EFFECTS OF CARDIAC DRUGS ON SODIUM-CALCIUM EXCHANGER

(1)KB-R7943is a drug we first reported to inhibit Na-Ca exchange current(INCX)with IC I D 250 ii D2 0.3µM for outward iNCX and with 17µM for inward iNCX when one directional iNCX flows.However，under an experimental condition where bi-directional iNCX flows.The drug inhibits both outward and inward iNCX equipotently.This result can be explained by different conformation between the binding forms for external Na and Ca.(2)A new cardioprotective drug，JTV-519 inhibited Na-，Ca-，and inwardly rectifying K-currents in guinea pig cardiac ventricular cells。The block of Na current，was voltage-and use-dependent and was similar to quinidine rather than to lidocaine。IC I D 250 I D 2 for Na-current was 2µM at-90 mV and 1.2µM at-60 mV。The drug shortened the plateau of the action potential.(3)Butanedione monoxime(BDM)inhibited iNCX in guinea pig ventricular cells。IC D 250个D 2 value was 2.4 mM.A similar drug，pralidoxime also inhibited iNCX，indicating that dephosphorylation of the exchanger may be a reason.We are currently investigating mutated NCX for the mechanism of the drug action.(4)Class III antiarrhythmic drug，amiodarone inhibits iNCX.IC I D 250个D 2 was 3µM.Trypsin in the pipette solution diminished the inhibitory effect of amiodarone，indicating that the drug affects internal side of the exchanger.(5)Anti-diabetic drug，troglitazone inhibited L-type Ca current in guinea pig ventricular cells.The effect was voltage-dependent。IC I D 250个D 2 values were 0.8µM at a holding potential of-50 mV and larger than 10µM at-80 mV。

(1) KB-R7943 is a drug we first reported to inhibit Na-Ca exchange current (iNCX) with ICィイD250ィエD2 0.3 μM for outward iNCX and with 17μM for inward iNCX when one directional iNCX flows. However, under an experimental condition where bi-directional iNCX flows. The drug inhibits both outward and inward iNCX equipotently. This result can be explained by different conformation between the binding forms for external Na and Ca.(2) A new cardioprotective drug, JTV-519 inhibited Na-, Ca-, and inwardly rectifying K-currents in guinea pig cardiac ventricular cells. The block of Na current, was voltage- and use-dependent and was similar to quinidine rather than to lidocaine. ICィイD250ィエD2 for Na-current was 2 μM at -90 mV and 1.2 μM at -60 mV. The drug shortened the plateau of the action potential.(3) Butanedione monoxime (BDM) inhibited iNCX in guinea pig ventricular cells. ICィイD250ィエD2 value was 2.4 mM. A similar drug, pralidoxime also inhibited iNCX, indicating that dephosphorylation of the exchanger may be a reason. We are currently investigating mutated NCX for the mechanism of the drug action.(4) Class III antiarrhythmic drug, amiodarone inhibits iNCX. ICィイD250ィエD2 was 3 μM. Trypsin in the pipette solution diminished the inhibitory effect of amiodarone, indicating that the drug affects internal side of the exchanger.(5) Anti-diabetic drug, troglitazone inhibited L-type Ca current in guinea pig ventricular cells. The effect was voltage-dependent. ICィイD250ィエD2 values were 0.8 μM at a holding potential of -50 mV and larger than 10 μM at -80 mV.