Comparison of sodium-calcium exchanger and transient inward currents in single cells from rabbit ventricle.

1. Whole-cell voltage-clamp measurements have been made in rabbit ventricular myocytes under conditions in which both Na(+)-Ca2+ exchanger currents (IEX, slow tails) and transient inward currents (ITI or TI) can be recorded. A number of experimental manoeuvres have been used in an attempt to separate or dissociate these two currents. 2. As expected, partial inhibition of the Na(+)-K+ pump by application of 0.54 mM [K+] Tyrode solution or 10(-5) M-strophanthidin induced TI currents which were recorded in the presence of IEX slow tails. 3. Complete inhibition of the Na(+)-K+ pump with zero [K+] Tyrode solution resulted in larger and more frequent TIs but smaller IEX tails. 4. A somewhat similar dissociation between ITI and IEX was observed when NaCl was reduced to 37.5 mM by using LiCl to replace NaCl. This inhibited the Na(+)-Ca2+ exchanger current, but induced ITI. 5. Transient inward currents and IEX tails could also be separated by selected patterns of stimulation (voltage-clamp depolarizations): following the second pulse of a pair of stimuli, IEX was significantly reduced whereas the TIs increased in size and frequency. 6. Additional experimental tests involving changes in external divalent ions could also separate these two currents. Increasing [Ca2+]o 3-fold increased the TIs without changing IEX. Shortly after [Ca2+]o was replaced with either [Ba2+]o or [Sr2+]o the TIs were blocked but IEX was unchanged. Application of MnCl2 (1 mM) and elevation of [K+]o inhibited IEX but did not significantly change the TI currents. 7. Application of caffeine (5-10 mM) or ryanodine (2 x 10(-6) M) blocked the TI currents at times when the IEX tails were not changed. 8. In combination these results suggest that even though both IEX and ITI are triggered (activated) by increases in [Ca2+]i, these two currents are distinct. IEX is generated by electrogenic Na(+)-Ca2+ exchange, while the TI currents may be due to Ca2(+)-activated cation-selective channels in the sarcolemma.