Dihydropyridine Ca2+ Channel Blockers Increase Cytosolic [Ca2+] by Activating Ca2+-sensing Receptors in Pulmonary Arterial Smooth Muscle Cells

Rationale: An increase in cytosolic free Ca2+ concentration ([Ca2+](cyt)) in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and an important stimulus for PASMC proliferation and pulmonary vascular remodeling. The dihydropyridine Ca2+ channel blockers, such as nifedipine, have been used for treatment of idiopathic pulmonary arterial hypertension (IPAH). Objective: Our previous study demonstrated that the Ca2+-sensing receptor (CaSR) was upregulated and the extracellular Ca2+-induced increase in [Ca2+](cyt) was enhanced in PASMC from patients with IPAH and animals with experimental pulmonary hypertension. Here, we report that the dihydropyridines (eg, nifedipine) increase [Ca2+](cyt) by activating CaSR in PASMC from IPAH patients (in which CaSR is upregulated), but not in normal PASMC. Methods and Results: The nifedipine-mediated increase in [Ca2+](cyt) in IPAH-PASMC was concentration dependent with a half maximal effective concentration of 0.20 mu mol/L. Knockdown of CaSR with siRNA in IPAH-PASMC significantly inhibited the nifedipine-induced increase in [Ca2+](cyt), whereas overexpression of CaSR in normal PASMC conferred the nifedipine-induced rise in [Ca2+](cyt). Other dihydropyridines, nicardipine and Bay K8644, had similar augmenting effects on the CaSR-mediated increase in [Ca2+](cyt) in IPAH-PASMC; however, the nondihydropyridine blockers, such as diltiazem and verapamil, had no effect on the CaSR-mediated rise in [Ca2+] cyt. Conclusions: The dihydropyridine derivatives increase [Ca2+](cyt) by potentiating the activity of CaSR in PASMC independently of their blocking (or activating) effect on Ca2+ channels; therefore, it is possible that the use of dihydropyridine Ca2+ channel blockers (eg, nifedipine) to treat IPAH patients with upregulated CaSR in PASMC may exacerbate pulmonary hypertension. (Circ Res. 2013; 4:640-650.)