Effects of ropivacaine on a potassium channel (hKv1.5) cloned from human ventricle.
BACKGROUND
Ropivacaine, a new amide local anesthetic agent chemically related to bupivacaine, is able to induce early after depolarizations in isolated cardiac preparations. The underlying mechanism by which ropivacaine induces this effect has not been explored, but it is likely to involve K+ channel block.


METHODS
Cloned human cardiac K+ channels (hKv1.5) were stably transfected in Ltk cells, and the effects of ropivacaine on the expressed hKv1.5 currents were assessed using the whole-cell configuration of the patch-clamp technique.


RESULTS
Ropivacaine (100 microM) did not modify the initial activation time course of the current, but induced a fast subsequent decline to a lower steady-state current level with a time constant of 12.2 +/- 0.6 ms. Ropivacaine inhibited hKv1.5 with an apparent KD of 80 +/- 4 microM. Block displayed an intrinsic voltage-dependent, consistent with an electrical distance for the binding site of 0.153 +/- 0.007 (n = 6) (from the cytoplasmic side). Ropivacaine reduced the tail current amplitude recorded at -40 mV, and slowed the deactivation time course, resulting in a "crossover" phenomenon when control and ropivacaine tail currents were superimposed.


CONCLUSIONS
These results indicate that: (1) ropivacaine is an open channel blocker of hKv1.5; (2) binding occurs in the internal mouth of the ion pore; and (3) unbinding is required before the channel can close. These effects explain the ropivacaine availability of induction early after depolarizations and could be clinically relevant.
Valenzuela
C
C
Institute of Pharmacology and Toxicology, CSIC, School of Medicine, Madrid, Spain.
Delpón
E
E
Franqueza
L
L
Gay
P
P
Snyders
D J
DJ
Tamargo
J
J
D000577:Amides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000493:pharmacokinetics / Q000494:pharmacology*; D001665:Binding Sites; D002478:Cells, Cultured; D003001:Cloning, Molecular; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology; D000077212:Ropivacaine; D014162:Transfection; D016276:Ventricular Function
D000577:Amides; D000779:Anesthetics, Local; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D000077212:Ropivacaine