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 (e.g., 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 an EC50 of 0.20 µM. 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 non-dihydropyridine 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 use the dihydropyridine Ca2+ channel blockers (e.g., nifedipine) to treat IPAH patients with upregulated CaSR in PASMC may exacerbate pulmonary hypertension.
- calcium-sensing receptor
- pulmonary hypertension
- calcium channel blocker
- calcium signaling
- smooth muscle cell
- Received January 6, 2013.
- Accepted January 8, 2013.
- Copyright © 2013, Circulation Research