Inhibition of tetrodotoxin (TTX)-resistant and TTX-sensitive neuronal Na(+) channels by the secretolytic ambroxol

Mol Pharmacol. 2002 Sep;62(3):433-8. doi: 10.1124/mol.62.3.433.

Abstract

Ambroxol has a long history for the treatment of airway diseases because of its beneficial effects on surfactant synthesis and mucus-modifying properties. Some findings, however, point to an additional effect on neuronal signal transduction: ambroxol can suppress reflexes such as the cough or the corneal reflex. The airways and the cornea are innervated by C-fibers, which express voltage-gated Na(+) channels with and without sensitivity to tetrodotoxin (TTX). In this study, we performed voltage-clamp experiments to investigate whether ambroxol affects these channel types. In rat dorsal root ganglia, TTX-resistant Na(+) currents were suppressed in a concentration-dependent manner with IC(50) values of 35.2 and 22.5 microM for tonic and phasic block, respectively. Depolarizing prepulses increased the potency of ambroxol, and steady-state inhibition curves were shifted to more negative values. The inhibition was not frequency-dependent. TTX-sensitive currents were inhibited with lower potency (approximately 50% inhibition with 100 microM). Recombinant rat brain IIA channels in Chinese hamster ovary cells were blocked with IC(50) values of 111.5 and 57.6 microM for tonic and phasic block, respectively; in contrast to TTX-resistant channels the block was frequency-dependent. Thus, ambroxol indeed blocks neuronal voltage-gated Na(+) channels, and TTX-resistant channels in sensory neurons were more sensitive than TTX-sensitive. Compared with known local anesthetics (e.g., lidocaine or benzocaine), the potency for Na(+) channel block was relatively high. A recent clinical trial has further confirmed that ambroxol relieved pain and was beneficial in patients who suffered from sore throat.

MeSH terms

  • Ambroxol / pharmacology*
  • Anesthetics, Local / pharmacology
  • Animals
  • Electrophysiology
  • Expectorants / pharmacology*
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism
  • Patch-Clamp Techniques
  • Rats
  • Rats, Wistar
  • Sodium Channel Blockers*
  • Sodium Channels / physiology
  • Tetrodotoxin / pharmacology*
  • Transfection

Substances

  • Anesthetics, Local
  • Expectorants
  • Sodium Channel Blockers
  • Sodium Channels
  • Ambroxol
  • Tetrodotoxin