title: Effects of endothelin 1 on calcium and sodium currents in isolated human cardiac myocytes.
abstract: We have used the whole-cell voltage-clamp technique to study the effects of endothelin 1 (ET-1, 10 nM) on L-type Ca2+ currents and voltage-dependent Na+ inward currents in human cardiac cells. Myocytes were enzymatically isolated from atrial specimens obtained during open-heart surgery and from human ventricular tissues of explanted hearts. Extracellular application of ET-1 decreased the peak amplitude of Ca2+ currents by 26 +/- 6% (n = 13) in atrial myocytes and by 19 +/- 3% (n = 8) in ventricular myocytes. In three atrial cells, treatment with 1 microM BQ123 prevented the decrease in Ca2+ currents induced by ET-1. When GTP (0.2 mM) was added to the dialyzing pipette solution, ET-1 still caused a small decline by 12 +/- 5% (n = 16), in peak Ca2+ currents, in atrial myocytes. When Ca2+ currents were increased (+210 +/- 19%) by a beta-adrenoceptor agonist (0.1 microM isoproterenol) or by the phosphodiesterase inhibitor isobutylmethylxanthine (10 microM), ET-1 reduced Ca2+ currents by 35 +/- 6% (n = 4) and 30 +/- 4% (n = 5), respectively. In human ventricular myocytes in the presence of 1 microM isoproterenol, which increased the peak Ca2+ currents by 150 +/- 30%, ET-1 also induced a drastic reduction in Ca2+ currents, by 40 +/- 11% (n = 5). The tetrodotoxin-sensitive Na+ currents measured in the presence of 5 mM [Na]o were significantly enhanced (+28 +/- 7%) by ET-1 in five atrial myocytes. The stimulatory effect of ET-1 on Na+ currents was partially reversible. The present findings in human cardiac cells show that ET-1 did not enhance the Ca2+ currents in the absence or presence of internal GTP. The positive inotropic actions induced by ET-1 in human heart may be mediated mainly by signal-transduction pathways other than the G-protein-adenylyl cyclase-cAMP system.
authors.affiliation: Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan, Republic of China.
authors.forename: T H
authors.initials: TH
authors.lastname: Cheng
authors.forename: C Y
authors.initials: CY
authors.lastname: Chang
authors.forename: J
authors.initials: J
authors.lastname: Wei
authors.forename: C I
authors.initials: CI
authors.lastname: Lin
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000328:Adult; D015220:Calcium Channels / Q000187:drug effects*; D002469:Cell Separation; D004357:Drug Synergism; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology; D015222:Sodium Channels / Q000187:drug effects*
chemical_list: D015220:Calcium Channels; D019332:Endothelin-1; D011943:Receptors, Adrenergic, beta; D015222:Sodium Channels; D015124:8-Bromo Cyclic Adenosine Monophosphate; D015056:1-Methyl-3-isobutylxanthine