Abstract
Hypoxic pulmonary vasoconstriction (HPV) occurs with ascent to high altitude and can contribute to development of high altitude pulmonary edema (HAPE). Vascular smooth muscle contains carbonic anhydrase (CA), and acetazolamide (AZ), a CA inhibitor, blunts HPV and might be useful in the prevention of HAPE. The mechanism by which AZ impairs HPV is uncertain. Originally developed as a diuretic, AZ also has direct effects on systemic vascular smooth muscle, including modulation of pH and membrane potential; however, the effect of AZ on pulmonary arterial smooth muscle cells (PASMCs) is unknown. Since HPV requires Ca2+ influx into PASMCs and can be modulated by pH, we hypothesized that AZ alters hypoxia-induced changes in PASMC intracellular pH (pHi) or Ca2+ concentration ([Ca 2+]i). Using fluorescent microscopy, we tested the effect of AZ as well as two other potent CA inhibitors, benzolamide and ethoxzolamide, which exhibit low and high membrane permeability, respectively, on hypoxia-induced responses in PASMCs. Hypoxia caused a significant increase in [Ca2+]i but no change in pHi. All three CA inhibitors slightly decreased basal pHi, but only AZ caused a concentration-dependent decrease in the [Ca2+]i response to hypoxia. AZ had no effect on the KCl-induced increase in [Ca 2+]i or membrane potential. N-methyl-AZ, a synthesized compound lacking the unsubstituted sulfonamide group required for CA inhibition, had no effect on pHi but inhibited hypoxia-induced Ca2+ responses. These results suggest that AZ attenuates HPV by selectively inhibiting hypoxia-induced Ca2+ responses via a mechanism independent of CA inhibition, changes in pHi, or membrane potential.
| Original language | English (US) |
|---|---|
| Journal | American Journal of Physiology - Lung Cellular and Molecular Physiology |
| Volume | 292 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2007 |
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Keywords
- Intracellular Ca
- Pulmonary vascular smooth muscle
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
- Cell Biology
- Physiology
Cite this
Inhibition of hypoxia-induced calcium responses in pulmonary arterial smooth muscle by acetazolamide is independent of carbonic anhydrase inhibition. / Shimoda, Larissa; Luke, Trevor; Sylvester, J. T.; Shih, Hui Wen; Jain, Ahamindra; Swenson, Erik R.
In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 292, No. 4, 04.2007.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Inhibition of hypoxia-induced calcium responses in pulmonary arterial smooth muscle by acetazolamide is independent of carbonic anhydrase inhibition
AU - Shimoda, Larissa
AU - Luke, Trevor
AU - Sylvester, J. T.
AU - Shih, Hui Wen
AU - Jain, Ahamindra
AU - Swenson, Erik R.
PY - 2007/4
Y1 - 2007/4
N2 - Hypoxic pulmonary vasoconstriction (HPV) occurs with ascent to high altitude and can contribute to development of high altitude pulmonary edema (HAPE). Vascular smooth muscle contains carbonic anhydrase (CA), and acetazolamide (AZ), a CA inhibitor, blunts HPV and might be useful in the prevention of HAPE. The mechanism by which AZ impairs HPV is uncertain. Originally developed as a diuretic, AZ also has direct effects on systemic vascular smooth muscle, including modulation of pH and membrane potential; however, the effect of AZ on pulmonary arterial smooth muscle cells (PASMCs) is unknown. Since HPV requires Ca2+ influx into PASMCs and can be modulated by pH, we hypothesized that AZ alters hypoxia-induced changes in PASMC intracellular pH (pHi) or Ca2+ concentration ([Ca 2+]i). Using fluorescent microscopy, we tested the effect of AZ as well as two other potent CA inhibitors, benzolamide and ethoxzolamide, which exhibit low and high membrane permeability, respectively, on hypoxia-induced responses in PASMCs. Hypoxia caused a significant increase in [Ca2+]i but no change in pHi. All three CA inhibitors slightly decreased basal pHi, but only AZ caused a concentration-dependent decrease in the [Ca2+]i response to hypoxia. AZ had no effect on the KCl-induced increase in [Ca 2+]i or membrane potential. N-methyl-AZ, a synthesized compound lacking the unsubstituted sulfonamide group required for CA inhibition, had no effect on pHi but inhibited hypoxia-induced Ca2+ responses. These results suggest that AZ attenuates HPV by selectively inhibiting hypoxia-induced Ca2+ responses via a mechanism independent of CA inhibition, changes in pHi, or membrane potential.
AB - Hypoxic pulmonary vasoconstriction (HPV) occurs with ascent to high altitude and can contribute to development of high altitude pulmonary edema (HAPE). Vascular smooth muscle contains carbonic anhydrase (CA), and acetazolamide (AZ), a CA inhibitor, blunts HPV and might be useful in the prevention of HAPE. The mechanism by which AZ impairs HPV is uncertain. Originally developed as a diuretic, AZ also has direct effects on systemic vascular smooth muscle, including modulation of pH and membrane potential; however, the effect of AZ on pulmonary arterial smooth muscle cells (PASMCs) is unknown. Since HPV requires Ca2+ influx into PASMCs and can be modulated by pH, we hypothesized that AZ alters hypoxia-induced changes in PASMC intracellular pH (pHi) or Ca2+ concentration ([Ca 2+]i). Using fluorescent microscopy, we tested the effect of AZ as well as two other potent CA inhibitors, benzolamide and ethoxzolamide, which exhibit low and high membrane permeability, respectively, on hypoxia-induced responses in PASMCs. Hypoxia caused a significant increase in [Ca2+]i but no change in pHi. All three CA inhibitors slightly decreased basal pHi, but only AZ caused a concentration-dependent decrease in the [Ca2+]i response to hypoxia. AZ had no effect on the KCl-induced increase in [Ca 2+]i or membrane potential. N-methyl-AZ, a synthesized compound lacking the unsubstituted sulfonamide group required for CA inhibition, had no effect on pHi but inhibited hypoxia-induced Ca2+ responses. These results suggest that AZ attenuates HPV by selectively inhibiting hypoxia-induced Ca2+ responses via a mechanism independent of CA inhibition, changes in pHi, or membrane potential.
KW - Intracellular Ca
KW - Pulmonary vascular smooth muscle
UR - http://www.scopus.com/inward/record.url?scp=34247260402&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34247260402&partnerID=8YFLogxK
U2 - 10.1152/ajplung.00161.2006
DO - 10.1152/ajplung.00161.2006
M3 - Article
VL - 292
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 0363-6135
IS - 4
ER -