Dihydropyridine Ca2+ channel blockers increase cytosolic [Ca2+] by activating Ca2+-sensing receptors in pulmonary arterial smooth muscle cells

Aya Yamamura, Hisao Yamamura, Qiang Guo, Adriana M. Zimnicka, Jun Wan, Eun A. Ko, Kimberly A. Smith, Nicole M. Pohl, Shanshan Song, Amy Zeifman, Ayako Makino, Jason Yuan

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Rationale: An increase in cytosolic free Ca 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 channel blockers, such as nifedipine, have been used for treatment of idiopathic pulmonary arterial hypertension (IPAH). Objective: Our previous study demonstrated that the Ca-sensing receptor (Ca2+SR) was upregulated and the extracellular Ca-induced increase in [Ca2+]cyt was enhanced in PASMC from patients with IPAH and animals with experimental pulmonary hypertension. Here, we report that the dihydropyridines (eg, nifedipine) increase [Ca2+]cyt by activating CaSR in PASMC from IPAH patients (in which Ca2+SR is upregulated), but not in normal PASMC. Methods and Results: The nifedipine-mediated increase in [Ca2+]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 [Ca2+]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 [Ca2+]cyt in IPAH-PASMC; however, the nondihydropyridine blockers, such as diltiazem and verapamil, had no effect on the CaSR-mediated rise in [Ca2+]cyt. Conclusions: The dihydropyridine derivatives increase [Ca2+]cyt by potentiating the activity of CaSR in PASMC independently of their blocking (or activating) effect on Ca channels; therefore, it is possible that the use of dihydropyridine Ca channel blockers (eg, nifedipine) to treat IPAH patients with upregulated CaSR in PASMC may exacerbate pulmonary hypertension.

Original languageEnglish (US)
Pages (from-to)640-650
Number of pages11
JournalCirculation Research
Volume112
Issue number4
DOIs
StatePublished - Feb 15 2013
Externally publishedYes

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Calcium-Sensing Receptors
Smooth Muscle Myocytes
Lung
Nifedipine
Dihydropyridines
Pulmonary Hypertension
1,4-dihydropyridine
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
Nicardipine
Diltiazem
Verapamil
Familial Primary Pulmonary Hypertension
Vasoconstriction
Small Interfering RNA

Keywords

  • Ca2+-sensing receptor
  • calcium channel blocker
  • nicardipine
  • nifedipine
  • pulmonary hypertension
  • smooth muscle cell

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Dihydropyridine Ca2+ channel blockers increase cytosolic [Ca2+] by activating Ca2+-sensing receptors in pulmonary arterial smooth muscle cells. / Yamamura, Aya; Yamamura, Hisao; Guo, Qiang; Zimnicka, Adriana M.; Wan, Jun; Ko, Eun A.; Smith, Kimberly A.; Pohl, Nicole M.; Song, Shanshan; Zeifman, Amy; Makino, Ayako; Yuan, Jason.

In: Circulation Research, Vol. 112, No. 4, 15.02.2013, p. 640-650.

Research output: Contribution to journalArticle

Yamamura, Aya ; Yamamura, Hisao ; Guo, Qiang ; Zimnicka, Adriana M. ; Wan, Jun ; Ko, Eun A. ; Smith, Kimberly A. ; Pohl, Nicole M. ; Song, Shanshan ; Zeifman, Amy ; Makino, Ayako ; Yuan, Jason. / Dihydropyridine Ca2+ channel blockers increase cytosolic [Ca2+] by activating Ca2+-sensing receptors in pulmonary arterial smooth muscle cells. In: Circulation Research. 2013 ; Vol. 112, No. 4. pp. 640-650.
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abstract = "Rationale: An increase in cytosolic free Ca 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 channel blockers, such as nifedipine, have been used for treatment of idiopathic pulmonary arterial hypertension (IPAH). Objective: Our previous study demonstrated that the Ca-sensing receptor (Ca2+SR) was upregulated and the extracellular Ca-induced increase in [Ca2+]cyt was enhanced in PASMC from patients with IPAH and animals with experimental pulmonary hypertension. Here, we report that the dihydropyridines (eg, nifedipine) increase [Ca2+]cyt by activating CaSR in PASMC from IPAH patients (in which Ca2+SR is upregulated), but not in normal PASMC. Methods and Results: The nifedipine-mediated increase in [Ca2+]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 [Ca2+]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 [Ca2+]cyt in IPAH-PASMC; however, the nondihydropyridine blockers, such as diltiazem and verapamil, had no effect on the CaSR-mediated rise in [Ca2+]cyt. Conclusions: The dihydropyridine derivatives increase [Ca2+]cyt by potentiating the activity of CaSR in PASMC independently of their blocking (or activating) effect on Ca channels; therefore, it is possible that the use of dihydropyridine Ca channel blockers (eg, nifedipine) to treat IPAH patients with upregulated CaSR in PASMC may exacerbate pulmonary hypertension.",
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AU - Yamamura, Aya

AU - Yamamura, Hisao

AU - Guo, Qiang

AU - Zimnicka, Adriana M.

AU - Wan, Jun

AU - Ko, Eun A.

AU - Smith, Kimberly A.

AU - Pohl, Nicole M.

AU - Song, Shanshan

AU - Zeifman, Amy

AU - Makino, Ayako

AU - Yuan, Jason

PY - 2013/2/15

Y1 - 2013/2/15

N2 - Rationale: An increase in cytosolic free Ca 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 channel blockers, such as nifedipine, have been used for treatment of idiopathic pulmonary arterial hypertension (IPAH). Objective: Our previous study demonstrated that the Ca-sensing receptor (Ca2+SR) was upregulated and the extracellular Ca-induced increase in [Ca2+]cyt was enhanced in PASMC from patients with IPAH and animals with experimental pulmonary hypertension. Here, we report that the dihydropyridines (eg, nifedipine) increase [Ca2+]cyt by activating CaSR in PASMC from IPAH patients (in which Ca2+SR is upregulated), but not in normal PASMC. Methods and Results: The nifedipine-mediated increase in [Ca2+]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 [Ca2+]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 [Ca2+]cyt in IPAH-PASMC; however, the nondihydropyridine blockers, such as diltiazem and verapamil, had no effect on the CaSR-mediated rise in [Ca2+]cyt. Conclusions: The dihydropyridine derivatives increase [Ca2+]cyt by potentiating the activity of CaSR in PASMC independently of their blocking (or activating) effect on Ca channels; therefore, it is possible that the use of dihydropyridine Ca channel blockers (eg, nifedipine) to treat IPAH patients with upregulated CaSR in PASMC may exacerbate pulmonary hypertension.

AB - Rationale: An increase in cytosolic free Ca 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 channel blockers, such as nifedipine, have been used for treatment of idiopathic pulmonary arterial hypertension (IPAH). Objective: Our previous study demonstrated that the Ca-sensing receptor (Ca2+SR) was upregulated and the extracellular Ca-induced increase in [Ca2+]cyt was enhanced in PASMC from patients with IPAH and animals with experimental pulmonary hypertension. Here, we report that the dihydropyridines (eg, nifedipine) increase [Ca2+]cyt by activating CaSR in PASMC from IPAH patients (in which Ca2+SR is upregulated), but not in normal PASMC. Methods and Results: The nifedipine-mediated increase in [Ca2+]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 [Ca2+]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 [Ca2+]cyt in IPAH-PASMC; however, the nondihydropyridine blockers, such as diltiazem and verapamil, had no effect on the CaSR-mediated rise in [Ca2+]cyt. Conclusions: The dihydropyridine derivatives increase [Ca2+]cyt by potentiating the activity of CaSR in PASMC independently of their blocking (or activating) effect on Ca channels; therefore, it is possible that the use of dihydropyridine Ca channel blockers (eg, nifedipine) to treat IPAH patients with upregulated CaSR in PASMC may exacerbate pulmonary hypertension.

KW - Ca2+-sensing receptor

KW - calcium channel blocker

KW - nicardipine

KW - nifedipine

KW - pulmonary hypertension

KW - smooth muscle cell

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