RATIONALE: 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. METHODS AND 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.
RATIONALE: 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 dihydropyridineCa(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. METHODS AND 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 dihydropyridineCa(2+) channel blockers (eg, nifedipine) to treat IPAH patients with upregulated CaSR in PASMC may exacerbate pulmonary hypertension.
Authors: S L Archer; B London; V Hampl; X Wu; A Nsair; L Puttagunta; K Hashimoto; R E Waite; E D Michelakis Journal: FASEB J Date: 2001-08 Impact factor: 5.191
Authors: O Platoshyn; Y Yu; V A Golovina; S S McDaniel; S Krick; L Li; J Y Wang; L J Rubin; J X Yuan Journal: Am J Physiol Lung Cell Mol Physiol Date: 2001-04 Impact factor: 5.464
Authors: Jimmy Y C Chow; Christine Estrema; Tiffany Orneles; Xiao Dong; Kim E Barrett; Hui Dong Journal: Am J Physiol Cell Physiol Date: 2011-05-11 Impact factor: 4.249
Authors: M Gowen; G B Stroup; R A Dodds; I E James; B J Votta; B R Smith; P K Bhatnagar; A M Lago; J F Callahan; E G DelMar; M A Miller; E F Nemeth; J Fox Journal: J Clin Invest Date: 2000-06 Impact factor: 14.808
Authors: O Sitbon; M Humbert; J L Jagot; O Taravella; M Fartoukh; F Parent; P Herve; G Simonneau Journal: Eur Respir J Date: 1998-08 Impact factor: 16.671
Authors: Ying Yu; Ivana Fantozzi; Carmelle V Remillard; Judd W Landsberg; Naomi Kunichika; Oleksandr Platoshyn; Donna D Tigno; Patricia A Thistlethwaite; Lewis J Rubin; Jason X-J Yuan Journal: Proc Natl Acad Sci U S A Date: 2004-09-09 Impact factor: 11.205
Authors: Ryan M Fryer; Jason A Segreti; Deborah L Widomski; Pamela H Franklin; Patricia N Banfor; Kristin A Koch; Masaki Nakane; J Ruth Wu-Wong; Bryan F Cox; Glenn A Reinhart Journal: J Pharmacol Exp Ther Date: 2007-07-16 Impact factor: 4.030
Authors: Anna R Hemnes; Min Zhao; James West; John H Newman; Stuart Rich; Stephen L Archer; Ivan M Robbins; Timothy S Blackwell; Joy Cogan; James E Loyd; Zhongming Zhao; Christa Gaskill; Christopher Jetter; Jonathan A Kropski; Susan M Majka; Eric D Austin Journal: Am J Respir Crit Care Med Date: 2016-08-15 Impact factor: 21.405
Authors: Krishna C Penumatsa; Deniz Toksoz; Rod R Warburton; Andrew J Hilmer; Tiegang Liu; Chaitan Khosla; Suzy A A Comhair; Barry L Fanburg Journal: Am J Physiol Lung Cell Mol Physiol Date: 2014-08-15 Impact factor: 5.464
Authors: Xi He; Shanshan Song; Ramon J Ayon; Angela Balisterieri; Stephen M Black; Ayako Makino; W Gil Wier; Wei-Jin Zang; Jason X-J Yuan Journal: Am J Physiol Cell Physiol Date: 2018-01-03 Impact factor: 4.249