Factors affecting intracellular sodium during repetitive activity in isolated sheep Purkinje fibres.

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Abstract
1. Intracellular Na+ activity .**GRAPHIC**. was measured using neutral-carrier Na+-sensitive micro-electrodes in voltage-clamped sheep Purkinje fibres during and after 4 min sequences of depolarizing pulses applied to around 0 mV, at a rate of 2.5 Hz. After trains of pulse duration 50 ms the mean increase in .**GRAPHIC**. was 0.65 .+-. 0.3 mM (mean .+-. S.D., n = 18) whereas with longer pulse durations this rise became progressively smaller. At pulse durations of 300 ms a fall in .**GRAPHIC**. was usually found. 2. Recovery of .**GRAPHIC**. after a pulse sequence followed a roughly exponential time course. The half-time of decline after a rise in .**GRAPHIC**. using 50 ms pulses was 111 .+-. 52 s (n = 10), compared with a half-time of 318 .+-. 116 s (n = 6) for recovery from a fall in .**GRAPHIC**. during a sequence of 300 ms pulses. 3. Application of 2 mM-Cs+ to block the pace-marker current (if) resulted in a decrease in resting .**GRAPHIC**. by 0.85 .+-. 0.45 mM (n = 6) and an outward current shift. Na+ loading during a depolarizing pulse train was greater in 2 mM-Cs+ than in control solution. The rise in .**GRAPHIC**. produced by a train of 50 ms pulses in Cs+ was 1.15 .+-. 0.4 mM (n = 10). At short pulse durations in the presence of Cs+, Na+ loading at the end of a pulse train increased as a function of pulse duration, becoming maximal at a duration of approximately 50 ms and then diminishing at longer pulse durations. 4. Application of 2.5 .times. 10-5 M-tetrodotoxin (TTX) produced a fall in resting .**GRAPHIC**. of 0.55 .+-. 0.2 mM (n = 6) and an outward current shift, suggesting that a TTX-sensitive component of steady-state Na+ current exits at potentials in the region -65 to -80 mV. 5. TTX greatly reduced the rise in .**GRAPHIC**. during a depolarizing pulse train at all pulse durations tested. A fall in .**GRAPHIC**. was now found after trains of shorter pulse duration than in control solution. Similar results were obtained in the absence of TTX if the pulse train was initiated from a holding potential which was positive to the Na+ current (iNa) threshold. When iNa had been blocked, using either TTX or a low holding potential, them mean rise in .**GRAPHIC**. after a train of 50 ms pulses was 0.25 .+-. 0.2 mM (n = 8). 6. The component of Na+ loading remaining at short pulse durations in the presence of TTX was abolished by 9.6 .times. 10-6 M-gallopamil (D600). The fall in .**GRAPHIC**. at the end of a pulse train in the presence of TTX and gallopamil increases at longer pulse durations. 7. Na+ loading in TTX was unchanged or only slightly reduced by 5 mM-Mn2+. 8. The increment in .**GRAPHIC**. during a pulse train was greater if the membrane was hyperpolarized during the interpulse interval. 9. These results show that during repetitive activity mechanisms operate which tend to reduce .**GRAPHIC**. namely a diminished leak current and deactivation of if, together with mechanisms which increase .**GRAPHIC**. i.e. the fast Na+ current and a second route for Na+ entry which is resistant to TTX but sensitive to gallopamil. We suggest that the TTX-insensitive component of Na+ loading may occur via Na-Ca exchange and that the increment in .**GRAPHIC**. through this pathway during repetitive activity may depend, indirectly but principally, on Ca2+ entry via a slow Ca2+ channel.

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