QX-OH/Levobupivacaine: A Structurally Novel, Potent Local Anesthetic Produces Fast-Onset and Long-Lasting Regional Anesthesia in Rats

Abstract

Yang Yang,1,2 Chiyi Wang,1,2 Jin Liu,1,2 Daqing Liao,2 Wensheng Zhang,1,2 Cheng Zhou2 1Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People’s Republic of ChinaCorrespondence: Cheng ZhouLaboratory of Anaesthesia & Critical Care Medicine, Translational Neuroscience Center, The Research Units of West China (2018RU012), Chinese Academy of Medical Sciences, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China, Tel [phone], Fax [phone], Email [email protected]; Wensheng ZhangDepartment of Anaesthesiology and Laboratory of Anaesthesia & Critical Care Medicine, Translational Neuroscience Center, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, People’s Republic of China, Tel/Fax [phone], Email [email protected]: Local anesthetics (LAs) are an important alternative for postoperative analgesia; however, the short duration of LAs limits their use. Thus, we previously developed LL-1, a mixture of QX-OH and levobupivacaine (LB) that produces regional anesthesia for more than 10 h in rats. The aim of this study is to investigate the long-acting mechanism of LL-1 in vivo and in vitro.Methods: Regional anesthetic effects and local toxicity of the LL-1, QX-OH and LB treatment groups were investigated in a sciatic nerve block rat model. Whole-cell patch-clamping recordings were used to measure the inhibition Nav currents (INa) in ND7/23 cells.Results: The onset of LL-1 (35mM QX-OH+10mM LB) and 10 mM LB was 10 min, which was much faster than 35 mM QX-OH (27 [18, 60] min, t[12] = − 4.535, p = 0.001). The duration of LL-1 (35mM QX-OH+10 mM LB) was significantly longer than 35 mM QX-OH or 10 mM LB alone (F[3, 35] = 191.336, p < 0.0001). No differences in local tissue toxicity were found between LL-1 and LB. In patch-clamping recordings, 5 mM QX-OH produced ∼ 20% inhibition of INa currents. LB at 40 μM inhibited INa by 65.51%± 3.63%, while QX-OH 2 mM+LB 40 μM inhibited INa by 77.37%± 3.36% (t[14] = 2.358, p = 0.025), and QX-OH 5 mM+LB 40 μM inhibited INa by 83.88%± 1.57% (t[13] = 4.191, p = 0.0003). Furthermore, INa inhibition by QX-OH+LB was more persistent than that of LB alone during washout.Conclusion: LL-1 can produce an additive and stable inhibition of Nagv currents, which can contribute to the long-lasting regional anesthetic action.Keywords: long-lasting local anesthetics, QX-OH, levobupivacaine, voltage-gated sodium channel, Nav

Keywords

• long-lasting local anesthetics
• qx-oh
• levobupivacaine
• voltage-gated sodium channel
• nav.