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 μM and apparent maximum effect at 5 μM nifedipine. In the presence of 20 mM D-glucose, the inhibitory effects of 0.5, 1 or 5 μM 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 μM. 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 β-cell.

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