Sodium current block caused by group IIb cations in calf Purkinje fibres and in guinea-pig ventricular myocytes.

The action of group IIb cations [Cadmium (Cd2+), Zinc (Zn2+), Mercury (Hg2+)] on the cardiac fast sodium current (INa) was investigated in calf Purkinje fibres and in ventricular cells isolated from guinea-pig hearts. In calf Purkinje fibres, INa was depressed by submillimolar concentrations of Zn2+ and Hg2+. With both cations, the current reduction occurred at all voltages in the range of current activation and the voltage dependence of peak current was unchanged. The degree of peak current inhibition depended on the cation concentration but not on voltage. The position of the inactivation curve on the voltage axis was unaltered at cation concentrations giving substantial current inhibition, and moved to the right only with concentration exceeding 1-1.5 mM. These effects can be interpreted as due to INa channel blockade. The action of Zn2+ and Hg2+ was similar to that described earlier of Cd2+ on Purkinje fibres (DiFrancesco et al. 1985b). INa was also inhibited by group IIb cations in isolated guinea-pig ventricular cells. Depression of INa by Cd2+, Zn2+ and Hg2+ was essentially voltage-independent, in agreement with its being caused by channel block. The dependence of INa block by Cd2+ upon external Na concentration [Na+0] was investigated in ventricular myocytes. The fraction of INa block by 0.1 mM CdCl2 was 0.50 at 140 mM, 0.81 at 70 mM and 0.83 at 35 mM [Na+]0. A similar increase of block efficiency at low [Na+0] was observed with 0.05 mM CdCl2. In both the Purkinje fibre and the ventricular cell, the order of potency of INa block by group IIb cations was Hg2+ greater than Zn2+ greater than Cd2+. Manganese (Mn2+, 2-5 mM), an ion of group VIIa, also depressed the INa in Purkinje fibres and ventricular myocytes. This effect was however due mainly to a positive shift on the voltage dependence of current kinetics rather than to a reduction of the conductance of the channel (GNa), and can be accounted for by an ion-screening action of Mn2+ on the external membrane surface. The block by group IIb cations is a typical property of cardiac Na+ channels and characterizes the cardiac as opposed to other types of Na+ channel.