Biomaterial Database

Diazoxide- and leptin-activated K(ATP) currents exhibit differential sensitivity to englitazone and ciclazindol in the rat CRI-G1 insulin-secreting cell line. 1998

J Harvey, and M L Ashford

Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill.

1. The effects of the antidiabetic agent englitazone and the anorectic drug ciclazindol on ATP-sensitive K+ (K(ATP)) channels activated by diazoxide and leptin were examined in the CRI-G1 insulin-secreting cell line using whole cell and single channel recording techniques. 2. In whole cell current clamp mode, the hyperglycaemic agent diazoxide (200 microM) and the ob gene product leptin (10 nM) hyperpolarised CRI-G1 cells by activation of K(ATP) currents. K(ATP) currents activated by either agent were inhibited by tolbutamide, with an IC50 for leptin-activated currents of 9.0 microM. 3. Application of englitazone produced a concentration-dependent inhibition of K(ATP) currents activated by diazoxide (200 microM) with an IC50 value of 7.7 microM and a Hill coefficient of 0.87. In inside-out patches englitazone (30 microM) also inhibited K(ATP) channel currents activated by diazoxide by 90.8+/-4.1%. 4. In contrast, englitazone (1-30 microM) failed to inhibit K(ATP) channels activated by leptin, although higher concentrations (> 30 microM) did inhibit leptin actions. The englitazone concentration inhibition curve in the presence of leptin resulted in an IC50 value and Hill coefficient of 52 microM and 3.2, respectively. Similarly, in inside-out patches englitazone (30 microM) failed to inhibit the activity of K(ATP) channels in the presence of leptin. 5. Ciclazindol also inhibited K(ATP) currents activated by diazoxide (200 microM) in a concentration-dependent manner, with an IC50 and Hill coefficient of 127 nM and 0.33, respectively. Furthermore, application of ciclazindol (1 microM) to the intracellular surface of inside-out patches inhibited K(ATP) channel currents activated by diazoxide (200 microM) by 86.6+/-8.1%. 6. However, ciclazindol was much less effective at inhibiting KATP currents activated by leptin (10 nM). Ciclazindol (0.1-10 microM) had no effect on K(ATP) currents activated by leptin, whereas higher concentrations (> 10 microM) did cause inhibition with an IC50 value of 40 microM and an associated Hill coefficient of 2.7. Similarly, ciclazindol (1 microM) had no significant effect on K(ATP) channel activity following leptin addition in excised inside-out patches. 7. In conclusion, K(ATP) currents activated by diazoxide and leptin show different sensitivity to englitazone and ciclazindol. This may be due to differences in the mechanism of activation of K(ATP) channels by diazoxide and leptin.

UI	MeSH Term	Description	Entries
D007004	Hypoglycemic Agents	Substances which lower blood glucose levels.	Antidiabetic,Antidiabetic Agent,Antidiabetic Drug,Antidiabetics,Antihyperglycemic,Antihyperglycemic Agent,Hypoglycemic,Hypoglycemic Agent,Hypoglycemic Drug,Antidiabetic Agents,Antidiabetic Drugs,Antihyperglycemic Agents,Antihyperglycemics,Hypoglycemic Drugs,Hypoglycemic Effect,Hypoglycemic Effects,Hypoglycemics,Agent, Antidiabetic,Agent, Antihyperglycemic,Agent, Hypoglycemic,Agents, Antidiabetic,Agents, Antihyperglycemic,Agents, Hypoglycemic,Drug, Antidiabetic,Drug, Hypoglycemic,Drugs, Antidiabetic,Drugs, Hypoglycemic,Effect, Hypoglycemic,Effects, Hypoglycemic
D007211	Indoles	Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.
D007328	Insulin	A 51-amino acid pancreatic hormone that plays a major role in the regulation of glucose metabolism, directly by suppressing endogenous glucose production (GLYCOGENOLYSIS; GLUCONEOGENESIS) and indirectly by suppressing GLUCAGON secretion and LIPOLYSIS. Native insulin is a globular protein comprised of a zinc-coordinated hexamer. Each insulin monomer containing two chains, A (21 residues) and B (30 residues), linked by two disulfide bonds. Insulin is used as a drug to control insulin-dependent diabetes mellitus (DIABETES MELLITUS, TYPE 1).	Iletin,Insulin A Chain,Insulin B Chain,Insulin, Regular,Novolin,Sodium Insulin,Soluble Insulin,Chain, Insulin B,Insulin, Sodium,Insulin, Soluble,Regular Insulin
D008564	Membrane Potentials	The voltage differences across a membrane. For cellular membranes they are computed by subtracting the voltage measured outside the membrane from the voltage measured inside the membrane. They result from differences of inside versus outside concentration of potassium, sodium, chloride, and other ions across cells' or ORGANELLES membranes. For excitable cells, the resting membrane potentials range between -30 and -100 millivolts. Physical, chemical, or electrical stimuli can make a membrane potential more negative (hyperpolarization), or less negative (depolarization).	Resting Potentials,Transmembrane Potentials,Delta Psi,Resting Membrane Potential,Transmembrane Electrical Potential Difference,Transmembrane Potential Difference,Difference, Transmembrane Potential,Differences, Transmembrane Potential,Membrane Potential,Membrane Potential, Resting,Membrane Potentials, Resting,Potential Difference, Transmembrane,Potential Differences, Transmembrane,Potential, Membrane,Potential, Resting,Potential, Transmembrane,Potentials, Membrane,Potentials, Resting,Potentials, Transmembrane,Resting Membrane Potentials,Resting Potential,Transmembrane Potential,Transmembrane Potential Differences
D011506	Proteins	Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.	Gene Products, Protein,Gene Proteins,Protein,Protein Gene Products,Proteins, Gene
D002460	Cell Line	Established cell cultures that have the potential to propagate indefinitely.	Cell Lines,Line, Cell,Lines, Cell
D003981	Diazoxide	A benzothiadiazine derivative that is a peripheral vasodilator used for hypertensive emergencies. It lacks diuretic effect, apparently because it lacks a sulfonamide group.	Hyperstat,Proglycem
D000078790	Insulin Secretion	Production and release of insulin from PANCREATIC BETA CELLS that primarily occurs in response to elevated BLOOD GLUCOSE levels.	Secretion, Insulin
D000255	Adenosine Triphosphate	An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter.	ATP,Adenosine Triphosphate, Calcium Salt,Adenosine Triphosphate, Chromium Salt,Adenosine Triphosphate, Magnesium Salt,Adenosine Triphosphate, Manganese Salt,Adenylpyrophosphate,CaATP,CrATP,Manganese Adenosine Triphosphate,MgATP,MnATP,ATP-MgCl2,Adenosine Triphosphate, Chromium Ammonium Salt,Adenosine Triphosphate, Magnesium Chloride,Atriphos,Chromium Adenosine Triphosphate,Cr(H2O)4 ATP,Magnesium Adenosine Triphosphate,Striadyne,ATP MgCl2
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia