Effect of retigabine on median effective dose of bupivacaine and chloroprocaine for induction of convulsion in mice

Abstract

Objective To investigate the effect of KCNQ2/3 channel opener retigabine on the median effective dose (ED50) of bupivacaine and chloroprocaine for induction of convulsion in mice and the relationship between KCNQ2/3 channels and the neurotoxicity of local anesthetics.Methods Pathogen-free female Kunming mice,weighing 20-30 g,were used in the study.The experiment was performed in two parts.Part Ⅰ Sixty mice were randomly divided into 2 groups (n =30 each):control group (group C) and retigabine group (group R).The C and R groups were further divided into 3 subgroups with different doses of chlorprocaine (C + L1,C + L2 and C+ L3 groups,and R+ L1,R+ L2 and R+ L3 groups,n =10 each).In groups C and R,0.9％ normal saline 0.005 ml/g and retigabine 20 mg/kg were injected intraperitoneally,respectively,and chlorprocaine was injected intraperitoneally 20 min later.The doses of chlorprocaine were 150.0,172.5 and 198.4 mg/kg in C + L1,C + L2 and C + L3 groups,respectively,and 198.4,228.2 and 262.4 mg/kg in R+ L1,R+ 12 and R+ L3 groups,respectively.Part Ⅱ Eighty mice were randomly divided into 2 groups (n =40 each):control group (group C) and retigabine group (group R).The C and R groups were further divided into 4 subgroups with different doses of bupivacaine (C + B1,C + B2,C + B3 and C + B4 groups,and R + B1,R + B2,R + B3 and R + B4 groups,n =10 each).In groups C and R,0.9％ normal saline 0.005 ml/g and retigabine 20 mg/kg were injected intraperitoneally,respectively,and bupivacaine was injected intraperitoneally 20 min later.The doses of bupivacaine were 37.8,43.5,50.0 and 57.5 mg/kg in C + B1,C + B2,C + B3 and C + B4 groups,respectively,and 50.0,57.5,66.1 and 76.0 mg/kg in R + B1,R + B2,R + B3 and R + B4 groups,respectively.The ED50 and 95％ confidence interval (CI) of bupivacaine and chloroprocaine for induction of convulsion were calculated by Probit analysis.Results The ED50(95％ CI) of chloroprocaine was 165.3 (155.8-175.0) mg/kg,and the ED50(95％CI) of bupivacaine was 41.1 (36.7-44.5) mg/kg in C group.The ED50 (95％ CI) of chloroprocaine was 212.4 (200.2-224.3) mg/kg,and the ED5o (95％ CI)of bupivacaine was 51.5 (945.1-56.0)mg/kg in R group.Compared with group C,the ED50 of bupivacaine and chloroprocaine for induction of convulsion was significantly increased in group R (P ＜ 0.01).Conclusion KCNQ2/3 channel opener retigabine can significantly increase the ED50 of bupivacaine and chloroprocaine for induction of convulsion and reduce convulsion induced by bupivacaine and chloroprocaine in mice,indicating that the neurotoxicity of local anesthetics is related to inhibition of KCNQ2/3 channels. Key words: KCNQ2 potassium channel; KCNQ3 potassium channel; Anesthetics, local; Drug toxicity ; Dose-response relationship, drug