatives in the cardiovascular system may have deleterious effects. Human studies on this issue have just been initiated, and preliminary results point towards a significant interaction between glibenclamide and cardiovascular KATP-channels at clinically relevant concentrations. In this regard, the introduction of more pancreas specific sulphonylurea derivatives like glimepiride, which do not interact with cardiovascular KATP-channels, is a promising development.
Topics: Adenosine Triphosphate; Animals; Cardiovascular System; Diabetes Mellitus, Type 2; Glyburide; Humans; Hypoglycemic Agents; Potassium Channels; Sulfonylurea Compounds; Tolbutamide
PubMed: 8864641
DOI: 10.1016/0168-8227(96)01230-2 -
Molecules (Basel, Switzerland) Mar 2017Glycation process occurs in protein and becomes more pronounced in diabetes when an increased amount of reducing sugar is present in bloodstream. Glycation of protein...
Glycation process occurs in protein and becomes more pronounced in diabetes when an increased amount of reducing sugar is present in bloodstream. Glycation of protein may cause conformational changes resulting in the alterations of its binding properties even though they occur at a distance from the binding sites. The changes in protein properties could be related to several pathological consequences such as diabetic and nondiabetic cardiovascular diseases, cataract, renal dysfunction and Alzheimer's disease. The experiment was designed to test the impact of glycation process on sulfonylurea drug tolbutamide-albumin binding under physiological (T = 309 K) and inflammatory (T = 311 K and T = 313 K) states using fluorescence and UV-VIS spectroscopies. It was found in fluorescence analysis experiments that the modification of serum albumin in tryptophanyl and tyrosyl residues environment may affect the tolbutamide (TB) binding to albumin in subdomain IIA and/or IIIA (Sudlow's site I and/or II), and also in subdomains IB and IIB. We estimated the binding of tolbutamide to albumin described by a mixed nature of interaction (specific and nonspecific). The association constants Ka (L∙mol) for tolbutamide at its high affinity sites on non-glycated albumin were in the range of 1.98-7.88 × 10⁴ L∙mol (λ = 275 nm), 1.20-1.64 × 10⁴ L∙mol (λ = 295 nm) and decreased to 1.24-0.42 × 10⁴ L∙mol at λ = 275 nm (T = 309 K and T = 311 K) and increased to 2.79 × 10⁴ L∙mol at λ = 275 nm (T = 313 K) and to 4.43-6.61 × 10⁴ L∙mol at λ = 295 nm due to the glycation process. Temperature dependence suggests the important role of van der Waals forces and hydrogen bonding in hydrophobic interactions between tolbutamide and both glycated and non-glycated albumin. We concluded that the changes in the environment of TB binding of albumin in subdomain IIA and/or IIIA as well as in subdomains IB and IIB influence on therapeutic effect and therefore the studies of the binding of tolbutamide (in diabetes) to transporting protein under glycation that refers to the modification of a protein are of great importance in pharmacology and biochemistry. This information may lead to the development of more effective drug therapy in people with diabetes.
Topics: Animals; Cattle; Glycation End Products, Advanced; Kinetics; Protein Binding; Protein Stability; Serum Albumin; Serum Albumin, Bovine; Spectrometry, Fluorescence; Temperature; Tolbutamide; Glycated Serum Albumin
PubMed: 28362348
DOI: 10.3390/molecules22040569 -
American Journal of Physiology.... Apr 2000Arginine vasopressin (AVP), bombesin, and ACh increase cytosolic free Ca(2+) and potentiate glucose-induced insulin release by activating receptors linked to...
Arginine vasopressin (AVP), bombesin, and ACh increase cytosolic free Ca(2+) and potentiate glucose-induced insulin release by activating receptors linked to phospholipase C (PLC). We examined whether tolbutamide and diazoxide, which close or open ATP-sensitive K(+) channels (K(ATP) channels), respectively, interact with PLC-linked Ca(2+) signals in HIT-T15 and mouse beta-cells and with PLC-linked insulin secretion from HIT-T15 cells. In the presence of glucose, the PLC-linked Ca(2+) signals were enhanced by tolbutamide (3-300 microM) and inhibited by diazoxide (10-100 microM). The effects of tolbutamide and diazoxide on PLC-linked Ca(2+) signaling were mimicked by BAY K 8644 and nifedipine, an activator and inhibitor of L-type voltage-sensitive Ca(2+) channels, respectively. Neither tolbutamide nor diazoxide affected PLC-linked mobilization of internal Ca(2+) or store-operated Ca(2+) influx through non-L-type Ca(2+) channels. In the absence of glucose, PLC-linked Ca(2+) signals were diminished or abolished; this effect could be partly antagonized by tolbutamide. In the presence of glucose, tolbutamide potentiated and diazoxide inhibited AVP- or bombesin-induced insulin secretion from HIT-T15 cells. Nifedipine (10 microM) blocked both the potentiating and inhibitory actions of tolbutamide and diazoxide on AVP-induced insulin release, respectively. In glucose-free medium, AVP-induced insulin release was reduced but was again potentiated by tolbutamide, whereas diazoxide caused no further inhibition. Thus tolbutamide and diazoxide regulate both PLC-linked Ca(2+) signaling and insulin secretion from pancreatic beta-cells by modulating K(ATP) channels, thereby determining voltage-sensitive Ca(2+) influx.
Topics: Animals; Calcium Channels; Calcium Signaling; Carbachol; Cell Line; Diazoxide; Diuretics; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Mice; Muscarinic Agonists; Sodium Chloride Symporter Inhibitors; Tolbutamide; Type C Phospholipases
PubMed: 10751197
DOI: 10.1152/ajpendo.2000.278.4.E639 -
Bristol Medico-chirurgical Journal... Oct 1969
Topics: Aged; Androsterone; Anticholesteremic Agents; Butyrates; Chlorpropamide; Coronary Disease; Ethylestrenol; Female; Fibrinogen; Fibrinolysis; Humans; Intermittent Claudication; Male; Metformin; Middle Aged; Phenformin; Platelet Adhesiveness; Tolbutamide
PubMed: 5824915
DOI: No ID Found -
Proceedings of the Royal Society of... Feb 1964
Topics: Glucose Tolerance Test; Humans; Hypoglycemia; Infant; Leucine; Metabolism; Methylprednisolone; Seizures; Tolbutamide
PubMed: 14116028
DOI: No ID Found -
The Journal of Clinical Investigation Jun 2019Beta-arrestin-1 and -2 (Barr1 and Barr2, respectively) are intracellular signaling molecules that regulate many important metabolic functions. We previously demonstrated...
Beta-arrestin-1 and -2 (Barr1 and Barr2, respectively) are intracellular signaling molecules that regulate many important metabolic functions. We previously demonstrated that mice lacking Barr2 selectively in pancreatic beta-cells showed pronounced metabolic impairments. Here we investigated whether Barr1 plays a similar role in regulating beta-cell function and whole body glucose homeostasis. Initially, we inactivated the Barr1 gene in beta-cells of adult mice (beta-barr1-KO mice). Beta-barr1-KO mice did not display any obvious phenotypes in a series of in vivo and in vitro metabolic tests. However, glibenclamide and tolbutamide, two widely used antidiabetic drugs of the sulfonylurea (SU) family, showed greatly reduced efficacy in stimulating insulin secretion in the KO mice in vivo and in perifused KO islets in vitro. Additional in vivo and in vitro studies demonstrated that Barr1 enhanced SU-stimulated insulin secretion by promoting SU-mediated activation of Epac2. Pull-down and co-immunoprecipitation experiments showed that Barr1 can directly interact with Epac2 and that SUs such as glibenclamide promote Barr1/Epac2 complex formation, triggering enhanced Rap1 signaling and insulin secretion. These findings suggest that strategies aimed at promoting Barr1 signaling in beta-cells may prove useful for the development of efficacious antidiabetic drugs.
Topics: Animals; Genotype; Glyburide; Guanine Nucleotide Exchange Factors; Hypoglycemic Agents; Insulin Secretion; Insulin-Secreting Cells; Male; Mice; Mice, Knockout; Mice, Transgenic; Phenotype; Signal Transduction; Sulfonylurea Compounds; Tolbutamide; beta-Arrestin 1; beta-Arrestin 2
PubMed: 31184597
DOI: 10.1172/JCI126309 -
FEBS Letters Dec 2021Selenium is an essential trace element of interest for its potential role in glucose homeostasis. The present study investigated the impact of selenium supplementation...
Selenium is an essential trace element of interest for its potential role in glucose homeostasis. The present study investigated the impact of selenium supplementation as selenomethionine (SeMet) on insulin secretion in MIN6-K8 cells, a pancreatic β-cell model. We found that SeMet enhanced percent glucose-induced insulin secretion, while also increasing tolbutamide- and KCl-induced percent insulin secretion. RNA-sequencing showed that SeMet supplementation altered expression of several selenoproteins, including glutathione peroxidase 3 (Gpx3) and selenoprotein P (SelP). Targeted knockdown of Gpx3 increased both percent and total insulin release, while SelP knockdown increased insulin content and insulin release. Collectively, these studies support a putative role for selenium and selenoproteins in the regulation of insulin secretion, glucose homeostasis, and diabetes risk.
Topics: Animals; Calcium; Cell Death; Cell Line, Tumor; Cell Survival; Gene Expression Regulation, Neoplastic; Glutathione Peroxidase; Insulin; Insulin Secretion; Insulinoma; Mice; Potassium; RNA, Messenger; Selenomethionine; Selenoproteins; Tolbutamide
PubMed: 34780071
DOI: 10.1002/1873-3468.14232 -
British Medical Journal Nov 1964
Topics: Diabetes Mellitus; Diabetic Neuropathies; Hypoglycemia; Insulin; Pancreatic Diseases; Tolbutamide; Toxicology
PubMed: 14201227
DOI: 10.1136/bmj.2.5420.1330-d