Effect of tetramethyl pyrazine on L-type calcium channel in rat ventricular myocytes

To elucidate possible ionic mechanisms of antimyocardial ischemia and antiarrythmia of tetramethyl pyrazine (TP), we studied L-type Ca2+ currents (I-Ca.L) in adult rat ventricular myocytes using the whole-cell patch-clamp technique. The results showed: (i) under physiological conditions, 0.25 mmol/L TP decreased amplitude of I-Ca.L to 60.6% and this inhibition was increased with increasing concentration of TP. ID50 was 0.20 mmol/L. (ii) The Ca2+-antagonistic effect of TP was voltage-dependent. A marked negative shift of the steady-state inactivation curve was observed with long (10 s) conditioning prepulses, but not with short (350 ms) ones. (iii) The time course of inhibition during TP treatment was increased with an increase in drug concentration, and recovery from TP-induced inactivation of I-Ca.L was slower than in control cases. (iv) Tonic block and use-dependent block with TP treatment, which was induced by increasing the frequency of stimulation, occurred. We suggest that TP inhibits the I-Ca.L mainly by binding to inactivated Ca2+ channels. The high affinity of TP for the inactivated state of I-Ca.L may play an important role in developing therapies for pathological conditions.