Inhibitory action of SR33557 on L-type calcium current in single ventricular myocytes of rat

摘要

1. The effect of SR33557 on L-type Ca~(2+) currents in rat ventricular myocytes was investigated by use of the whole-cell patch-clamp technique. 2. SR33557 inhibited Ca~(2+) current (I_(Ca)) in a concentration-dependent manner without change in the current-voltage relationship. 3. The inhibitory effect of SR33557 on I_(Ca) was dependent on the holding potential (V_h). The IC_(50) values were estimated to be 2.2 x 10~(-8) M at V_h=-50mV and 9.0 x10~(-6)M at V_h=-80mV. SR33557 (10~(-7) M) shifted the steady state inactivation curve of I_(Ca) toward more negative potentials. Thus, the affinity of the drug for inactivated channels was considerably higher than for resting channels. 4. Blockade of I_(Ca) by SR33557 was both tonic and use-dependent. 5. The time constant of onset of block was 36.4 s at - 50 mV and 41.9 ± 11.1 s at -40mV. 6. The time course of unblock was voltage-dependent. The time constant declined from 400.7 ± 68.1 s at -50 mV to 5.2 ± 1.2 s at -80 mV. 7. The rate of block of I_(Ca) was related to the number of openings per unit time and to the amount of time spent depolarized. The affinity of drug for open channels was considered to be similar to that for inactivated channels. 8. These results suggest that SR33557 inhibits L-type Ca~(2+) current through binding to both open and inactivated channels in rat ventricular myocytes.