The effect of hyperpolarization-activated cyclic nucleotide-gated ion channel inhibitors on the vagal control of guinea pig airway smooth muscle tone

McGovern, Alice E., Robusto, Jed, Rakoczy, Joanna, Simmons, David G., Phipps, Simon and Mazzone, Stuart B. (2014) The effect of hyperpolarization-activated cyclic nucleotide-gated ion channel inhibitors on the vagal control of guinea pig airway smooth muscle tone. British Journal of Pharmacology, 171 15: 3633-3650. doi:10.1111/bph.12745


Author McGovern, Alice E.
Robusto, Jed
Rakoczy, Joanna
Simmons, David G.
Phipps, Simon
Mazzone, Stuart B.
Title The effect of hyperpolarization-activated cyclic nucleotide-gated ion channel inhibitors on the vagal control of guinea pig airway smooth muscle tone
Journal name British Journal of Pharmacology   Check publisher's open access policy
ISSN 1476-5381
0007-1188
Publication date 2014-08
Year available 2014
Sub-type Article (original research)
DOI 10.1111/bph.12745
Open Access Status
Volume 171
Issue 15
Start page 3633
End page 3650
Total pages 18
Place of publication Chichester, West Sussex, United Kingdom
Publisher John Wiley and Sons
Collection year 2015
Language eng
Formatted abstract
Background and Purpose
Subtypes of the hyperpolarization-activated cyclic nucleotide-gated (HCN) family of cation channels are widely expressed on nerves and smooth muscle cells in many organ systems, where they serve to regulate membrane excitability. Here we have assessed whether HCN channel inhibitors alter the function of airway smooth muscle or the neurons that regulate airway smooth muscle tone.

Experimental Approach
The effects of the HCN channel inhibitors ZD7288, zatebradine and Cs+ were assessed on agonist and nerve stimulation-evoked changes in guinea pig airway smooth muscle tone using tracheal strips in vitro, an innervated tracheal tube preparation ex vivo or in anaesthetized mechanically ventilated guinea pigs in vivo. HCN channel expression in airway nerves was assessed using immunohistochemistry, PCR and in situ hybridization.

Key Results
HCN channel inhibition did not alter airway smooth muscle reactivity in vitro to exogenously administered smooth muscle spasmogens, but significantly potentiated smooth muscle contraction evoked by the sensory nerve stimulant capsaicin and electrical field stimulation of parasympathetic cholinergic postganglionic neurons. Sensory nerve hyperresponsiveness was also evident in in vivo following HCN channel blockade. Cs+, but not ZD7288, potentiated preganglionic nerve-dependent airway contractions and over time induced autorhythmic preganglionic nerve activity, which was not mimicked by inhibitors of potassium channels. HCN channel expression was most evident in vagal sensory ganglia and airway nerve fibres.

Conclusions and Implications
HCN channel inhibitors had a previously unrecognized effect on the neural regulation of airway smooth muscle tone, which may have implications for some patients receiving HCN channel inhibitors for therapeutic purposes.
Keyword Guinea pigs
Ion channel inhibitors
Muscle tone
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Biomedical Sciences Publications
 
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