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Cardiovascular Research Advance Access originally published online on April 7, 2009
Cardiovascular Research 2009 83(1):97-105; doi:10.1093/cvr/cvp105
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Extracellular acidosis suppresses endothelial function by inhibiting store-operated Ca2+ entry via non-selective cation channels

Masayoshi Asai1, Kazuhiko Takeuchi2, Masao Saotome1, Tsuyoshi Urushida1, Hideki Katoh1, Hiroshi Satoh1, Hideharu Hayashi1 and Hiroshi Watanabe2,*

1 Departments of Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan
2 Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan

* Corresponding author. Tel: +81 53 435 2385; fax: +81 53 434 2386. E-mail address: hwat{at}hama-med.ac.jp

Aims: Hypoxia, ischaemia, and exogenous chemicals can induce extracellular and intracellular acidosis, but it is not clear which of these types of acidosis affects endothelial cell function. The synthesis and release of endothelium-derived relaxing factors (EDRFs) are linked to an increase in cytosolic Ca2+ concentration, and we therefore examined the effects of extracellular and intracellular acidosis on Ca2+ responses and EDRF production in cultured porcine aortic endothelial cells.

Methods and results: Cytosolic pH (pHi) and Ca2+ were measured using fluorescent dyes, BCECM/AM (pH-indicator) and fura-2/AM (Ca2+-indicator), respectively. EDRFs, nitric oxide (NO) and prostaglandin I2 (PGI2) were assessed using DAF-FM/DA (NO-indicator dye) fluorometry and 6-keto PGF1{alpha} enzyme immunoassay, respectively. HEPES buffers titrated to pH 6.4, 6.9, and 7.4 were used to alter extracellular pH (pHo), and propionate (20 mmol/L) was applied to cause intracellular acidosis. Extracellular acidosis strongly suppressed bradykinin (BK, 10 nmol/L)- and thapsigargin (TG, 1 µmol/L)-induced Ca2+ responses by 30 and 23% at pHo 6.9, and by 80 and 97% at pHo 6.4, respectively. During the examinations, there were no significant differences in pHi among the three groups at pHo 7.4, 6.9, and 6.4. Extracellular acidosis also inhibited BK-stimulated PGI2 production by 55% at pHo 6.9 and by 77% at pHo 6.4, and NO production by 38% at pHo 6.9 and by 91% at pHo 6.4. The suppressive effects of extracellular acidosis on Ca2+ responses and NO production were reversible. Propionate changed pHi from 7.3 to 6.9, without altering pHo (7.4). Intracellular acidosis had no effect on BK- and TG-induced Ca2+ responses or NO production.

Conclusion: These results indicate that extracellular, but not intracellular, acidosis causes endothelial dysfunction by inhibiting store-operated Ca2+ entry, so helping to clarify the vascular pathophysiology of conditions such as ischaemia, hypoxia, acidosis, and ischaemia-reperfusion.

KEYWORDS Acidosis; Store-operated calcium entry; Endothelial cells; PGI2; NO

Time for primary review: 39 days


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