title: Differential effects of bupivacaine enantiomers, ropivacaine and lidocaine on up-regulation of cell surface voltage-dependent sodium channels in adrenal chromaffin cells.
abstract: In cultured bovine adrenal chromaffin cells, (+/-)-bupivacaine inhibited veratridine-induced 22Na(+) influx (IC(50) 6.8 microM). The IC(50) of (+)-bupivacaine (2.8 microM) was 6.2-, 7.4-, and 17.1-fold lower than those of (-)-bupivacaine (17.3 microM), (-)-ropivacaine (20.6 microM), and lidocaine (47.8 microM). Chronic (i.e. 3-h) treatment of cells with (+/-)-bupivacaine increased cell surface [3H]saxitoxin ([3H]STX) binding capacity by 48% (EC(50) of 233 microM; t(1/2)=7.4 h), without changing the K(d) value. Treatment for 24 h with either (+)- or (-)-bupivacaine, or (-)-ropivacaine elevated [3H]STX binding, whereas 24-h treatment with lidocaine had no effect. The rise of [3H]STX binding by (+/-)-bupivacaine was prevented by cycloheximide, an inhibitor of protein synthesis, or brefeldin A, an inhibitor of cell surface vesicular exit from the trans-Golgi network; however, (+/-)-bupivacaine did not increase Na(+) channel alpha- and beta(1)-subunit mRNA levels. In cells subjected to (+/-)-bupivacaine treatment (1 mM for 24 h) followed by 3-h washout, veratridine-induced 22Na(+) influx was enhanced, even when measured in the presence of ouabain, an inhibitor of Na(+),K(+)-ATPase. Ptychodiscus brevis toxin-3 potentiated veratridine-induced 22Na(+) influx by 2.3-fold in the (+/-)-bupivacaine-treated cells, as in non-treated cells. These results suggest that lipophilic bupivacaine enantiomers or (-)-ropivacaine acutely inhibit Na(+) channel gating, whereas its chronic treatment up-regulates cell surface expression of Na(+) channels via translational and externalization events.
authors.affiliation: Department of Pharmacology, Miyazaki Medical College, Miyazaki 889-1692, Kiyotake, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Shiraishi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yokoo
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yanagita
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Minami
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Saitoh
authors.forename: Mayumi
authors.initials: M
authors.lastname: Takasaki
authors.forename: Akihiko
authors.initials: A
authors.lastname: Wada
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D015152:Blotting, Northern; D002045:Bupivacaine / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008012:Lidocaine / Q000494:pharmacology*; D010042:Ouabain / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D000077212:Ropivacaine; D012530:Saxitoxin / Q000378:metabolism; D012604:Scorpion Venoms / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D014316:Tritium / Q000378:metabolism; D015854:Up-Regulation; D014701:Veratridine / Q000494:pharmacology
chemical_list: D000577:Amides; D000779:Anesthetics, Local; D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D012604:Scorpion Venoms; D015222:Sodium Channels; C454815:parabutoxin 3 protein, Parabuthus transvaalicus; D014316:Tritium; D012530:Saxitoxin; D010042:Ouabain; D014701:Veratridine; D000077212:Ropivacaine; D008012:Lidocaine; D012964:Sodium; D002045:Bupivacaine