Hypertensive effect of calcilytic NPS 2143 administration in rats

Abstract

Secretion of parathormone (PTH), the main parathyroid hormone, which is under the control of the calcium sensing receptor, might be inhibited by calcimimetics and stimulated by calcilytics. Parathyroid glands also secrete parathyroid hypertensive factor. Recently, it was shown that calcimimetic NPS R-568 induced decreased blood pressure in spontaneously hypertensive rats (SHR) in the presence of parathyroid glands. Therefore, the aim of this study was to determine whether administration of the calcilytic NPS 2143 provoked an increase of mean arterial blood pressure (MAP) in normotensive rats. We used male Wistar rats anaesthetized with thiopental. Clearance experiments were performed and the effect of bolus, 1 mg/kg body weight i.v. of NPS 2143 on MAP in the presence and absence of thyroparathyroidectomy (TPTX) was monitored continuously. Calcilytic properties of NPS 2143 were confirmed directly by a significant (P!0$05) increase of plasma PTH concentration, and indirectly by a rise of plasma Ca 2C concentration and urinary fractional phosphate excretion (FE Pi). NPS 2143 administration markedly (P!0$05) increased MAP, calculated as the difference (D) in MAP between sequential measurements and the time of bolus injection of calcilytic. The observed increase of blood pressure in the NPS 2143 group was also significant (P!0$05) compared with the control group. Performance of TPTX prevented the hypertensive effect of NPS 2143. We conclude that NPS 2143 is responsible for increased blood pressure in rats in the presence of parathyroid glands.

Involvement of the Calcium-sensing Receptor in Human Taste Perception

“…Cinacalcet (13) and NPS-2143 (14) were chemically synthesized by methods described in the literature, and their activity was determined using HEK-293 cells that were transiently transformed with the human CaSR (hCaSR). All other reagents were a special purity grade purchased from Sigma-Aldrich Japan.…”

“…The total RNA was isolated from the epithelial papillae and from the epithelium without taste buds (RNA micro kit, Stratagene). The purified RNA was denatured at 60°C for 5 min, and first-strand cDNA was synthesized at 50°C for 60 min using oligo(dT) [12][13][14][15][16][17][18] primer and reverse transcriptase (SuperScript III, Invitrogen) in a final volume of 20 l. After synthesizing the cDNA, 1 l of cDNA was used as a template in 20 l of PCR mixture with Taq polymerase (Invitrogen). The PCR conditions were as follows: 94°C for 2 min and 29 -35 cycles at 94°C for 30 s, 58°C for 20 s, and 72°C for 45 s. The PCR products were analyzed by gel electrophoresis (2% agarose gel) with GelRed staining (Biotium).…”

Novel Role of the Calcium-Sensing Receptor in Blood Pressure Modulation

“…Accordingly, administration of a calcilytic NPS-2143 increases blood pressure in normotensive rats in the presence of parathyroid glands. 8 The effect of the calcimimetic is probably not directly related to the reduced PTH secretion, because PTH causes vasodilation and lowers blood pressure. 79 More likely, activation of the CaR in parathyroid glands by the calcimimetic might suppress secretion of parathyroid hypertensive factor.…”

Activation of the gut calcium-sensing receptor by peptide agonists reduces rapid elevation of plasma glucose in response to oral glucose load in rats

“…To determine the involvement of CaSR in the effect of test peptides on the glycemic response, an oral glucose tolerance test (OGTT) was performed after duodenal administration of the CaSR antagonist NPS-2143 (26,34). NPS-2143 was chemically synthesized following previously described methods, and its activity was determined using HEK-293 cells that were transiently transformed with the human CaSR (28).…”

“…The involvement of CaSR on the effect of test peptides was examined by duodenal administration of the CaSR antagonist NPS-2143 (26,34). Significant reduction of plasma glucose by duodenal ␥EC (␥EC/vehicle group) at 15 min was disappeared by duodenal pretreatment with NPS-2143 (␥EC/NPS group).…”