title: Potent and use-dependent block of cardiac sodium channels by U-50,488H, a benzeneacetamide kappa opioid receptor agonist.
abstract: OBJECTIVE
  To determine whether the kappa opioid receptor agonist U-50,488H, a benzacetamide derivative of the cyclo-hexane-1,2-diamine analgesics, may be a useful molecular probe to define the structural requirements of this class of drugs for cardiac sodium channel blockade.
  
  
  METHODS
  The electrophysiological effects of U-50,488H were compared with those of lidocaine, a clinically used class Ib antiarrhythmic agent, in rat heart sodium currents expressed in Xenopus laevis oocytes by using two-electrode voltage clamp.
  
  
  RESULTS
  Both U-50,488H and lidocaine produced a concentration-dependent tonic block of sodium current, but U-50,488H was approximately fourfold more potent than lidocaine. Both drugs produced a hyperpolarizing shift in the voltage dependence of sodium channel inactivation and both delayed recovery from inactivation. Both drugs exhibited use-dependent block, but U-50,488H showed a 1.8-fold increase in potency compared with lidocaine at a high frequency of stimulation (30 Hz).
  
  
  CONCLUSIONS
  The more potent tonic and use-dependent block of cardiac sodium channels by U-50,488H suggests that structural features of this molecule may provide it with a greater ability to block the channel. An understanding of these structural features may provide information needed in the development of novel arylacetamide-based antiarrhythmic drugs and insight into possible mechanisms describing channel block, resulting in a highly efficacious antiarrhythmic action in the heart.
authors.affiliation: Department of Microbiology & Molecular Genetics, University of California, Irvine, California, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Pugsley
authors.forename: E J
authors.initials: EJ
authors.lastname: Yu
authors.forename: A L
authors.initials: AL
authors.lastname: Goldin