Age-dependent changes in Na current magnitude and TTX-sensitivity in the canine sinoatrial node.
In rabbit, sodium current (I(Na)) 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 I(Na) is functional in adult mouse SAN. Given the slower heart rates of large mammals, we asked if I(Na) 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. I(Na) was observed in >80% of cells from each age. However, current density was markedly greater in newborn, decreasing with age. At all ages, I(Na) was sensitive to nanomolar tetrodotoxin (TTX); 100 nmol/L inhibited I(Na) 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, I(Na) 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 I(Na) protects against excess rate slowing from strong vagal stimulation. The results show that canine SAN cells have TTX-sensitive I(Na) 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 I(Na) is large and parasympathetic/sympathetic balance favors vagal tone.
Protas
Lev
L
Columbia University, Department of Pharmacology, 630 West 168 Street, PH7West-318, New York, NY 10032, USA. lp141@columbia.edu
Oren
Ronit V
RV
Clancy
Colleen E
CE
Robinson
Richard B
RB
D000367:Age Factors; D000818:Animals; D002478:Cells, Cultured; D003198:Computer Simulation; D004285:Dogs; D051379:Mice; D018408:Patch-Clamp Techniques; D011817:Rabbits; D012849:Sinoatrial Node / Q000187:drug effects* / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology*
D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D012964:Sodium