Tetrodotoxin-sensitive inactivation-resistant sodium channels in pacemaker cells influence heart rate

There is currently some uncertainty about whether cardiac pacemaker cells contain tetrodotoxin (TTX)-sensitive Na+ channels although TTX is known to slow heart rate. We have recorded transient and persistent single-channel currents activated by depolarization in myocytes isolated from the toad sinus venosus. The myocytes were identified as pacemaker cells by their characteristic morphology, spontaneous action potentials that were blocked by cobalt but not by TTX, and lack of an inwardly rectifying K+ current. The voltage dependence of the single-channel currents, their presence in solutions containing no K+ or Ca2+, or in solutions to which Cs+ and Co2+ had been added, their dependence on [Na+] and their sensitivity to TTX indicated that they were Na+ channel currents. The persistent Na+ channel currents were resistant to inactivation and were activated over the range of potentials that occur during diastole in pacemaker cells: they would therefore contribute to the pacemaker current that sets heart rate. It was concluded that TTX slows heart rate by blocking these channels in pacemaker cells.