title: Molecular Mechanism of Dihydropyridine Ca2+Channel Blockers in Pulmonary Hypertension.
abstract: 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+]cytresponses and augmented cell proliferation. In this study, the effects of dihydropyridine Ca2+channel blockers on [Ca2+]cytresponses mediated by CaSR were examined in IPAH-PASMCs. Nifedipine (dihydropyridines) enhanced the CaSR-mediated increase in [Ca2+]cytin 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+]cytincrease in IPAH-PASMCs. In contrast, non-dihydropyridine Ca2+channel blockers such as diltiazem (benzothiazepines) and verapamil (phenylalkylamines) had no effect on the [Ca2+]cytresponse 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.
authors.affiliation: Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University.
authors.forename: Aya
authors.initials: A
authors.lastname: Yamamura
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000009:adverse effects*; D020013:Calcium Signaling / Q000187:drug effects; D004095:Dihydropyridines / Q000009:adverse effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology* / Q000235:genetics; D058990:Molecular Targeted Therapy; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D009529:Nicardipine / Q000009:adverse effects*; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D066253:Vascular Remodeling / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D044169:Receptors, Calcium-Sensing; C038806:1,4-dihydropyridine; D009529:Nicardipine; D002118:Calcium