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

Abstract

The action potential configuration in guinea pig ventricular myocytes was unaffected by low concentrations (0.3–1 μM) of tetrodotoxin (TTX); high concentrations (10–30 μM) depressed both the overshoot (5–10 mV) and duration (5–10%). Although the control$\dot V_{max}$ was unaffected by stimulation rate (0.1–5 Hz), the depression of$\dot V_{max}$ by TTX was greatly potentiated at rates above 1 Hz: on dose-response curves, 50% control$\dot V_{max}$ occurred at 4.3 μM (5 Hz) versus 22 μM (≤ 1 Hz). The frequency dependent component of the$\dot V_{max}$ 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$\dot V_{max}$ and available Na conductance.