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.
Pugsley
M K
MK
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
Saint
D A
DA
Walker
M J
MJ
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008839:Microelectrodes; D009206:Myocardium / Q000166:cytology; D009292:Narcotic Antagonists / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D009292:Narcotic Antagonists; D015221:Potassium Channels; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D015222:Sodium Channels; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer