Potent and use-dependent block of cardiac sodium channels by U-50,488H, a benzeneacetamide kappa opioid receptor agonist.
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.
Pugsley
M K
MK
Department of Microbiology & Molecular Genetics, University of California, Irvine, California, USA.
Yu
E J
EJ
Goldin
A L
AL