High frequency-induced upregulation of human cardiac calcium currents.
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.


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). Beta-Adrenergic stimulation of the cells by isoproterenol (1 micromol/L), which is well known to induce a slow (approximately 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 beta-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 beta-adrenergic stimulation, may be crucial in adaptation to exercise and stress.
Piot
C
C
Centre de Recherches de Biochimie Macromoléculaire, INSERM U 249, Hôpital Arnaud de Villeneuve, Montpellier, France.
LeMaire
S A
SA
Albat
B
B
Seguin
J
J
Nargeot
J
J
Richard
S
S
D000328:Adult; D000368:Aged; D002118:Calcium / Q000502:physiology*; D015220:Calcium Channels / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D005260:Female; D006321:Heart / Q000502:physiology*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000502:physiology*; D018408:Patch-Clamp Techniques; D015854:Up-Regulation
D015220:Calcium Channels; D002316:Cardiotonic Agents; D007545:Isoproterenol; D002118:Calcium