Abstract
The action of group IIb cations [Cadmium (Cd2+), Zinc (Zn2+), Mercury (Hg2+)] on the cardiac fast sodium current (I Na) was investigated in calf Purkinje fibres and in ventricular cells isolated from guinea-pig hearts. In calf Purkinje fibres, I Na 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 I Na channel blockade. The action of Zn2+ and Hg2+ was similar to that described earlier of Cd2+ on Purkinje fibres (DiFrancesco et al. 1985b). I Na was also inhibited by group IIb cations in isolated guinea-pig ventricular cells. Depression of I Na by Cd2+, Zn2+ and Hg2+ was essentially voltage-independent, in agreement with its being caused by channel block. The dependence of I Na block by Cd2+ upon external Na concentration [Na+ 0] was investigated in ventricular myocytes. The fraction of I Na 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 I Na block by group IIb cations was Hg2+> Zn2+> Cd2+. Manganese (Mn2+, 2–5 mM), an ion of group VIIa, also depressed the I Na 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 (G Na), 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.
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References
Århem P (1980) Effects of some heavy metal cations on the ionic currents of myelinated fibres from Xenopus laevis. J Physiol (Lond) 306: 219–231
Begenisich T, Lynch C (1974) Effects of internal divalent cations on voltage-clamped sqid axons. J Gen Physiol 63: 675–689
Bendukidze Z, Isenberg G, Klockner U (1985) Ca-tolerant guinea-pig ventricular myocytes as isolated by pronase in the presence of 250 μM free calcium. Basic Res Cardiol 80: 1–13
Bodewei R, Hering S, Lemke B, Rosenhstraukh LV, Undrovinas AI, Wollenberger A (1982) Characterization of the fast sodium current in isolated rat myocardial cells: simulation of the clamped membrane potential. J Physiol (Lond) 325: 301–315
Bossu JL, Feltz A (1984) Patch-clamp study of the tetrodotoxin-resistant sodium current in group C sensory neurones. Neurosci Letts 51: 241–246
Brismar T (1980) The effect of divalent and trivalent cations on the sodium permeability of myelinated nerve fibres of Xenopus laevis. Acta Physiol Scand 108: 23–29
Brown AM, Lee KS, Powell T (1981a) Voltage clamp and internal perfusion of single rat heart muscle cells. J Physiol (Lond) 318: 455–477
Brown AM, Lee KS, Powell T (1981b) Sodium current in single rat heart muscle cells. J Physiol (Lond) 318: 479–500
Caterall WA (1988) Structure and function of voltage-sensitive ion channels. Science 242: 50–61
Cohen CJ, Bean BP, Colatski TJ, Tsien RW (1981) Tetrodotoxin block of Na channels in rabbit Purkinje fibres. Nature 278: 265–269
Colatsky TJ (1980) Voltage clamp measurements of sodium channel properties in rabbit cardiac Purkinje fibres. J Physiol (Lond) 305: 215–234
Colatsky TJ, Tsien RW (1979) Sodium channels in rabbit cardiac Purkinje fibres. Nature 278: 265–268
D'Arrigo JS (1973) Possible screening of surface charges on crayfish axons by polyvalent metal ions. J Physiol (Lond) 231: 117–128
Datyner NB, Gintant GA, Cohen IS (1985) Microprocessor controlled trituration device for the dissociation of cardiac and other tissues. Pflügers Arch 403: 105–108
DiFrancesco D, Ferroni A, Mazzanti M, Tromba C (1985a) Fast Na current inhibition by cations of group 2b in isolated guinea-pig and neonatal rat cardiac cells. J Physiol (Lond) 369: 87P
DiFrancesco D, Ferroni A, Mazzanti M, Tromba C (1986) Properties of the hyperpolarizing-activated current (if) in cells isolated from the rabbit sino-atrial node. J Physiol (Lond) 377: 61–88
DiFrancesco D, Ferroni A, Visentin S, Zaza A (1985b) Cadmiuminduced blockade of the cardiac fast Na channels in calf Purkinje fibres. Proc R Soc Lond [Biol] 223: 475–484
Duval A, Leoty C (1985) Changes in the ionic currents sensitivity to inhibitors in twitch skeletal muscles following denervation. Pflügers Arch 403: 407–414
Frelin C, Cognard C, Vigne P, Lazdunski M (1985) Tetrodotoxinsensitive and tetrodotoxin-resistant Na channels differ in their sensitivety to Cd and Zn. Eur J Pharmacol 122: 245–250
Frelin C, Vijverberg HPM, Romey G, Vigne P, Lazdunski M (1984) Different functional states of tetrodotoxin sensitive and tetrodotoxin resistant Na channels occur during the in vitro development of rat skeletal muscle. Pflügers Arch 402: 121–128
Gilly FWM, Armstrong CM (1982) Slowing of sodium channel opening kinetics in squid axon by extracellular zinc. J Gen Physiol 79: 935–964
Gonoi T, Sherman SJ, Caterall WA (1985) Voltage clamp analysis of tetrodotoxin-sensitive and insensitive sodium channels in rat muscle cells developing in vitro. J Neurosci 5: 2559–2564
Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflügers Arch 391: 85–100
Hartshorne RP, Caterall WA (1984) The Na channel from rat brain: purification and subunit composition. J Biol Chem 259: 1667–1675
Hille B (1984) Ionic channels of excitable membranes. Sinauer, New York
Hille B, Woodhull AM, Shapiro BI (1975) Negative surface charge near sodium channels of nerve: divalent ions, monovalent ions and pH. Philos Trans R Soc Lond [Biol] 270: 301–318
Isenberg G, Ravens U (1984) The effects of the anemonia sulcata toxin (ATX II) on membrane currents of isolated mammalian myocytes. J Physiol (Lond) 357: 127–149
Jones SW (1987) Sodium currents in dissociated bull-frog sympathetic neurones. J Physiol (Lond) 389: 605–627
Josephson IR, Sanchez-Chapula J, Brown AM (1984) A comparison of calcium currents in rat and guinea-pig single ventricular cells. Circ Res 54: 144–156
Kass RS, Sheuer T, Malloy KJ (1982) Block of outward current in cardiac Purkinje fibres by injection of quaternary ammonium ions. J Gen Physiol 79: 1041–1063
Kleinhaus AL, Pritchard JW (1976) Sodium-dependent tetrodotoxin-resistant action potentials in leech neurones. Brain Res 102: 368–373
Kostyuk PG, Veselovsky NS, Tsyndrenko AY (1981) Ionic currents in the somatic membrane of rat dorsal root ganglion neurons-I. Sodium currents. Neuroscience 6: 2423–2430
Lansman JB, Hess P, Tsien RW (1986) Blockade of current through single calcium channels by Cd2+, Mg2+ and Ca2+. J. Gen. Physiol. 88: 321–347
Lee KS, Weeks TA, Kao RL, Akaike N, Brown AM (1979a) Sodium current in single heart muscle cells. Nature 278: 269–271
Marban E, Tsien RW (1982) Effects of nystatin-mediated intracellular ion substitution on membrane currents in calf Purkinje fibres. J Physiol (Lond) 329: 569–587
McLaughlin S (1977) Electrostatic potentials at membrane-solution interfaces. Curr Top Memb Transp 9: 71–14
Miller JA, Agnew WS, Levinson SR (1983) Principal glycopeptide of the tetrodotoxin/saxitoxin binding protein from Electroforus electricus. Biochemistry 22: 462–470
Neumke B, Stampfli R (1982) Sodium currents and sodium-current fluctuations in rat myelinated nerve fibres. J Physiol (Lond) 329: 163–184
Noda M, Takayuki I, Suzuki H, Takeshima H, Takahashi T, Kuno M, Numa S (1986) Expression of functional sodium channels from cloned cDNA. Nature 322: 826–828
Pappone PA (1980) Voltage clamp experiments in normal and denervated mammalian skeletal muscle fibres. J Physiol (Lond) 306: 377–410
Patlak JB, Horn R (1982) Effect of N-bromoacetamide on single sodium channel currents in excised membrane patches (1982) J Gen Physiol 79: 333–351
Shrager P (1977) Slow sodium inactivation in nerve after exposure to sulfydryl blocking reagents. J Gen Physiol 69: 183–202
Siegelbaum SA, Tsien RW (1980) Calcium-activated transient outward current in calf Purkinje fibres. J Physiol (Lond) 299: 485–506
Sigworth FJ (1983) Electronic design of the patch-clamp. In: Sackmann B, Neher E (eds) Single channel recording. Plenum, New York, pp 3–35
Sigworth FJ, Neher E (1980) Single Na channel currents observed in cultured rat muscle cells. Nature 287: 447–449
Sutton F, Davidson N, Lester HA (1988) Tetrodotoxin-sensitive voltage-dependent Na currents recorded from Xenopus oocytes injected with mammalian cardiac muscle RNA. Mol Brain Res 3: 187–192
Tseng G, Hoffman BF (1989) Two components of transient outward current in canine ventricular myocytes. Circ Res 64: 633–647
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Visentin, S., Zaza, A., Ferroni, A. et al. Sodium current block caused by group IIb cations in calf Purkinje fibres and in guinea-pig ventricular myocytes. Pflugers Arch. 417, 213–222 (1990). https://doi.org/10.1007/BF00370702
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DOI: https://doi.org/10.1007/BF00370702