Abstract In pancreatic islets of fetal rats the effect of glucose (3 and 16.7 mM), glyceraldehyde (10 mM), leucine (20 mM), b-BCH (20 mM), tolbutamide (100 μg/ml), gtibenclamide (0.5 and 5.0 μg/ml) arginine (20 mM), KCl (20 mM) and theophylline (2.5 mM) on 45Ca 2+ net uptake and secretion of insulin was studied. All compounds tested failed to stimulate 45Ca 2+ net uptake. However, in contrast to glucose and glyceraldehyde, leucine, b-BCH, tolbutamide, glibenclamide, arginine, KCl and theophylline signiflcantly stimulated release of insulin. This effect could not be inhibited by the calcium antagonist verapamil (20 μM). Elevation of the glucose concentration from 3 to 5.6 mM did not alter 86Rb + efflux of fetal rat islets but inhibited 86Rb + efflux of adult rat islets. Stimulation of 86Rb + efflux with tolbutamide (100 μg/ml), leucine (20 mM) or b-BCH (20 mM) in the presence of 3 mM glucose was also ineffective in fetal rat islets. Our data suggest that stimulation of calcium uptake via the voltage dependent calcium channel is not possible in the fetal state. They also provide evidence that stimulators of insulin release which are thought not to act through their metabolism, initiate insulin secretion from fetal islets by a mechanism which is different from stimulation of calcium influx.