Tetrodotoxin (TTX) shortens Purkinje fiber action potential duration (APD) at concentrations (greater than or equal to 3.3 x 10(-8) M) lower than that at which the maximum rate of rise decreases (approximately 10(-6) M). The shortening effect of TTX occurs either at low or high driving rate and is much greater in Purkinje fibers than in bundle branch and muscle fibers. As a result, at a TTX concentration of 1.3 x 10(-6) M, the APD is no longer statistically different all along the conducting system, i.e., the gating mechanism described by Myerburg et al. (Circ. Res. 26: 361-378, 1970) is suppressed. It is concluded that this gating mechanism is attributable, at least in part, to the existence of a TTX-sensitive inward sodium current lengthening the plateau of the Purkinje fiber action potential. Our experimental results and reconstruction of Purkinje fiber action potentials suggest that this current, which is more sensitive to TTX than the normal rapid sodium current, flows through a background sodium conductance or/and a small proportion of sodium channels with no inactivation mechanism (or inactivation mechanism different from normal). The importance of this finding for the mechanism of action of antiarrhythmic drugs is pointed out.

No abstract

It has been suggested in a previous article [Escande et al., Am. J. Physiol. 249 (Heart Circ. Physiol. 18): H843-H850, 1985] that transient outward currents may participate in the initial repolarization of human atrial fibers. The present study substantiates the existence of such currents in human myocardium. Membrane currents were recorded in enzymatically dissociated cells using the whole cell patch-clamp technique. Two kinds of transient outward currents were observed: 1) a long-lasting outward current, (ilo), which was suppressed by 4-aminopyridine. The time to peak of ilo was 18.0 +/- 0.7 ms, and its inactivation time constant was 35.7 +/- 2.1 ms at room temperature (test pulses, +20 mV; holding potential, -40 mV); 2) a brief outward current (ibo), which persisted with 3 mM 4-aminopyridine and exhibited a shorter time to peak (5.5 +/- 0.2 ms) and a faster decay (time constant, 9.1 +/- 1.8 ms). ilo was inhibited by Ba but was insensitive to the calcium blocker Co. Co blocked both the slow inward current (isi) and ibo. It is concluded that two different transient outward currents control the repolarization in human atrial cells.

Voltage clamp analysis of the transient outward (positive dynamic) current was performed in sheep Purkinje fibers at a pulse frequency of 1/min. 4-aminopyridine (4-AP, 1 mM) suppressed most of the transient outward current, thus revealing the slow inward current, isi, and an associated brief outward current ibo. The long lasting component of the current suppressed by 4-AP was labelled ilo. In the presence of 4-AP, ibo was suppressed either by caffeine 10 mM or when Sr was substituted for Ca, both conditions making isi clearly detectable. Mn ions suppressed both isi and ibo. Current decay was a monoexponential process for ibo (tau = 12 ms) and a two exponential process for ilo (tau 1 = 80-100 ms, tau 2 = 250-400 ms). The peak amplitude-Em relationships were different for the two currents. It was shown that the reversal potential of ilo was not measurable by the usual method probably because of the too fast activation-deactivation kinetics of the current. It is concluded that not one but two transient outward currents with different electrophysiological and pharmacological characteristics exist in the sheep Purkinje fiber. The reason of the caffeine-sensitivity of ibo is discussed.

The observation that in cells from dilated human atria the calcium current is more severely depressed than the total outward current can help to explain why in dilated human atria the action potential plateau is shorter and of lower amplitude than in non-dilated atria.