Glucose dependence of imidazoline-induced insulin secretion -: Different characteristics of two ATP-sensitive K+ channel-blocking compounds

The glucose dependence of the insulinotropic action of K-ATP channel-blocking imidazoline compounds was investigated. Administration of 100 mumol/l phentolamine, but not 100 mumol/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 mumol/l phentolamine was somewhat more effective than 100 jimol/l efaroxan to inhibit KATP channel activity in intact cultured P-cells (reduction by 96 vs. 83%). Both compounds were similarly effective to depolarize the beta-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 KATP 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.