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 language | English (US) |
|---|---|
| Pages (from-to) | 640-650 |
| Number of pages | 11 |
| Journal | Circulation Research |
| Volume | 112 |
| Issue number | 4 |
| DOIs | |
| State | Published - Feb 15 2013 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Dihydropyridine Ca2+ channel blockers increase cytosolic [Ca2+] by activating Ca2+-sensing receptors in pulmonary arterial smooth muscle cells
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
UR - http://www.scopus.com/inward/record.url?scp=84874234302&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84874234302&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.113.300897
DO - 10.1161/CIRCRESAHA.113.300897
M3 - Article
C2 - 23300272
AN - SCOPUS:84874234302
VL - 112
SP - 640
EP - 650
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 4
ER -