Spiradoline, a kappa opioid receptor agonist, produces tonic- and use-dependent block of sodium channels expressed in Xenopus oocytes.
Spiradoline, an arylacetamide kappa (kappa) opioid receptor agonist, produced a potent tonic block of rat neuronal (EC(50)= 34+/-5 microM) and heart (EC(50)= 183+/-13 microM) sodium channels and also blocked IFMQ3 mutant neuronal sodium channels (EC(50)= 130+/-34 microM) that lack fast inactivation when expressed in Xenopus oocytes. Spiradoline produced a hyperpolarizing shift in the voltage-dependence of sodium channel inactivation and exhibited a marked frequency-dependent component to blockade of sodium channels. The onset of open channel block of the IFMQ3 channel by spiradoline was best fit with a first-order blocking scheme, yielding an affinity constant of 116 +/- 33 microM. Thus, spiradoline blocks sodium channels by interacting with the major states of the channel which could result in local anesthetic action in nerves and antiarrhythmic action in the heart.
Pugsley
M K
MK
Department of Microbiology and Molecular Genetics, University of California, 92697-4025, Irvine, CA, USA.
Yu
E J
EJ
Goldin
A L
AL
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000819:agonists*; D002462:Cell Membrane / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects; D023421:Models, Animal; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism*; D018408:Patch-Clamp Techniques / Q000379:methods; D011759:Pyrrolidines / Q000819:agonists*; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000096:biosynthesis*; D014981:Xenopus / Q000378:metabolism*
D000889:Anti-Arrhythmia Agents; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C051272:spiradoline