An electrophysiological basis for the antiarrhythmic actions of the κ-opioid receptor agonist U-50,488H

Abstract

This study examined the actions of the selective κ-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 ED 50 of about 15 μM, and, at higher concentrations (40–50 μM), 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 κ-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 κ-opioid receptors.