TY - JOUR
T1 - Comparison of TRPA1-versus TRPV1-mediated cough in guinea pigs
AU - Brozmanova, Mariana
AU - Mazurova, Lenka
AU - Ru, Fei
AU - Tatar, Milos
AU - Kollarik, Marian
N1 - Funding Information:
This work was supported by CEVYPET (EU) and CEKR (EU) . M.T. is supported by the Department of Health (Slovakia) Grant 2007/54-UK-15 . M.K. is supported by DK074480 and HL062296 .
PY - 2012/8/15
Y1 - 2012/8/15
N2 - TRPA1 receptor is activated by endogenous inflammatory mediators and exogenous pollutant molecules relevant to respiratory diseases. Previous studies have implicated TRPA1 as a drug target for antitussive therapy. Here we evaluated the relative efficacy of TRPA1 activation to evoke cough. In conscious guinea pigs the TRPA1 agonist allyl-isothiocyanate (AITC) evoked cough with a maximally effective concentration of 10 mM that was abolished by the selective TRPA1 antagonist AP-18. AITC (10 mM) was approximately 3-times less effective in inducing cough than capsaicin (50 μM). Ex vivo single fiber extracellular recordings revealed that, similarly to capsaicin, AITC evoked activation in airway jugular C-fibers, but not in airway nodose Aδ-fibers. Consistent with the cough studies, AITC was approximately 3-times less effective than capsaicin in evoking sustained activation of the jugular C-fibers. Another TRPA1 agonist, cinnamaldehyde, was approximately twofold more effective than AITC in inducing cough. However, the cinnamaldehyde (10 mM)-induced cough was only partially inhibited by the TRPA1 antagonist AP-18, and was abolished by combination of AP-18 and the TRPV1 antagonist I-RTX. We conclude that in naïve guinea pigs, TRPA1 activation initiates cough that is relatively modest compared to the cough initiated by TRPV1, likely due to lower efficacy of TRPA1 stimulation to induce sustained activation of airway C-fibers.
AB - TRPA1 receptor is activated by endogenous inflammatory mediators and exogenous pollutant molecules relevant to respiratory diseases. Previous studies have implicated TRPA1 as a drug target for antitussive therapy. Here we evaluated the relative efficacy of TRPA1 activation to evoke cough. In conscious guinea pigs the TRPA1 agonist allyl-isothiocyanate (AITC) evoked cough with a maximally effective concentration of 10 mM that was abolished by the selective TRPA1 antagonist AP-18. AITC (10 mM) was approximately 3-times less effective in inducing cough than capsaicin (50 μM). Ex vivo single fiber extracellular recordings revealed that, similarly to capsaicin, AITC evoked activation in airway jugular C-fibers, but not in airway nodose Aδ-fibers. Consistent with the cough studies, AITC was approximately 3-times less effective than capsaicin in evoking sustained activation of the jugular C-fibers. Another TRPA1 agonist, cinnamaldehyde, was approximately twofold more effective than AITC in inducing cough. However, the cinnamaldehyde (10 mM)-induced cough was only partially inhibited by the TRPA1 antagonist AP-18, and was abolished by combination of AP-18 and the TRPV1 antagonist I-RTX. We conclude that in naïve guinea pigs, TRPA1 activation initiates cough that is relatively modest compared to the cough initiated by TRPV1, likely due to lower efficacy of TRPA1 stimulation to induce sustained activation of airway C-fibers.
KW - Airway C-fiber
KW - Allyl-isothiocyanate
KW - Capsaicin
KW - Cinnamaldehyde
KW - Cough
KW - TRPA1
KW - TRPV1
KW - Vagus nerve
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U2 - 10.1016/j.ejphar.2012.05.048
DO - 10.1016/j.ejphar.2012.05.048
M3 - Article
C2 - 22683866
AN - SCOPUS:84864288800
SN - 0014-2999
VL - 689
SP - 211
EP - 218
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -