The voltage-gated sodium channel NaV1.8 blocker A-803467 inhibits cough in the guinea pig.

Abstract

Cough in respiratory diseases is attributed to the activation of airway C-fibers by inflammation. Inflammatory mediators can act on multiple receptors expressed in airway C-fibers, nonetheless, the action potential initiation in C-fibers depends on a limited number of voltage-gated sodium channel (NaV1) subtypes. We have recently demonstrated that NaV1.8 substantially contributes to the action potential initiation in the airway C-fiber subtype implicated in cough. We therefore hypothesized that the NaV1.8 blocker A-803467 inhibits cough. We evaluated the cough evoked by the inhalation of C-fiber activator capsaicin in awake guinea pigs. Compared to vehicle, intraperitoneal or inhaled A-803467 caused 30-50% inhibition of cough at the doses that did not alter respiratory rate. We conclude that the NaV1.8 blocker A-803467 inhibits cough in a manner consistent with its action on the C-fiber nerve terminals in the airways. Targeting voltage-gated sodium channels mediating action potential initiation in airway C-fibers may offer a means of cough inhibition that is independent of the stimulus.

• Authors: M Brozmanova, S Svajdova, N Pavelkova, Y Muroi, B J Undem, M Kollarik
• Journal: Respiratory physiology & neurobiology (Respir Physiol Neurobiol) Vol. 270 Pg. 103267 (12 2019) ISSN: 1878-1519 [Electronic] Netherlands
• PMID: 31398537 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019. Published by Elsevier B.V.

Chemical References

• A 803467
• Aniline Compounds
• Antitussive Agents
• Furans
• NAV1.8 Voltage-Gated Sodium Channel
• Sodium Channel Blockers

Topics

• Action Potentials (drug effects)
• Administration, Inhalation
• Aniline Compounds (adverse effects, therapeutic use)
• Animals
• Antitussive Agents (adverse effects, therapeutic use)
• Bronchi (innervation)
• Cough (drug therapy)
• Dose-Response Relationship, Drug
• Furans (adverse effects, therapeutic use)
• Guinea Pigs
• Injections, Intraperitoneal
• Lung (innervation)
• Male
• NAV1.8 Voltage-Gated Sodium Channel (drug effects)
• Nerve Fibers, Unmyelinated (drug effects)
• Presynaptic Terminals (drug effects)
• Sodium Channel Blockers (adverse effects, therapeutic use)