Heterogeneous characteristics of imidazoline-induced insulin secretion

Imidazolines are regarded as a pharmacological group of insulin secretagogu es with one uniform mechanism of action, namely closure of ATP-dependent K channels (K-ATP channels) and, in consequence, depolarization of the plasm a membrane, Ca2+ influx and stimulation of secretion. This assumption was i nvestigated by measuring insulin secretion from perifused pancreatic islets in response to three imidazoline compounds and comparing the characteristi cs of secretion with changes in membrane potential and cytosolic Ca2+ conce ntration [Ca2+](i) of single beta-cells. Phentolamine (32 mu M) stimulated insulin secretion from perifused mouse islets in the presence of stimulator y (10 mM and 30 mM) and substimulatory (5 mM) glucose concentrations and ev en in the absence of glucose. Idazoxan in concentrations up to 500 mu M was virtually ineffective in the presence of 5 mM glucose. At 10 mM glucose, t here was a moderate but significant increase of secretion by idazoxan, 20 m u M being nearly as effective as 100 mu M. The effect of phentolamine was o f slow onset and irreversible in the time frame of the experiments, while t he effect of idazoxan was of fast onset and reversible. Alinidine also stim ulated secretion in the presence of 10 mM glucose with fast and reversible kinetics, but in contrast to idazoxan, 100 mu M was clearly more effective than 20 mu M. These heterogeneous characteristics of secretion were reflect ed by changes of [Ca2+](i): the increase of [Ca2+](i) by phentolamine was s low and only partially reversible, whereas idazoxan led to a smaller, but f aster and reversible response. The increase of [Ca2+](i) by phentolamine an d idazoxan was abolished by the Ca2+ channel blocker D 600. Surprisingly, a ll three compounds depolarized the beta-cell plasma membrane from a resting potential of -71 mV to about -36 mV. Again, the effect of phentolamine was slow and that of idazoxan and alinidine fast. Thus, the characteristics of phentolamine-induced secretion appear to be attributable to the consequenc es of K-ATP channel closure. It is unclear, however, why all three test com pounds achieved the same degree of depolarization in spite of their known d ifferent efficiency to close K-ATP channels. Apparently, there are addition al mechanisms involved in the action of idazoxan and alinidine, which may c ontribute to the obvious differences in the characteristics of secretion.