Inhibition Of Ca2+-Sensing Receptors Attenuates Pulmonary Hypertension In Rats

and animals with monocrotaline (MCT)-induced pulmonary hypertension (PH). In hypertension (IPAH) this study, we investigated the potential therapeutic effect of the CaSR antagonist, NPS2143, on animals with MCT-induced PH. Methods: CaSR expression in lung tissue, pulmonary arteries, and PASMCs from MCT-induced PH rats and IPAH [Ca ] was measured in primary cultured patients were measured with Western blot and immunohistochemistry. 2+ cyt PASMCs loaded with fura-2/AM by a digital fluorescence microscopy system. NPS2143 (4.5 mg/kg/day, i.p.) emodynamics, right was given to control and MCT-injected rats from day 1 to 10 after MCT injection (Day 0, 60 mg/kg, i.p.). H heart hypertrophy (RV/LV+S ratio), and were measured and compared in control rats, MCT-injected rats and MCT-injected rats treated with NPS2143 two weeks after initial MCT injection. Results: CaSR expression was significantly upregulated ) in the lung tissue, pulmonary arteries, and a PASMCs from MCT-induced PH rats in comparison to those from control rats; and ) in PASMC b isolated from . Intraperitoneal injection of the CaSR antagonist, NPS2143, significantly IPAH patients attenuated the MCT-mediated increases in right ventricular systolic pressure (RVSP) (33.26 ±3.30 vs. ­ 39.02±3.92 mmHg, <0.05), right ventricular hypertrophy (RV/LV+S ratio: 0.29±0.05 vs. 0.40±0.03, P P <0.05), and the thickening of small pulmonary arteries in rats injected with MCT. The CaSR antagonist also markedly inhibited the extracellular Ca -induced rise in [Ca ] due to 2+ 2+ cyt upregulated CaSR in MCT-injected rats. PASMCs from IPAH patient and Conclusions: Enhanced CaSR expression and function contribute to the sustained vasoconstriction and severe structural remodeling of the distal pulmonary arteries in patients and animals with PH. Targeting of CaSR is potentially a novel strategy to develop therapeutic for pulmonary hypertension.