THE CALCIUM-ANTAGONIST D600 INHIBITS CALCIUM-INDEPENDENT TRANSIENT OUTWARD CURRENT IN ISOLATED RAT VENTRICULAR MYOCYTES

1. The whole-cell voltage-clamp technique was applied to isolated rat ventricular myocytes to investigate the effects of D600 (10(-9)-10(-3)M) on the intracellular calcium-independent component of transient outward current, I(lo), recorded in a sodium-free medium containing 0.5 x 10(-3)M-cadmium and 10(-6) M-ryanodine. 2. Externally applied D600 reduced I(lo) in a dose-dependent, reversible manner, and accelerated the decay of the current. 3. Current-voltage relationships and corresponding activation curves (determined assuming I(lo) to be a pure potassium current) were shifted towards positive potentials in the presence of 10(-3) M but not 10(-5)M-D600. Steady-state inactivation curves were not affected by either low or high concentrations of D600. 4. Under control conditions, the inactivation of I(lo) is composed of a fast and a slow component. The amplitude of the slow component was more strongly reduced by D600 than that of the fast one. In the presence of 10(-3) M-D600, the slow constant of was entirely suppressed. 5. Both the time to peak I(lo) and the time constant of the fast component of inactivation were markedly reduced at all potentials by D600. The time constant of the slow component was less sensitive to the drug. 6. When the relative quantity of charge carried by each kinetic component of I(lo) was plotted versus the concentration of D600, the data could be fitted by two distinctly separate dose-response curves with an almost 100-fold difference between the two apparent dissociation constants, of which the values were 2.88 x 10(-6) M for the slow phase of inactivation and 2.07 x 10(-4) M for the fast one with Hill coefficients of 0.68 and 0.73 respectively. 7. The inhibition of I(lo) by D600 displayed little or no use dependence, one of the major characteristics of the effects of phenylalkylamines on the cardiac calcium current I(Ca). 8. Our results show that at least part of I(lo) is sensitive to D600 in the same range of concentrations as I(Ca). Although the effects of D600 on the two currents differ in several points, this observation raises the possibility that, besides clear differences, certain similarities may exist between the channels responsible for I(lo) and I(Ca).