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

Neuroscience. 2015 Mar 19:289:9-18. doi: 10.1016/j.neuroscience.2014.12.045. Epub 2015 Jan 9.

Abstract

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±9.6μM and 26.1±5.3μM at holding potentials of -80mV and -60mV, respectively. The inhibition of Na(+) channels by DMED was also frequency dependent. 100μM DMED shifted the Na(+) channel inactivation curves to the hyperpolarizing direction by 9.8mV (P<0.01) and slowed the recovery from inactivation by 8.9ms (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±2.4μM 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.

Keywords: dexmedetomidine; nicotinic acetylcholine receptor channel currents.; patch clamp; sodium channel currents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atropine / pharmacology
  • Cells, Cultured
  • Dexmedetomidine / pharmacology*
  • Dose-Response Relationship, Drug
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Membrane Transport Modulators / pharmacology*
  • Neurons / drug effects*
  • Neurons / physiology
  • Patch-Clamp Techniques
  • Phentolamine / pharmacology
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, alpha-2 / metabolism
  • Receptors, Nicotinic / metabolism
  • Sodium Channels / metabolism
  • Superior Cervical Ganglion / drug effects*
  • Superior Cervical Ganglion / physiology
  • Yohimbine / pharmacology

Substances

  • Membrane Transport Modulators
  • Receptors, Adrenergic, alpha-2
  • Receptors, Nicotinic
  • Sodium Channels
  • Yohimbine
  • Dexmedetomidine
  • Atropine
  • Phentolamine