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Background The Ca2+ triggered insulin exocytosis in β cells of the pancreatic islets may be the result of Ca2+ influx through L-type voltage dependent calcium channels (VDCC) localized in the plasma membrane, as well as of liberation of Ca2+ from intracellular storages, induced by activation of the calcium receptor (CaR) coupled with the PLC enzyme present in the pancreatic islets. The present study was designated to determine, in in vivo experiments, the effects of CaR activation by R-568 and inhibition of the receptor by NPS 2143 on the plasma glucose and insulin levels in the presence of verapamil, a calcium channel blocker. Methods Wistar rats, after fasting for 14 h before the experiment, were anesthetized with inactin and loaded ip with 1 g/kg glucose. Results In comparison to the control group, the verapamil-induced blockade of the calcium channels in glucose loaded animals increased the blood glucose level and decreased the insulin level, whereas CaR activation with R-568 induced opposite effects. However, in the presence of verapamil, R-568 did not change the concentration of glucose or insulin versus the control animals. Verapamil infusion did not alter elevated glucose concentration in the NPS 2143 animals. At the same time, verapamil reduced the plasma insulin level and potentiated the drop of insulin concentration induced by NPS 2143. Conclusion The observations suggest that under the in vivo conditions, calcium channel blockade may prevent changes in the blood glucose and insulin concentrations induced by the CaR activation.

Background The calcium-sensing receptor (CaR) has been found not only in parathyroid glands but also in other tissues, e.g. in β cells of the pancreatic islets. Therefore, CaR might likely mediate the mechanism of insulin secretion. The present study was designed to examine the in vivo effects of R-568, a CaR agonist, and NPS2143, a CaR inhibitor, on plasma insulin and blood glucose concentrations. Methods Wistar rats, after fasting for 14 h before the experiment, were anesthetized with inactin and loaded ip with 1 g/kg glucose. Results 20, 120 and 180 min after iv R-568 administration, plasma insulin increased markedly (by approximately 30%), in glucose-loaded rats, as compared to the control animals. S imultaneously, 180 min after R-568 administration, a significant drop by approximately 12% in blood glucose was observed. In contrast, administration of R-568 in rats not given glucose, did not influence the blood glucose or plasma insulin concentrations vs. the control group. Administration of NPS2143 increased the blood glucose level markedly (by about 18% vs. control group) at 180 and 210 min of the experiment. Simultaneously, a significant decrease of insulin concentration was observed vs. control group (by about 18 and 23%, respectively). Conclusion We suggest that modulation of the CaR activity may participate in the mechanisms which mediate insulin secretion in rats.

Background Synthesis and hypotensive properties of centrally acting imidazoline agents: 1-[(imidazolidin-2-yl)imino]-1 H -indazole (Marsanidine) and 7-chloro-1-[(4,5-dihydro-1 H -imidazol-2-yl)methyl]-1 H -indazole (TCS-80) were tested in rats. We have recently synthesized two novel Marsanidine analogues which decrease blood pressure and heart rate in rats: 1-[(4,5-dihydro-1 H -imidazol-2-yl)methyl]-1 H -indole (TCS-54), and 7-chloro-1-[(4,5-dihydro-1 H -imidazol-2-yl)methyl]-1 H -indole (TCS-213). Among all these analogues, compound TCS-80 exhibits the highest affinity to I 1 -imidazoline receptors and the lowest α 2 /I 1 selectivity ratio. The observed cardiovascular effects of the compounds might be mediated through α 2 -adrenergic and I 1 -imidazoline receptors and subsequent decrease of the symphathetic nerve activity. The present studies were performed to determine whether α 2 -adrenergic and/or I 1 -imidazoline receptors are involved in the decrease of blood pressure and heart rate induced by Marsanidine, TCS-54, TCS-80, and TCS-213 in rats. Methods Anesthetized rats were infused iv with the tested compounds and selective α 2 -adrenoceptor antagonist, RX821002, or nonselective α 2 -adrenergic/I 1 -imidazoline receptor antagonist, Efaroxan. The mean arterial blood pressure and heart rate were monitored directly and continuously throughout the experiment. Results Efaroxan inhibited the hypotensive effect of TCS-80 stronger than RX821002. The degree of inhibition of the hypotensive effect of the remaining compounds was similar for both antagonists. The presence of Efaroxan and RX821002 diminished the heart rate decrease induced by all compounds administration, though the influence on the maximal chronotropic effect was attenuated significantly in the TCS-80 and TCS-213 treated animals only. Conclusion Our results indicate that hypotensive and negative chronotropic activities of all tested compounds are mediated by both the α 2 -adrenergic and I 1 -imidazoline receptors. Moreover, the circulatory effect of TCS-80 might be mediated to relatively higher degree by the I 1 -imidazoline receptors than by the α 2 -adrenergic ones.