Dihydropyridine Ca 2+ Channel Blockers Increase Cytosolic [Ca 2+ ] by Activating Ca 2+ -sensing Receptors in Pulmonary Arterial Smooth Muscle Cells

• DOI: 10.1161/circresaha.113.300897
• Publication Date: 2013-01-09T13:40:46Z
• Authors: Aya Yamamura; Hisao Yamamura; Qiang Guo; Adriana M. Zimnicka; Jun Wan; Eun A. Ko; Kimberly A. Smith; Nicole M. Pohl; Shanshan Song; Amy Zeifman; Ayako Makino; Jason X.-J. Yuan
• Keywords: Channel blocker

Rationale: An increase in cytosolic free Ca 2+ concentration ([Ca ] cyt ) pulmonary arterial smooth muscle cells (PASMC) is a major trigger for vasoconstriction and an important stimulus PASMC proliferation vascular remodeling. The dihydropyridine channel blockers, such as nifedipine, have been used treatment of idiopathic hypertension (IPAH). Objective: Our previous study demonstrated that the -sensing receptor (CaSR) was upregulated extracellular -induced [Ca enhanced from patients with IPAH animals experimental hypertension. Here, we report dihydropyridines (eg, nifedipine) by activating CaSR (in which upregulated), but not normal PASMC. Methods Results: nifedipine-mediated IPAH-PASMC dependent half maximal effective 0.20 µmol/L. Knockdown siRNA significantly inhibited nifedipine-induced , whereas overexpression conferred rise . Other dihydropyridines, nicardipine Bay K8644, had similar augmenting effects on CaSR-mediated IPAH-PASMC; however, nondihydropyridine diltiazem verapamil, no effect Conclusions: derivatives potentiating activity independently their blocking (or activating) channels; therefore, it possible use blockers to treat may exacerbate