Effects of endothelin 1 on calcium and sodium currents in isolated human cardiac myocytes

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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 μM 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 β-adrenoceptor agonist (0.1 μM isoproterenol) or by the phosphodiesterase inhibitor isobutylmethylxanthine (10 μM), 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 μM 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]owere 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.Key words: endothelin 1, human cardiac myocytes, whole-cell voltage-clamp technique, calcium currents, sodium currents.