The effect of heart rate on the arrhythmogenic transient inward current in isolated sheep cardiac Purkinje fibres.

1. The effect of heart rate on the arrhythmogenic transient inward current (ITI) has been studied in sheep cardiac Purkinje fibres. 2. Transient inward current and force (active force, tonic force and the after-contraction) have been measured in voltage-clamped preparations. Intracellular Na+ activity (aiNa) was measured simultaneously using Na(+)-sensitive microelectrodes. The effects of changes in voltage-clamp pulse frequency on the ITI amplitude, active force, tonic force, the after-contraction and aiNa have been investigated in different bathing solutions. 3. After a stepwise increase in pulse rate there was a biphasic response of ITI amplitude: a short-lasting (50 s) phase during which ITI amplitude increased followed by a decline in ITI amplitude. The second phase could be fitted by an exponential with a time constant between 102 and 184 s. The after-contraction changed in a similar biphasic manner whereas force and aiNa declined monophasically; active force first declined, increased and then declined again. These changes were greater at faster rates of pulsing. 4. Linear relationships between ITI amplitude, after-contraction amplitude and tonic force were observed in all experiments. 5. In K(+)-free solution the response of the ITI was markedly changed. After an increase in pulse rate the initial increase in ITI was enhanced, whereas the subsequent decline was strongly reduced or even abolished. Potassium-free solution blocks the Na+ pump, and activation of the Na+ pump by addition of Cs+ or K+ restored the phase of decay of ITI amplitude during rapid stimulation. 6. A reduction of external Na+ to about 50% or elevation of external Ca2+ increased ITI but had little effect on the rate-dependent changes in the current. 7. When stimulation was resumed at the basic pulse rate after a period of rapid pulsing the ITI amplitude initially continued to decline: this was followed by a slow recovery (over 10-15 min) of ITI amplitude back to its steady-state value prior to fast pulsing. 8. These results are consistent with the hypothesis that changes of ITI are the result of rate-dependent changes in intracellular Ca2+, which in turn are in part dependent on changes of intracellular Na+.