Interaction between perchlorate and nifedipine on insulin secretion from mouse pancreatic islets

In order to elucidate the mechanisms responsible for the stimulatory effect of perchlorate (ClO4-) on insulin secretion, we have investigated the interaction between this chaotropic anion and the organic calcium antagonist nifedipine. This drug, known as a blocker of L-type calcium channels, was chosen as a tool to test the idea that ClO4- acts on insulin secretion by stimulating the gating of voltage-controlled Ca2+ channels. ClO4- amplified the stimulatory effect of D-glucose on insulin release from perfused pancreas (first and second phases) as well as from isolated islets incubated in static incubations for 60 min. This indicates that ClO4- amplifies physiologically regulated insulin secretion. Nifedipine reduced D-glucose-induced (20 mM) insulin release in a dose-dependent manner with half-maximum effect at about 0.8 microM and apparent maximum effect at 5 microM nifedipine. In the presence of 20 mM D-glucose, the inhibitory effects of 0.5, 1 or 5 microM nifedipine were only slightly, if at all, counteracted by perchlorate. When 12 mM ClO4- and 20 mM D-glucose were combined, calculation of the specific effect of ClO4- revealed that nifedipine produced almost maximum inhibition already at 0.05 microM. Thus, the perchlorate-induced amplification of D-glucose-stimulated insulin release shows higher sensitivity to nifedipine than the D-glucose-effect as such. This supports the hypothesis that perchlorate primarily affects the voltage-sensitive L-type calcium channel in the beta-cell.