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). 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.
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). 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.
Authors: Xiaoxiao Chen; Javier A Sala-Mercado; Robert L Hammond; Masashi Ichinose; Soroor Soltani; Ramakrishna Mukkamala; Donal S O'Leary Journal: Am J Physiol Heart Circ Physiol Date: 2010-04-30 Impact factor: 4.733
Authors: B Pieske; M Sütterlin; S Schmidt-Schweda; K Minami; M Meyer; M Olschewski; C Holubarsch; H Just; G Hasenfuss Journal: J Clin Invest Date: 1996-08-01 Impact factor: 14.808