AN ELECTROPHYSIOLOGICAL BASIS FOR THE ANTIARRHYTHMIC ACTIONS OF THE KAPPA-OPIOID RECEPTOR AGONIST U-50,488H

This study examined the actions of the selective kappa-opioid receptor agonist, U-50,488H, on voltage activated Na+ and K+ currents in isola ted rat cardiac myocytes. U-50,488H produced a concentration-dependent block of the transient Na+ current with an ED(50) of about 15 mu M, a nd, at higher concentrations (40-50 mu M), a block of the plateau K+ c urrent and an increase in the rate of decay of the transient K+ curren t. In addition U-50,488H produced a hyperpolarising shift in the inact ivation curve for the transient Na+ current without altering the volta ge dependence for activation and without an effect on the voltage depe ndence of inactivation or activation of K+ currents. The block of Nacurrents by U-50,488H showed pronounced use dependence. The kappa-opio id receptor antagonist MR2266 did not itself produce any change in the Na+ or K+ currents and did not change the channel blocking properties of U-50,488H. Thus, since the antiarrhythmic actions of U-50,488H are not blocked by MR2266 or naloxone, the effects of U-50,488H to block Na+ and K+ currents are the most likely reasons for its antiarrhythmic actions, rather than an action at kappa-opioid receptors.