肺高血圧症を増悪させるカルシウムブロッカーの分子機構

抄録

 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 Ca²⁺ concentration ([Ca²⁺]_cyt) triggers vasoconstriction and stimulates cell proliferation leading to vascular remodeling. However, dihydropyridine-type voltage-dependent Ca²⁺ channel blockers are only effective in very few patients with IPAH (<10%). It is unclear why dihydropyridine Ca²⁺ channel blockers are not therapeutically effective in a majority of IPAH patients. We have previously shown that extracellular Ca²⁺-sensing receptor (CaSR) is upregulated in PASMCs from IPAH patients, and it contributes to enhanced [Ca²⁺]_cyt responses and augmented cell proliferation. In this study, the effects of dihydropyridine Ca²⁺ channel blockers on [Ca²⁺]_cyt responses mediated by CaSR were examined in IPAH-PASMCs. Nifedipine (dihydropyridines) enhanced the CaSR-mediated increase in [Ca²⁺]_cyt in IPAH-PASMCs, but not in PASMCs from normal subjects. Nicardipine (dihydropyridines) and Bay K 8644 (a dihydropyridine Ca²⁺ channel activator) also augmented the CaSR-mediated [Ca²⁺]_cyt increase in IPAH-PASMCs. In contrast, non-dihydropyridine Ca²⁺ channel blockers such as diltiazem (benzothiazepines) and verapamil (phenylalkylamines) had no effect on the [Ca²⁺]_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 Ca²⁺ channel blockers could exacerbate symptoms of pulmonary hypertension in IPAH patients with upregulated CaSR in PASMCs.