A novel Na+ channel agonist, dimethyl lithospermate B, slows Na+ current inactivation and increases action potential duration in isolated rat ventricular myocytes

Voltage-gated Na(+) channel blockers have been widely used as local anaesthetics and antiarrhythmic agents. It has recently been proposed that Na(+) channel agonists can be used as inotropic agents. Here, we report the identification of a natural substance that acts as a Na(+) channel agonist. Using the patch-clamp technique in isolated rat ventricular myocytes, we investigated the electrophysiological effects of the substances isolated from the root extract of Salvia miltiorrhiza, which is known as 'Danshen' in Asian traditional medicine. By the intensive activity-guided fractionation, we identified dimethyl lithospermate B (dmLSB) as the most active component, while LSB, which is the major component of the extract, showed negligible electrophysiological effect. Action potential duration (APD(90)) was increased by 20 microM dmLSB from 58.8 +/- 12.1 to 202.3 +/- 9.5 ms. In spite of the prolonged APD, no early after-depolarization (EAD) was observed. dmLSB had no noticeable effect on K(+) or Ca(2+) currents, but selectively affected Na(+) currents (I(Na)). dmLSB slowed the inactivation kinetics of I(Na) by increasing the proportion of slowly inactivating component without inducing any persistent I(Na). The relative amplitude of slow component compared to the peak fast I(Na) was increased dose dependently by dmLSB (EC(50) = 20 microM). Voltage dependence of inactivation was not affected by dmLSB, while voltage dependence of activation shifted by 5 mV to the depolarised direction. Since the APD prolongation by dmLSB did not provoke EAD, which is thought as a possible mechanism for the proarrhythmia seen in other Na(+) channel agonists, dmLSB might be an excellent candidate for a Na(+) channel agonist.