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 (I_Ca) in human cardiomyocytes. I_Ca was potentiated in a graded manner with increasing rates of stimulation between 0.3 and 5 Hz. Both moderate increase of I_Ca peak amplitude and marked slowing of current decay contributed to large increases of Ca²⁺ influx (up to 80%). The maximal potentiation of I_Ca was reached rapidly after the change in the rate of stimulation (no more than a few seconds). β-Adrenergic stimulation of the cells by isoproterenol (1 μmol/L), which is well known to induce a slow (≈1 minute) cAMP-mediated potentiation of I_Ca, could enhance (when present) or promote (when absent) the HFIUR of I_Ca. As a consequence, the increasing effect of isoproterenol on Ca²⁺ influx through Ca²⁺ channels was dependent on the rate of stimulation. HFIUR of I_Ca was altered in patients with ejection fraction lower than 40% and in patients pretreated with Ca²⁺ antagonists or β-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 β-adrenergic stimulation, may be crucial in adaptation to exercise and stress.