Cellular mechanisms and role of endothelin-1-induced calcium oscillations in pulmonary arterial myocytes

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Abstract
The effect of endothelin (ET)-1 on both cytosolic Ca2+concentration ([Ca2+]i) and membrane current in freshly isolated myocytes, as well as on the contraction of arterial rings, was investigated in rat main pulmonary artery (RMPA) and intrapulmonary arteries (RIPA). ET-1 (5–100 nM, 30 s) induced a first [Ca2+]ipeak followed by 3–5 oscillations of decreasing amplitude. In RMPA, the ET-1-induced [Ca2+]iresponse was fully abolished by BQ-123 (0.1 μM). In RIPA, the response was inhibited by BQ-123 in only 21% of the cells, whereas it was abolished by BQ-788 (1 μM) in 70% of the cells. In both types of arteries, the response was not modified in the presence of 100 μM La3+or in the absence of external Ca2+but disappeared after pretreatment of the cells with thapsigargin (1 μM) or neomycin (0.1 μM). In RPMA myocytes clamped at −60 mV, ET-1 induced an oscillatory inward current, the reversal potential of which was close to the equilibrium potential for Cl−. This current was unaltered by the removal of external Ca2+but was abolished by niflumic acid (50 μM). In arterial rings, the ET-1 (100 nM)-induced contraction was decreased by 35% in the presence of either niflumic acid (50 μM) or nifedipine (1 μM). These results demonstrate that ET-1 via the ETAreceptor only in RMPA and both ETAand ETBreceptors in RIPA induce [Ca2+]ioscillations due to iterative Ca2+release from an inositol trisphosphate-sensitive Ca2+store. Ca2+release secondarily activates an oscillatory membrane Cl−current that can depolarize the cell membrane, leading to an influx of Ca2+, this latter contributing to the ET-1-induced vasoconstrictor effect.

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