Block of the transient inward current by R56865 in guinea-pig ventricular myocytes

Single myocytes isolated from the guinea-pig ventricle were used under voltage-clamp conditions to study the activity of a newly developed drug, R56865, a benzothiazolamine derivative, against digitalis toxicity. Multicellular Purkinje preparations were used in some experiments. The drug blocked the transient inward current (TI) with an apparent KD of 7.5 X 10(-8) M. The blockade was not due to a direct effect on the Na+, Ca2+ exchange current or on the non-selective cation current, the two components of TI. Blockade of TI was accompanied in time with inhibition of after-contractions, which suggests that the drug has an effect on Ca(2+)i transients. At concentrations effective on TI the drug did not block Ca2+ currents or Na+ currents; however the Na+ current was inhibited after the cells had been pretreated with DPI 201-106. It is suggested that the inhibitory effect on TI may be due to an effect on the release of Ca2+ from the sarcoplasmic reticulum or to a reduction in Ca2+ overload via blockade of the Na+ channel.