Mechanisms of extracellular divalent and trivalent cation block of the sodium current in canine cardiac Purkinje cells.
1. Single canine cardiac Purkinje cells were internally perfused and voltage clamped with a large-bore perfusion pipette for measurement of sodium ionic current (INa) in the absence and presence of extracellular group IIA divalent cations (Mg2+, Ba2+ and Ca2+), transition divalent cations (CO2+, Mn2+ and Ni2+), group IIB divalent cations (Cd2+ and Zn2+), and the trivalent cation La3+. 2. Open channel block of cardiac INa by external Ca2+, assessed from instantaneous INa-voltage (I-V) relationships, has been well described by a two-barrier, one-well model with a dissociation constant at 0 mV, KB(0), of 37 mM and an electrical distance, z' = delta, of 0.34. At the most negative test potentials there was less block of INa than predicted by the model, but correction of INa for the contribution of Na+ channel gating current (Ig) to the peak current improved the fit by the model. 3. The divalent cations Ba2+, Mg2+, CO2+ and Mn2+ produced voltage-dependent, open channel block of INa, which by the two-barrier, one-well model predicted a similar z' about one-third into the membrane field. The relative efficacy for voltage-dependent block was CO2+ > Mn2+ > Ca2+ > Mg2+ > Ba2+ with respective KB(0)s of 11, 13, 37, 43 and 61 mM. 4. Cd2+, Zn2+ and La3+ produced block of INa at low concentrations that was nearly voltage independent with z' < or = 0.13. Fits of single-site binding curves to peak INa in response to step depolarizations at positive test potentials gave the following apparent KD values: Zn2+ 0.14 mM, Cd2+ 0.27 mM and La3+ 0.50 mM. 5. In the presence of Cd2+, INa tail current relaxations were much faster than could be accounted for by Cd2+ binding to and/or screening of extracellular surface charges. Fits of the data to a model that assumed voltage-dependent open channel block during the tail current relaxations estimated the KB(0) for Cd2+ to be 0.80 mM. 6. Both z' and KB(0) for Ni2+ from fits of the two-barrier, one-well model to instantaneous I-V relationships varied as a function of [Ni2+], consistent with the hypothesis that Ni2+ blocked with similar affinity at a voltage-dependent and a voltage-independent site. At [Ni2+] > or = 5 mM, KB(0) was 7.6 mM and z' was 0.21.(ABSTRACT TRUNCATED AT 400 WORDS)
Sheets
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MF
Department of Medicine, Northwestern University Medical School, Chicago, IL 60611.
Hanck
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DA
D000818:Animals; D001464:Barium / Q000494:pharmacology; D002104:Cadmium / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002413:Cations, Divalent / Q000494:pharmacology*; D003035:Cobalt / Q000494:pharmacology; D004285:Dogs; D007811:Lanthanum / Q000494:pharmacology*; D008274:Magnesium / Q000494:pharmacology; D008345:Manganese / Q000494:pharmacology; D009532:Nickel / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects*; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects*; D015032:Zinc / Q000494:pharmacology
D002413:Cations, Divalent; D015222:Sodium Channels; D002104:Cadmium; D001464:Barium; D003035:Cobalt; D008345:Manganese; D007811:Lanthanum; D009532:Nickel; D012964:Sodium; D008274:Magnesium; D015032:Zinc; D002118:Calcium