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The effect of hyperpolarization‐activated cyclic nucleotide‐gated ion channel inhibitors on the vagal control of guinea pig airway smooth muscle tone
Author(s) -
McGovern Alice E,
Robusto Jed,
Rakoczy Joanna,
Simmons David G,
Phipps Simon,
Mazzone Stuart B
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12745
Subject(s) - hyperpolarization (physics) , hcn channel , potassium channel , chemistry , muscle contraction , stimulation , medicine , anatomy , neuroscience , endocrinology , biology , ion channel , receptor , organic chemistry , nuclear magnetic resonance spectroscopy
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 ZD 7288, 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 ZD 7288, 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.