Molecular mechanisms of the inhibitory effects of bupivacaine, levobupivacaine, and ropivacaine on sarcolemmal adenosine triphosphate-sensitive potassium channels in the cardiovascular system.
BACKGROUND
Sarcolemmal adenosine triphosphate-sensitive potassium (KATP) channels in the cardiovascular system may be involved in bupivacaine-induced cardiovascular toxicity. The authors investigated the effects of local anesthetics on the activity of reconstituted KATP channels encoded by inwardly rectifying potassium channel (Kir6.0) and sulfonylurea receptor (SUR) subunits.


METHODS
The authors used an inside-out patch clamp configuration to investigate the effects of bupivacaine, levobupivacaine, and ropivacaine on the activity of reconstituted KATP channels expressed in COS-7 cells and containing wild-type, mutant, or chimeric SURs.


RESULTS
Bupivacaine inhibited the activities of cardiac KATP channels (IC50 = 52 microm) stereoselectively (levobupivacaine, IC50 = 168 microm; ropivacaine, IC50 = 249 microm). Local anesthetics also inhibited the activities of channels formed by the truncated isoform of Kir6.2 (Kir6.2 delta C36) stereoselectively. Mutations in the cytosolic end of the second transmembrane domain of Kir6.2 markedly decreased both the local anesthetics' affinity and stereoselectivity. The local anesthetics blocked cardiac KATP channels with approximately eightfold higher potency than vascular KATP channels; the potency depended on the SUR subtype. The 42 amino acid residues at the C-terminal tail of SUR2A, but not SUR1 or SUR2B, enhanced the inhibitory effect of bupivacaine on the Kir6.0 subunit.


CONCLUSIONS
Inhibitory effects of local anesthetics on KATP channels in the cardiovascular system are (1) stereoselective: bupivacaine was more potent than levobupivacaine and ropivacaine; and (2) tissue specific: local anesthetics blocked cardiac KATP channels more potently than vascular KATP channels, via the intracellular pore mouth of the Kir6.0 subunit and the 42 amino acids at the C-terminal tail of the SUR2A subunit, respectively.
Department of Anesthesiology, Tokushima University School of Medicine, Kuramoto, Tokushima, 770-8503, Japan. haf26740@ams.odn.ne.jp
Takashi
T
Kawano
Shuzo
S
Oshita
Akira
A
Takahashi
Yasuo
Y
Tsutsumi
Yoshinobu
Y
Tomiyama
Hiroshi
H
Kitahata
Yasuhiro
Y
Kuroda
Yutaka
Y
Nakaya
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000465:Algorithms; D000577:Amides / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D002045:Bupivacaine / Q000031:analogs & derivatives / Q000494:pharmacology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D000077554:Levobupivacaine; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000187:drug effects* / Q000235:genetics; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000235:genetics; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism; D000077212:Ropivacaine; D013237:Stereoisomerism; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; D014162:Transfection
D018528:ATP-Binding Cassette Transporters; D000577:Amides; D000779:Anesthetics, Local; D008565:Membrane Proteins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; C117780:mitochondrial K(ATP) channel; D000077212:Ropivacaine; D000077554:Levobupivacaine; D002045:Bupivacaine