Abstract
Background and objectivesHyperpolarization-activation cyclic nucleotide-gated (HCN) channels contribute to the effects of lidocaine. Capsazepine (CPZ), a competitive inhibitor of capsaicin of transient receptor potential vanilloid-1 channel, has also been found to inhibit HCN channel currents (Ih). This study was designed to investigate whether CPZ could prolong durations of lidocaine in regional anesthesia.MethodsMouse HCN1 and HCN2 channels were expressed in human embryonic kidney 293 (HEK 293) cells. The effect of CPZ on Ih was measured by whole-cell patch-clamping recording. Sciatic nerve block model in mice was used for the study in vivo. The mice were randomly divided into seven groups, respectively, receiving lidocaine, CPZ, ZD7288 (HCN channel blocker), CPZ + lidocaine, ZD7288 + lidocaine, ZD7288 + CPZ + lidocaine, forskolin (an activator of adenylyl cyclase) + CPZ + lidocaine. Regional anesthetic durations of lidocaine were determined. Voltage-gated sodium channel currents (INa) and Ih were recorded in dorsal root ganglion neurons of mice. The effects of CPZ on INa and Ih with or without Cyclic adenosine monophosphate (cAMP) were assessed. Isolated mice sciatic nerve was prepared to evaluate the effect of CPZ on the compound action potentials (CAP).ResultsCapsazepine non-selectively inhibited transfected mHCN1 and mHCN2 channel currents in HEK 293 cells. In sciatic nerve block in vivo, compared to lidocaine alone, adding CPZ extended the durations of lidocaine for noxious sensory block (35.1 ± 3.3 vs. 20.3 ± 1.7 min), tactile sensory block (25.5 ± 4.4 vs. 20.0 ± 3.7 min), thermal sensory block (39.6 ± 6.6 vs. 26.8 ± 5.5 min), and motor function block (28.6 ± 4.1 vs. 20.9 ± 4.2 min). Duration of thermal sensory block was longer in CPZ + lidocaine group than that of ZD7288 + lidocaine group (39.6 ± 6.6 vs. 33.4 ± 4.5 min). Forskolin reversed the prolongation by CPZ on lidocaine durations. CPZ or ZD7288 alone did not produce typical regional anesthetic effects. Increased intracellular concentration of cAMP reversed the inhibition of CPZ on Ih. Although CPZ alone inhibited INa at the concentration more than 30 μM, it did not inhibit the CAP amplitudes in isolated sciatic nerves. CPZ dose-dependently enhanced the inhibitory effect of 1% lidocaine on the CAP amplitudes.ConclusionsCapsazepine may prolong durations of lidocaine in peripheral nerve block by modulation of HCN channel currents.
Highlights
Local anesthetics such as lidocaine have been widely used in clinics for decades, there are still many disadvantages for currently used local anesthetics including toxicities and unsatisfied durations (Mather, 2010)
Recent studies have identified that hyperpolarization-activation cyclic nucleotide-gated (HCN) channel might contribute to the effects of local anesthetics in regional anesthesia (Meng et al, 2011; Zhou et al, 2015)
The inhibitory potency of CPZ on HCN channel currents is similar between HCN1 and HCN2 channels, with IC50 of 9.6 ± 0.4 and 8.2 ± 0.3 mM for HCN1 and HCN2, respectively
Summary
Local anesthetics such as lidocaine have been widely used in clinics for decades, there are still many disadvantages for currently used local anesthetics including toxicities and unsatisfied durations (Mather, 2010). Recent studies have identified that hyperpolarization-activation cyclic nucleotide-gated (HCN) channel might contribute to the effects of local anesthetics in regional anesthesia (Meng et al, 2011; Zhou et al, 2015). Increased level of cAMP by activator of adenylyl cyclase (e.g., forskolin) can shorten the durations of lidocaine in vivo (Kroin et al, 2004; Zhou et al, 2015). Adding more potent HCN channel modulators (e.g., ZD7288, clonidine and dexmedetomidine) to local anesthetics have been found to extend the durations of lidocaine and ropivacaine in vivo (Brummett et al, 2011; Harris & Constanti, 1995; Kroin et al, 2004). Hyperpolarization-activation cyclic nucleotide-gated (HCN) channels contribute to the effects of lidocaine. CPZ alone inhibited INa at the concentration more than 30 mM, it did
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
