Tetrodotoxin exerts a large frequency-dependent depression of the maximum rate of rise of action potentials in guinea pig ventricular myocytes.

The action potential configuration in guinea pig ventricular myocytes was unaffected by low concentrations (0.3-1 microM) of tetrodotoxin (TTX); high concentrations (10-30 microM) depressed both the overshoot (5-10 mV) and duration (5-10%). Although the control Vmax was unaffected by stimulation rate (0.1-5 Hz), the depression of Vmax by TTX was greatly potentiated at rates above 1 Hz: on dose-response curves, 50% control Vmax occurred at 4.3 microM (5 Hz) versus 22 microM (less than or equal to 1 Hz). The frequency dependent component of the Vmax depression reported here is much larger than the "extra" block of Na channels observed by others in voltage clamp studies on Purkinje strands. This is not a discrepancy; rather it is a consequence of a non-linear relation between Vmax and available Na conductance.