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Impaired endothelin‐1‐induced receptor‐operated calcium entry in pulmonary vascular smooth muscle following chronic hypoxia
Author(s) -
Snow Jessica Bayne,
Broughton Brad R.S.,
Walker Benjimen R.,
Resta Thomas C.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a402-b
Subject(s) - hypoxia (environmental) , endothelin receptor , medicine , vascular smooth muscle , calcium , cardiology , endothelin 1 , endocrinology , chemistry , receptor , smooth muscle , oxygen , organic chemistry
We have recently demonstrated that store‐operated and UTP‐induced receptor‐operated Ca2+ entry (ROCE) are attenuated in pulmonary vascular smooth muscle following chronic hypoxia (CH). However, it is not clear whether this inhibitory effect of CH on ROCE represents a generalized response to receptor‐mediated vasoconstrictor agonists. We hypothesized that CH similarly diminishes ROCE in response to endothelin‐1 (ET‐1), an endothelium‐derived vasoconstrictor peptide that contributes to the development of CH‐induced pulmonary hypertension. To test this hypothesis, we examined ET‐1‐induced ROCE in isolated, endothelium‐denuded and pressurized pulmonary arteries (167 ¡Ó 18 £gm inner diameter) from control and CH (4 wk at 0.5 atm) rats. Arteries were loaded with fura‐2 AM to continuously monitor VSM [Ca2+]i. To isolate ROCE, we inhibited L‐type voltage‐operated Ca2+ channels with diltiazem (50 ƒÝM), and depleted intracellular Ca2+ stores with cyclopiazonic acid (10 ƒÝM) to induce influx of Ca2+ through store‐operated channels. The further increase in [Ca2+]i observed upon stimulation with ET‐1 (10‐10‐10‐7 M) was attributed to ROCE. We found that the change in VSM [Ca2+]i to 10‐8‐10‐7 M ET‐1 was significantly attenuated (p<0.05) in arteries from CH rats compared to controls. We conclude that CH inhibits ET‐1‐mediated ROCE in pulmonary VSM and may be reflective of a generalized inhibition of this pathway in the setting of CH. (Supported by NIH grants HL‐07736, HL‐77876, HL‐58124 and HL‐63207)