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

Abstract

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.

Perchlorate stimulates insulin secretion by shifting the gating of L-type Ca2+ currents in mouse pancreatic B-cells towards negative potentials

“…In fact, the 70% increase in action potential frequency (Fig. 1D) compares favourably with the reported stimulation of insulin secretion [15].…”

“…A series of preliminary experiments were performed on B-cells isolated from ob/ob-mice taken from the Umeå colony, i.e. the type of cells used in previous studies [15,16]. The effects of ClO 4 -were qualitatively and quantitatively similar in the two preparations of B-cells.…”

“…It has been demonstrated that the inorganic and chaotrophic anion perchlorate (ClO 4 -), when applied at millimolar concentrations, amplifies glucose-induced insulin secretion [16,27] and elevates [Ca 2+ ] i [16]. These actions probably account for the ability of this anion to increase serum insulin levels and lower the blood glucose concentration [14,15,16]. In an earlier report [16] it was also observed that the agonistic effects of ClO 4 -on the glucose-induced rise of [Ca 2+ ] i and insulin secretion are reminiscent of those obtained with the L-type Ca 2+ channel agonist BAY K8644.…”

Effects of Cl^– Substitution on Electrophysiological Properties, Ca²⁺ Influx and Prolactin Secretion of Rat Lactotropes in vitro

“…Increased growth hormone release from rat somatotropes has also been reported for ClO – 4 , by Ohlson et al [24], as well as insulin release from pancreatic β cells which is potentiated by ClO – 4 [25, 26, 27]. This anion was considered by Frankel and Sehlin [26]to be a Ca 2+ channel agonist in this cell type, by acting on L-type calcium channels.…”

Development of a Cell-Based Fluorescence Polarization Biosensor Using Preproinsulin to Identify Compounds That Alter Insulin Granule Dynamics

“…This response was inhibited by the calcium channel blocker nifedipine that is known to inhibit insulin release. 19 These data suggest that PPI-mCherry reporter system: (1) undergoes GSIS and does not interfere with secretion of endogenous insulin and, (2) responds normally to known insulin-modulating compounds, such as exendin-4 and nifedipine in similar quantitative fashion as insulin. Labeling of primary human islets was performed with lentiviral transduction of the PPI-mCherry reporter system and proof-of-principal of b-cell sorting was performed.…”