The Effects Of Dexmedetomidine On Sodium Channels And Nicotinic Acetylcholine Receptor Channels Currents In Rat Superior Cervical Ganglion Neurons

Background:Dexmedetomidine (DMED), a highly selective a2-adrenoceptor agonist, is widely used for its sedation and analgesia. However, the fact that the drug frequently produces hypotension and bradycardia are issues that must be considered with its use. It was found DMED acts similarly as sympathetic ganglionic blockers, which inhibits norepinephrine release from sympathetic nerves. This inhibition maybe plays an alternative role in hypotension and bradycardia of DMED. To address its mechanisms, we made in vitro recordings of sodium currents (INa) and nicotinic acetylcholine receptor channel currents (IAChRs) in rat superior cervical ganglion (SCG) neurons and examined their responses to DMED.Methods:Neurons were enzymatically isolated from 6-10 day-old Sprague-Dawley rats’superior cervical ganglion (SCG). We examined the effects of DMED on the activities of sodium channels and acetycholine receptor channels. Each experiment was recorded from 5-10 neurons.Results:DMED concentration and voltage-dependently suppressed INa. with half maximal inhibitory concentration (IC50) values of 67.15±9.57 μM and 26.09±5.34 μM at holding potentials of -80 mV and -60 mV, respectively. At a concentration of 100 μM, DEX shifted the sodium channel inactivation curve to the hyperpolarizing direction by 9.77 mV (P<0.01). Inhibition of sodium channels by 10 Hz pulse stimulations was much more robust than 0.5 Hz stimulation, with relative peak amplitudes from 20th currents having values of 87.32±3.27% and 76.90±4.07% (P<0.001). Yohimbine, phentolamine, and H-89 pretreatment did not alter the inhibitory effects of DMED on INa and IAhRs.DMED dose-dependently inhibited IAChRs with an IC50 value of 6.56±1.20 μM in SCG neurons, and this inhibition was voltage-independent. DMED pretreatment caused a significantly larger IAChRs inhibition than fast co-application of DMED and acetylcholine (69.40±7.25% VS 39.87±9.51%,P<0.001).Conclusions:DMED directly inhibits INa and IAChRs in rat SCG neurons. The inhibition of INa is dose-, voltage-dependent; the inhibition of IAChRs is dose-dependent, but voltage-independent. Both mechanisms of inhibition are a2-adrenoceptor and PKA-independent. In SCG neurons inhibits sodium channels by preferential binding to the inactivated state of the sodium channels and by preferential binding to the closed state (resting state) of nAChR channels. nAChRs channels in rat SCG neurons were more sensitive to inhibition by than sodium channels. These results indicate that inhibitory effects on INa, especial IAChRs constitute one of the underlying mechanisms through which DMED might affect norepinephrine release from sympathetic nerves in vivo and cause hypotension and bradycardia.