Alpha2-adrenoceptor-independent inhibition of acetylcholine receptor channel and sodium channel by dexmedetomidine in rat superior cervical ganglion neurons

• DMED inhibits INa and IACh through an a2-adrenoceptor-independent pathway.
• DMED inhibits INa by binding to the inactivated state of Na+ channels.
• DMED inhibits IACh by binding to the resting state of nAChRs channels.

Both central and peripheral sympathetic nervous systems contribute to the cardiovascular effects of dexmedetomidine (DMED), a highly selective and widely used a2-adrenoceptor agonist for sedation, analgesia, and stress management. The central sympatholytic effects are augmented by peripheral inhibition of sympathetic ganglion transmission. The mechanism is not clear. In this research, using conventional patch-clamp recordings we investigated the direct effects of DMED on sodium (Na+) channel currents (INa) and nicotinic acetylcholine (ACh) receptor (nAChRs) channel currents (IACh) in rat superior cervical ganglion (SCG) neurons to explore the possible mechanisms of sympathetic ganglion transmission inhibition by DMED. DMED voltage-dependently suppressed INa with half maximal inhibitory concentration (IC50) values of 67.2 ± 9.6 μM and 26.1 ± 5.3 μM at holding potentials of −80 mV and −60 mV, respectively. The inhibition of Na+ channels by DMED was also frequency dependent. 100 μM DMED shifted the Na+ channel inactivation curves to the hyperpolarizing direction by 9.8 mV (P < 0.01) and slowed the recovery from inactivation by 8.9 ms (P < 0.01), but no effects were seen on the shape of the current–voltage relationship or Na+ channels activation curves. DMED dose-dependently inhibited IACh with an IC50 value of 5.5 ± 2.4 μM in SCG neurons, and this inhibition was voltage-independent. DMED pretreatment followed by fast co-application of DMED and ACh produced a significantly larger IACh inhibition than without DMED pretreatment. Yohimbine, phentolamine, and atropine pretreatment did not alter the inhibitory effects of DMED on INa and IACh.In conclusion, DMED dose-dependently inhibits INa and IACh in rat SCG neurons by preferential binding to the inactivated state of the Na+ channels and the closed state (resting) of nAChR channels respectively. Both inhibitions are a2-adrenoceptor independent. Furthermore, the nAChR channels in rat SCG neurons are much more sensitive to inhibition by DMED than Na+ channels.