Drugs online research references
Acta Diabetol. 1995 Dec;32(4):273-8.
A novel mechanism of glipizide sulfonylurea action: decreased metabolic clearance rate of insulin.
Barzilai N, Groop PH, Groop L, DeFronzo RA.
Division of Endocrinology, Albert Einstein College of Medicine, New York, NY 10461, USA.
To examine whether sulfonylureas inhibit the metabolic clearance rate (MCR) of insulin, 19 healthy young subjects participated in two experiments. In the first protocol (n = 10), a 3-h oral glucose load was performed with and without 2 mg of glipizide given 30 min before glucose ingestion. The total insulin response was 60% greater with than without glipizide (5.9 +/- 0.6 vs 3.7 +/- 0.5 microU/ml; P < 0.001). However, the total C-peptide responses were virtually identical (4.7 +/- 0.5 vs 4.8 +/- 0.4 nmol/l) in both studies. In the second protocol (n = 9), the MCR of insulin was measured during 4-h euglycemic insulin clamps performed with and without glipizide. In the study with glipizide, the subjects ingested 5 mg of glipizide at 120 min. The steady-state plasma insulin concentration during the 4th h, i.e., 1-2 h after glipizide ingestion, was significantly higher than during the 2nd h, i.e., before glipizide ingestion (99 +/- 22 vs 78 +/- 17 microU/ml; P < 0.01). In addition, glucose uptake during the 4th h was greater (8.0 +/- 1.6 vs 6.4 +/- 1.5 mg/kg.min) and the MCR of insulin was reduced (503 +/- 126 vs 621 +/- 176 ml/m2.min; P < 0.01). We conclude that glipizide augments plasma insulin levels both by enhancing its secretion and by decreasing the MCR of insulin.
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J Cell Physiol. 1996 Sep;168(3):678-83.
Inhibitory effect of ATP-sensitive K+ channel regulators on forskolin-stimulated short-circuit current across the isolated mucosa of the rat colon.
Huang Y, Wong PY.
Department of Physiology, Faculty of Medicine, Chinese University of Hong Kong, Shatin, NT, Hong Kong.
Forskolin concentration-dependently increased the short-circuit current (Isc) across the isolated mucosa of rat colon, which was carried mainly by Cl- secretion from the mucosal membrane. The sulfonylureas such as glibenclamide, tolbutamide, glipizide and the ATP-sensitive K+ channel opener cromakalim inhibited the forskolin (1 microM)-induced increase of short-circuit current (delta Isc) when these drugs were applied to the basolateral side. The rank order of potency for inhibition of delta Isc was: glibenclamide > cromakalim > tolbutamide > glipizide. Glibenclamide (100 microM) and cromakalim (100 microM) caused transient or small reduction of the A23187-induced delta Isc when applied to the basolateral side. Glibenclamide, tolbutamide and cromakalim decreased the forskolin-induced delta Isc when applied to the mucosal side; however, the responses produced by basolateral application were greater and faster than those elicited by mucosal application. None of these four agents affected the basal transepithelial current. The results indicate that the cAMP-dependent Cl- secretion in the rat colon could be modulated by ATP-sensitive K+ channel regulators.
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Neuroscience. 1996 Apr;71(3):709-19.
Sulfonylurea-sensitive potassium current evoked by sodium-loading in rat midbrain dopamine neurons.
Seutin V, Shen KZ, North RA, Johnson SW.
Vollum Institute, Oregon Health Sciences University, Portland 97201, USA.
In Parkinson's disease, there is evidence of impaired mitochondrial function which reduces the capacity to synthesize ATP in dopamine neurons. This would be expected to reduce the activity of the sodium pump (Na+/K+ ATPase), causing increased intracellular levels of Na+. Patch pipettes were used to introduce Na+ (40 mM in pipette solutions) into dopamine neurons in the rat midbrain slice in order to study the electrophysiological effects of increased intracellular Na+. We found that intracellular Na+ loading evoked 100-300 pA of outward current (at -60 mV) and increased whole-cell conductance; these effects developed gradually during the first 10 min after rupture of the membrane patch. Extracellular Ba2+ reduced most of the outward current evoked by Na+ loading; this Ba(2+)-sensitive current reversed direction at the expected reversal potential for K+ (EK), and was also blocked by extracellular tetraethylammonium (30 mM) and intracellular Cs+ (which replaced K+ in pipette solutions). The sulfonylurea drugs glipizide (IC50 = 4.9 nM), tolbutamide (IC50 = 23 microM) and glibenclamide (1 microM) were as effective as 300 microM Ba2+ in reducing the K+ current evoked by Na+ loading. When recording with "control" pipettes containing 15 mM Na+, diazoxide (300 microM) increased chord conductance and evoked outward current at -60 mV, which also reversed direction near EK. Effects of diazoxide were blocked by glibenclamide (1 microM) or glipizide (300 nM). Diazoxide (300 microM) and baclofen (3 microM), which also evoked K(+)-mediated outward currents recorded with control pipettes, caused little additional increases in outward currents during Na+ loading. Raising ATP concentrations to 10 mM in pipette solutions failed to significantly reduce currents evoked by diazoxide or Na+ loading, suggesting that these currents may not be mediated by ATP-sensitive K+ channels. Finally, Na+ loading using pipettes containing Cs+ in place of K+ evoked a relatively small outward current (50-150 pA at -60 mV), which developed gradually over the first 10 min after rupturing the membrane patch. This current was reduced by dihydro-ouabain (3 microM) and a low extracellular concentration of K+ (0.5 mM instead of 2.5 mM), but was not affected by Ba2+. We conclude that intracellular Na+ loading evokes a current generated by Na+/K+ ATPase in addition to sulfonylurea-sensitive K+ current. This Na(+)-dependent K+ current is unusual in its sensitivity to sulfonylureas, and could protect dopamine neurons against toxic effects of intracellular Na+ accumulation.
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