Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and fatal disease of unidentified pathogenesis. IPAH is pathologically characterized as sustained vasoconstriction and vascular remodeling of the pulmonary artery. In pulmonary arterial smooth muscle cells (PASMCs), an increase in cytosolic Ca
2+ concentration ([Ca
2+]
cyt) triggers vasoconstriction and stimulates cell proliferation leading to vascular remodeling. However, dihydropyridine-type voltage-dependent Ca
2+ channel blockers are only effective in very few patients with IPAH (<10%). It is unclear why dihydropyridine Ca
2+ channel blockers are not therapeutically effective in a majority of IPAH patients. We have previously shown that extracellular Ca
2+-sensing receptor (CaSR) is upregulated in PASMCs from IPAH patients, and it contributes to enhanced [Ca
2+]
cyt responses and augmented cell proliferation. In this study, the effects of dihydropyridine Ca
2+ channel blockers on [Ca
2+]
cyt responses mediated by CaSR were examined in IPAH-PASMCs. Nifedipine (dihydropyridines) enhanced the CaSR-mediated increase in [Ca
2+]
cyt in IPAH-PASMCs, but not in PASMCs from normal subjects. Nicardipine (dihydropyridines) and Bay K 8644 (a dihydropyridine Ca
2+ channel activator) also augmented the CaSR-mediated [Ca
2+]
cyt increase in IPAH-PASMCs. In contrast, non-dihydropyridine Ca
2+ channel blockers such as diltiazem (benzothiazepines) and verapamil (phenylalkylamines) had no effect on the [Ca
2+]
cyt response in IPAH-PASMCs. Finally, in monocrotaline-induced pulmonary hypertensive rats, nifedipine caused further increase in right ventricular systolic pressure and thus right ventricular hypertrophy. In conclusion, dihydropyridine Ca
2+ channel blockers could exacerbate symptoms of pulmonary hypertension in IPAH patients with upregulated CaSR in PASMCs.
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