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 (5-100 nM, 30 s) induced a first [Ca2+]i peak followed by 3-5 oscillations of decreasing amplitude. In RMPA, the ET-1-induced [Ca2+]i response was fully abolished by BQ-123 (0.1 microM). In RIPA, the response was inhibited by BQ-123 in only 21% of the cells, whereas it was abolished by BQ-788 (1 microM) in 70% of the cells. In both types of arteries, the response was not modified in the presence of 100 microM La3+ or in the absence of external Ca2+ but disappeared after pretreatment of the cells with thapsigargin (1 microM) or neomycin (0.1 microM). 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 microM). In arterial rings, the ET-1 (100 nM)-induced contraction was decreased by 35% in the presence of either niflumic acid (50 microM) or nifedipine (1 microM). These results demonstrate that ET-1 via the ETA receptor only in RMPA and both ETA and ETB receptors in RIPA induce [Ca2+]i oscillations 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.
Laboratoire de Physiologie Cellulaire Respiratoire, Contrat de Recherche Institut National de la Santé et de la Recherche Médicale 9806, Université Bordeaux 2, 33076 Bordeaux, France.
J M
JM
Hyvelin
C
C
Guibert
R
R
Marthan
J P
JP
Savineau
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology* / Q000502:physiology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009355:Neomycin / Q000494:pharmacology; D009544:Niflumic Acid / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D009991:Oscillometry; D018408:Patch-Clamp Techniques; D010456:Peptides, Cyclic / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012430:Ruthenium Red / Q000494:pharmacology; D013748:Tetracaine / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D013748:Tetracaine; D012430:Ruthenium Red; D015240:Phorbol 12,13-Dibutyrate; D002110:Caffeine; C086539:BQ 788; D009544:Niflumic Acid; D019284:Thapsigargin; D015544:Inositol 1,4,5-Trisphosphate; D009355:Neomycin; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium