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 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 channel blockers, such as nifedipine, have been used for treatment of idiopathic pulmonary arterial hypertension (IPAH). Objective: Our previous study demonstrated that the Ca-sensing receptor (Ca²⁺SR) was upregulated and the extracellular Ca-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 Ca²⁺SR 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 μmol/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 [Ca ²⁺]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 Ca channels; therefore, it is possible that the use of dihydropyridine Ca channel blockers (eg, nifedipine) to treat IPAH patients with upregulated CaSR in PASMC may exacerbate pulmonary hypertension.