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1 Department of Pharmacology, Columbia University, New York, New York 10032; and 2 Dipartimento di Fisiologia e Biochimica Generali, Elettrofisiologia, Università di Milano, 20133 Milano, Italy
Isolated newborn, but not adult,
rabbit sinoatrial node (SAN) cells exhibit spontaneous activity that
(unlike adult) are highly sensitive to the Na+ current
(INa) blocker TTX. To investigate this TTX
action on automaticity, cells were voltage clamped with ramp
depolarizations mimicking the pacemaker phase of spontaneous cells
(
60 to
20 mV, 35 mV/s). Ramps elicited a TTX-sensitive current in
newborn (peak density 0.89 ± 0.14 pA/pF, n = 24)
but not adult (n = 5) cells. When depolarizing ramps
were preceded by steplike depolarizations to mimic action potentials,
ramp current decreased 54.6 ± 8.0% (n = 3) but
was not abolished. Additional experiments demonstrated that ramp
current amplitude depended on the slope of the ramp and that TTX did
not alter steady-state holding current at pacemaker potentials. This
excluded a steady-state Na+ window component and suggested
a kinetic basis, which was investigated by measuring TTX-sensitive
INa during long step depolarizations. INa exhibited a slow but complete inactivation
time course at pacemaker voltages (
= 33.9 ± 3.9 ms at
50 mV), consistent with the rate-dependent ramp data. The data
indicate that owing to slow inactivation of INa
at diastolic potentials, a small TTX-sensitive current flows during the
diastolic depolarization in neonatal pacemaker myocytes.
sinoatrial node; slow inactivation; patch clamp
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