Age-dependent changes in Na current magnitude and TTX-sensitivity in the canine sinoatrial node

• Published in: Journal of molecular and cellular cardiology 2010-01, Vol.48 (1), p.172-180
• Main Authors: Protas, Lev, Oren, Ronit V, Clancy, Colleen E, Robinson, Richard B
• Format: Article
• Language: English
• Subjects: Age Factors; Animals; Cardiovascular; Cells, Cultured; Computer Simulation; Development; Dogs; Mice; Na current; Pacemaker; Patch-Clamp Techniques; Rabbits; Sinoatrial node; Sinoatrial Node - drug effects; Sinoatrial Node - metabolism; Sodium - metabolism; Sodium Channel Blockers - pharmacology; Tetrodotoxin - pharmacology
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2009.07.028

Abstract In rabbit, sodium current ( INa ) contributes to newborn sinoatrial node (SAN) automaticity but is absent in adult SAN, where heart rate is slower. In contrast, heart rate is high and INa is functional in adult mouse SAN. Given the slower heart rates of large mammals, we asked if INa is functionally active in SAN of newborn or adult canine heart. SAN cells were isolated from newborn (6–10 days), young (40–43 days) and adult mongrels. INa was observed in > 80% of cells from each age. However, current density was markedly greater in newborn, decreasing with age. At all ages, INa was sensitive to nanomolar tetrodotoxin (TTX); 100 nmol/L inhibited INa by 46.7%, 59.9% and 90.7% in newborn, young and adult cells, respectively. While high TTX sensitivity suggested the presence of non-cardiac isoforms, steady-state inactivation was relatively negative (midpoints − 89.7 ± 0.7 mV, − 95.1 ± 1.2 mV and − 93.4 ± 1.9 mV from newborn to adult). Consequently, INa should be unavailable at physiological potentials under normal conditions, and 100 nmol/L TTX did not change cycle length or action potential parameters of spontaneous adult SAN cells. However, computer modeling predicts the large newborn INa protects against excess rate slowing from strong vagal stimulation. The results show that canine SAN cells have TTX-sensitive INa which decreases with post-natal age. The current does not contribute to normal automaticity in isolated adult cells but can be recruited to sustain excitability if nodal cells are hyperpolarized. This is particularly relevant in newborn, where INa is large and parasympathetic/sympathetic balance favors vagal tone.