title: Extracellular calcium-sensing receptor is critical in hypoxic pulmonary vasoconstriction.
abstract: OBJECTIVE
  The initiation of hypoxic pulmonary vasoconstriction (HPV) involves an increase in cytosolic calcium ([Ca(2+)](i)) in pulmonary artery (PA) smooth muscle cells (PASMCs). Both the processes depend on extracellular Ca(2+). Extracellular Ca(2+) can be sensed by extracellular calcium-sensing receptor (CaSR). This study aims at determining whether CaSR is pivotal in the initiation of HPV.
  
  
  RESULTS
  Experiments were performed in cultured PASMCs, isolated PAs, and rats including CaSR knockdown preparations. Both hypoxia and H(2)O(2) equivalent to the level achieved by hypoxia increased [Ca(2+)](i) in an extracellular Ca(2+)-dependent manner in PASMCs, and this was inhibited by CaSR knockdown or its negative allosteric modulator, Calhex231. Hypoxia-increased H(2)O(2) generation was diminished by mitochondria depletion. Mitochondria depletion abolished hypoxia-induced [Ca(2+)](i) increase (HICI), which was reversed by H(2)O(2) repletion. CaSR knockdown or Calhex231, however, prevented the reversible effect of H(2)O(2). HICI was abolished by catalase-polyethylene glycol (PEG-Catalase), not superoxide dismutase-polyethylene glycol (PEG-SOD) pretreatment, attenuated by ryanodine receptor3-knockdown or inhibition of store-operated Ca(2+) entry. HPV in vitro and in vivo was inhibited by Calhex231 and by CaSR knockdown.
  
  
  METHODS
  A novel mechanism underlying HPV is revealed by the role of CaSR in orchestrating reactive oxygen species and [Ca(2+)](i) signaling.
  
  
  CONCLUSIONS
  The activation of mitochondrial H(2)O(2)-sensitized CaSR by extracellular Ca(2+) mediates HICI in PASMCs and, thus, initiates HPV.
authors.affiliation: Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, People's Republic of China.
authors.forename: Jiwei
authors.initials: J
authors.lastname: Zhang
authors.forename: Juan
authors.initials: J
authors.lastname: Zhou
authors.forename: Lei
authors.initials: L
authors.lastname: Cai
authors.forename: Yankai
authors.initials: Y
authors.lastname: Lu
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Liping
authors.initials: L
authors.lastname: Zhu
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Hu
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling; D015687:Cell Hypoxia; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003514:Cyclohexylamines / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D047028:Macrocyclic Compounds / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010080:Oxazoles / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014661:Vasoconstriction
chemical_list: D001549:Benzamides; D002121:Calcium Channel Blockers; D003514:Cyclohexylamines; D007546:Isoquinolines; D047028:Macrocyclic Compounds; C482333:N(1)-(4-chlorobenzoyl)-N(2)-(1-(1-naphthyl)ethyl)-1,2-diaminocyclohexane; D010080:Oxazoles; D044169:Receptors, Calcium-Sensing; D019837:Ryanodine Receptor Calcium Release Channel; D013449:Sulfonamides; C473605:extracellular calcium cation-sensing receptor, rat; C511704:xestospongin C; D012433:Ryanodine; D006861:Hydrogen Peroxide; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide