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 isolated rat cardiac myocytes. U-50,488H produced a concentration-dependent block of the transient Na+ current with an ED50 of about 15 microM, and, at higher concentrations (40-50 microM), a block of the plateau K+ current and an increase in the rate of decay of the transient K+ current. In addition U-50,488H produced a hyperpolarising shift in the inactivation curve for the transient Na+ current without altering the voltage dependence for activation and without an effect on the voltage dependence of inactivation or activation of K+ currents. The block of Na+ currents by U-50,488H showed pronounced use dependence. The kappa-opioid 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.