Different inhibition patterns of tedisamil for fast and slowly inactivating transient outward current in rat ventricular myocytes

Abstract

Tedisamil has been described as a selective inhibitor of a fast inactivating transient outward current (i_to,f) in rat ventricular myocytes. Because recent reports demonstrated the existence of a second slowly inactivating transient component (i_to,s) we investigated i_to,s and differentiated the effects of tedisamil on both transient outward current components and their influence on action potential duration. Standard electrophysiological techniques were used for whole cell recordings at 24–26° C from enzymatically isolated myocytes. Inhibition of i_to,f by tedisamil was the result of an acceleration of inactivation at positive test potentials with a concentration for halfmaximal inhibition (EC₅₀) of 4–7 μmol/l, which is confirmatory to reports from other investigators. Our new results show that i_to,s is more sensitive to tedisamil with an EC₅₀ of 0.5 μmol/l. Furthermore the pattern of i_to,s inhibition is different compared with i_to,f, because inactivation of i_to,s is not accelerated by tedisamil. Instead the amplitude of the steady state inactivation curve of i_to,s is attenuated which indicates a reduction of maximally available current. I_to,s was evaluated by three different methods as time-dependently inactivating current (7.5 s test pulse duration), voltage-dependently inactivated current and tedisamil-sensitive current. All approaches yield similar inactivation curves. The potential for halfmaximal inactivation of i_to,s lies about 35 mV more negative than that for i_to,f and the slope factor (K = –23 mV) is different to that of i_to,f (K = –3 mV). Effectiveness of tedisamil-induced modulation of i_to,f and i_to,s on action potential repolarization was tested. Action potentials stimulated at 0.5 Hz were not prolonged by 1 μmol/l tedisamil (dominant i_to,s block) at a repolarization level of 0 mV but prolonged to about 120% of control at –70 mV. This indicates that i_to,f was sufficient to guarantee a regular early repolarization whereas decrease of i_to,s delayed the final repolarization.

In conclusion, the observation that tedisamil inhibits i_to,f and i_to,s differently supports the hypothesis that the two i_to-components are related to two different channel populations expressed in rat ventricular myocytes.