title: Dihydropyridine Ca(2+) channel blockers increase cytosolic [Ca(2+)] by activating Ca(2+)-sensing receptors in pulmonary arterial smooth muscle cells.
abstract: BACKGROUND
  An increase in cytosolic free Ca(2+) 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(2+) channel blockers, such as nifedipine, have been used for treatment of idiopathic pulmonary arterial hypertension (IPAH).
  
  
  OBJECTIVE
  Our previous study demonstrated that the Ca(2+)-sensing receptor (CaSR) was upregulated and the extracellular Ca(2+)-induced increase in [Ca(2+)](cyt) was enhanced in PASMC from patients with IPAH and animals with experimental pulmonary hypertension. Here, we report that the dihydropyridines (eg, nifedipine) increase [Ca(2+)](cyt) by activating CaSR in PASMC from IPAH patients (in which CaSR is upregulated), but not in normal PASMC.
  
  
  RESULTS
  The nifedipine-mediated increase in [Ca(2+)](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 [Ca(2+)](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 [Ca(2+)](cyt) in IPAH-PASMC; however, the nondihydropyridine blockers, such as diltiazem and verapamil, had no effect on the CaSR-mediated rise in [Ca(2+)](cyt).
  
  
  CONCLUSIONS
  The dihydropyridine derivatives increase [Ca(2+)](cyt) by potentiating the activity of CaSR in PASMC independently of their blocking (or activating) effect on Ca(2+) channels; therefore, it is possible that the use of dihydropyridine Ca(2+) channel blockers (eg, nifedipine) to treat IPAH patients with upregulated CaSR in PASMC may exacerbate pulmonary hypertension.
authors.affiliation: Department of Medicine, Section of Pulmonary, Critical Care, Sleep, and Allergy Medicine and Department of Pharmacology, Institute for Personalized Respiratory Medicine, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Aya
authors.initials: A
authors.lastname: Yamamura
authors.forename: Hisao
authors.initials: H
authors.lastname: Yamamura
authors.forename: Qiang
authors.initials: Q
authors.lastname: Guo
authors.forename: Adriana M
authors.initials: AM
authors.lastname: Zimnicka
authors.forename: Jun
authors.initials: J
authors.lastname: Wan
authors.forename: Eun A
authors.initials: EA
authors.lastname: Ko
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Smith
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Pohl
authors.forename: Shanshan
authors.initials: S
authors.lastname: Song
authors.forename: Amy
authors.initials: A
authors.lastname: Zeifman
authors.forename: Ayako
authors.initials: A
authors.lastname: Makino
authors.forename: Jason X-J
authors.initials: JX
authors.lastname: Yuan
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000009:adverse effects* / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D003600:Cytosol / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology; D007295:Inositol Phosphates / Q000502:physiology; D008297:Male; D016686:Monocrotaline / Q000633:toxicity; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use; D009543:Nifedipine / Q000009:adverse effects* / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D007295:Inositol Phosphates; C436740:N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine; D009281:Naphthalenes; D044169:Receptors, Calcium-Sensing; D011993:Recombinant Fusion Proteins; C118500:inositol 3,4,5-trisphosphate; D016686:Monocrotaline; D009543:Nifedipine