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

Rationale: An increase in cytosolic free Ca 2+ concentration ([Ca 2+ ] 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 Ca 2+ channel blockers, such as nifedipine, have been used for treatment of idiopathic pulmonary arterial hypertension (IPAH). Objective: Our previous study demonstrated that the Ca 2+ -sensing receptor (CaSR) was upregulated and the extracellular Ca 2+ -induced increase in [Ca 2+ ] cyt was enhanced in PASMC from patients with IPAH and animals with experimental pulmonary hypertension. Here, we report that the dihydropyridines (eg, nifedipine) increase [Ca 2+ ] 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 [Ca 2+ ] cyt in IPAH-PASMC was concentration dependent with a half maximal effective concentration of 0.20 µmol/L. Knockdown of CaSR with siRNA in IPAH-PASMC significantly inhibited the nifedipine-induced increase in [Ca 2+ ] cyt , whereas overexpression of CaSR in normal PASMC conferred the nifedipine-induced rise in [Ca 2+ ] cyt . Other dihydropyridines, nicardipine and Bay K8644, had similar augmenting effects on the CaSR-mediated increase in [Ca 2+ ] cyt in IPAH-PASMC; however, the nondihydropyridine blockers, such as diltiazem and verapamil, had no effect on the CaSR-mediated rise in [Ca 2+ ] cyt . Conclusions: The dihydropyridine derivatives increase [Ca 2+ ] cyt by potentiating the activity of CaSR in PASMC independently of their blocking (or activating) effect on Ca 2+ channels; therefore, it is possible that the use of dihydropyridine Ca 2+ channel blockers (eg, nifedipine) to treat IPAH patients with upregulated CaSR in PASMC may exacerbate pulmonary hypertension.