CELLULAR MECHANISMS AND ROLE OF ENDOTHELIN-1-INDUCED CALCIUM OSCILLATIONS IN PULMONARY ARTERIAL MYOCYTES

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 (5-10 0 nM, 30 s) induced a first [Ca2+](i) peak followed by 3-5 oscillation s of decreasing amplitude. In RMPA, the ET-1-induced [Ca2+](i) respons e was fully abolished by BQ-123 (0.1 mu M). In RIPA, the response was inhibited by BQ-123 in only 21% of the cells, whereas it was abolished by BQ-788 (1 mu M) in 70% of the cells. In both types of arteries, th e response was not modified in the presence of 100 mu M La3+ or in the absence of external Ca2+ but disappeared after pretreatment of the ce lls with thapsigargin (1 mu M) or neomycin (0.1 mu M). In RPMA myocyte s clamped at -60 mV, ET-1 induced an oscillatory inward current, the r eversal potential of which was close to the equilibrium potential for Cl-. This current was unaltered by the removal of external Ca2+ but wa s abolished by niflumic acid (50 mu M). In arterial rings, the ET-1 (1 00 nM)-induced contraction was decreased by 35% in the presence of eit her niflumic acid (50 mu M) or nifedipine (1 mu M). These results demo nstrate that ET-1 via the ETA receptor only in RMPA and both ETA and E TB receptors in RIPA induce [Ca2+](i) oscillations due to iterative Ca 2+ release from an inositol trisphosphate-sensitive Ca2+ store. Ca2+ r elease secondarily activates an oscillatory membrane Cl- current that can depolarize the cell membrane, leading to an influx of Ca2+, this l atter contributing to the ET-1-induced vasoconstrictor effect.