Drug Design, Development and Therapy (Apr 2024)
Dexmedetomidine Prolongs Lidocaine Intravenous Regional Anesthesia in Rats by Blocking the Hyperpolarization-Activated Cation Current
Abstract
Tongtong Zhang,1,* Xincheng Liao,2,* Yuzhi Chen,3,* Xinru Shu,3 Deshan Liu,4 Yusheng Yao3,5 1Department of Anesthesiology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, People’s Republic of China; 2Department of Anesthesiology, The Second Affiliated Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, People’s Republic of China; 3Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, People’s Republic of China; 4Department of Neurology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, People’s Republic of China; 5Fujian Provincial Key Laboratory of Critical Care Medicine, Fuzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Deshan Liu; Yusheng Yao, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, 134, Dongjie Street, Fuzhou, 350001, People’s Republic of China, Email [email protected]; [email protected]: Intravenous regional anesthesia (IVRA) using lidocaine provides effective localized analgesia but its duration is limited. The mechanism by which dexmedetomidine enhances lidocaine IVRA is unclear but may involve modulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels.Materials and Methods: Lidocaine IVRA with varying dexmedetomidine concentrations was performed in the tails of Sprague-Dawley rats. Tail-flick and tail-clamping tests assessed IVRA analgesia and anesthesia efficacy and duration. Contributions of α2 adrenergic receptors and HCN channels were evaluated by incorporating an α adrenergic receptor antagonist, the HCN channel inhibitor ZD7288, and the HCN channel agonist forskolin. Furthermore, whole-cell patch clamp electrophysiology quantified the effects of dexmedetomidine on HCN channels mediating hyperpolarization-activated cation current (Ih) in isolated dorsal root ganglion neurons.Results: Dexmedetomidine dose-dependently extended lidocaine IVRA duration and analgesia, unaffected by α2 receptor blockade. The HCN channel inhibitor ZD7288 also prolonged lidocaine IVRA effects, while the HCN channel activator forskolin shortened effects. In dorsal root ganglion neurons, dexmedetomidine concentration-dependently inhibited Ih amplitude and shifted the voltage-dependence of HCN channel activation.Conclusion: Dexmedetomidine prolongs lidocaine IVRA duration by directly inhibiting HCN channel activity, independent of α2 adrenergic receptor activation. This HCN channel inhibition represents a novel mechanism underlying the anesthetic and analgesic adjuvant effects of dexmedetomidine in IVRA.Keywords: dexmedetomidine, hyperpolarization-activated cyclic nucleotide-gated channel, intravenous regional anesthesia, lidocaine
