title: Intrinsic lidocaine affinity for Na channels expressed in Xenopus oocytes depends on alpha (hH1 vs. rSkM1) and beta 1 subunits.
abstract: OBJECTIVE
  The affinity of lidocaine for the alpha-subunit of the Na channel has been reported to be greater for heart than for non-heart alpha-subunits, and also to be no different. Lidocaine block has a complex voltage dependence caused by a higher affinity for the inactivated state over the resting state. Inactivation kinetics, however, depend upon the alpha-subunit isoform and the presence of the auxiliary beta 1-subunit and will affect measures of block.
  
  
  METHODS
  We studied the voltage dependence of lidocaine block of Na currents by a two microelectrode voltage clamp in oocytes injected with RNA for the Na channel alpha-subunits of human heart (hH1a) or a rat skeletal muscle (rSkM1) alone, or coexpressed with the beta 1-subunit.
  
  
  RESULTS
  The midpoints of availability for a 25-s conditioning potential in control solutions were -65 mV for rSkM1, -50 for rSkM1 + beta 1, -78 mV for hH1a and -76 for hH1a + beta 1. The Kd of tonic lidocaine block was measured at -90, -100, -110, -120 and -130 mV in the same oocytes. The apparent Kd for both isoforms +/- beta 1 became greater with more negative holding potentials, but tended to reach different plateaus at -130 mV (Kd = 2128 microM for rSkM1, 1760 microM for rSkM1 + beta 1, 433 for hH1a, and 887 microM for hH1a + beta 1). Inactivated state affinities, assessed by fitting the shift in the Boltzmann midpoint of the availability relationship to the modulated receptor model, were 4 microM for rSkM1, 1 microM for rSkM1 + beta 1, 7 microM for hH1a and 9 microM for hH1a + beta 1.
  
  
  CONCLUSIONS
  The heart Na channel alpha-subunits expressed in oocytes have an intrinsically higher rest state affinity for lidocaine compared to rSkM1 after the voltage- and state dependence of block are considered. Coexpression with beta 1 modestly increased the rest affinity of lidocaine for rSkM1, but had the opposite effect for hH1a.
authors.affiliation: Department of Medicine, University of Wisconsin, Madison 53792, USA. jcm@medicine.wisc.edu
authors.forename: J C
authors.initials: JC
authors.lastname: Makielski
authors.forename: J
authors.initials: J
authors.lastname: Limberis
authors.forename: Z
authors.initials: Z
authors.lastname: Fan
authors.forename: J W
authors.initials: JW
authors.lastname: Kyle
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D005260:Female; D008012:Lidocaine / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D015222:Sodium Channels / Q000378:metabolism*; D014981:Xenopus
chemical_list: D000889:Anti-Arrhythmia Agents; D020033:Protein Isoforms; D015222:Sodium Channels; D008012:Lidocaine