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Glucose Dependence of Imidazoline-Induced Insulin Secretion

Different Characteristics of Two ATP-Sensitive K⁺ Channel–Blocking Compounds

Institute of Pharmacology and Toxicology, University of Braunschweig, Braunschweig, Germany

The glucose dependence of the insulinotropic action of K_ATP channel–blocking imidazoline compounds was investigated. Administration of 100 µmol/l phentolamine, but not 100 µmol/l efaroxan, markedly increased insulin secretion of freshly isolated mouse islets when the perifusion medium contained 5 mmol/l glucose. When the glucose concentration was raised to 10 mmol/l in the continued presence of either imidazoline, a clear potentiation of secretion occurred as compared with 10 mmol/l glucose alone. In the presence of efaroxan, a brisk first-phase–like increase was followed by a sustained phase, whereas a more gradual increase resulted in the presence of phentolamine. Administration of 100 µmol/l phentolamine was somewhat more effective than 100 µmol/l efaroxan to inhibit K_ATP channel activity in intact cultured ß-cells (reduction by 96 vs. 83%). Both compounds were similarly effective to depolarize the ß-cells. When measured by the perforated patch-technique, the depolarization by efaroxan was often oscillatory, whereas that by phentolamine was sustained. In perifused cultured islets, both compounds increased the cytosolic calcium concentration ([Ca²⁺]_c) in the presence of 5 and 10 mmol/l glucose. Efaroxan induced large amplitude oscillations of [Ca²⁺]_c, whereas phentolamine induced a sustained increase. It appears that a K_ATP channel block by imidazolines is not incompatible with a glucose-selective enhancement of insulin secretion. The glucose selectivity of efaroxan may involve an inhibitory effect distal to [Ca²⁺]_c increase and/or the generation of [Ca²⁺]_c oscillations.

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