(Circulation. 1996;93:120-128.)
© 1996 American Heart Association, Inc.
Articles |
High Frequency–Induced Upregulation of Human Cardiac Calcium Currents
From the Centre de Recherches de Biochimie Macromoléculaire, INSERM U 249 (C.P., S.L., J.N., S.R.), and the Service de Chirurgie Thoracique et Cardio-vasculaire, Hôpital Arnaud de Villeneuve (B.A., J.S.), Montpellier, France.
Correspondence to Sylvain Richard, PhD, Centre de Recherches de Biochimie Macromoléculaire, CNRS, UPR 9008, INSERM U 249, Route de Mende, BP 5051, 34033 Montpellier Cedex, France.
Background In mammalian heart cells, Ca2+ influx through voltage-gated L-type Ca2+ channels can be upregulated by high rates of stimulation. We have investigated this important adaptive regulation in human cardiomyocytes.
Methods and Results Using the whole-cell
patch-clamp technique, we found a high frequency–induced
upregulation (HFIUR) of the
dihydropyridine-sensitive L-type
Ca2+ current (ICa) in human
cardiomyocytes. ICa was potentiated in a graded
manner with increasing rates of stimulation between 0.3 and 5 Hz. Both
moderate increase of ICa peak amplitude and marked slowing
of current decay contributed to large increases of Ca2+
influx (up to 80%). The maximal potentiation of ICa was
reached rapidly after the change in the rate of stimulation (no more
than a few seconds). ß-Adrenergic stimulation of the cells by
isoproterenol (1 µmol/L), which is well known to induce a slow (
1
minute) cAMP-mediated potentiation of ICa, could
enhance (when present) or promote (when absent) the HFIUR of
ICa. As a consequence, the increasing effect of
isoproterenol on Ca2+ influx through Ca2+
channels was dependent on the rate of stimulation. HFIUR of
ICa was altered in patients with ejection fraction lower
than 40% and in patients pretreated with Ca2+
antagonists or ß-blockers.
Conclusions Upregulation of Ca2+ entry through voltage-gated Ca2+ channels by high rates of beating may be involved in the frequency-dependent regulation of contractility (Bowditch "staircase") of the human heart. This process, which is highly sensitive to ß-adrenergic stimulation, may be crucial in adaptation to exercise and stress.
Key Words: calcium channels • contractility • heart rate • electrophysiology • inotropic agents
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