Bradykinin sensitizes the cough reflex via a B2 receptor dependent activation of TRPV1 and TRPA1 channels through metabolites of cyclooxygenase and 12-lipoxygenase

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Abstract

Background: Inhaled bradykinin (BK) has been reported to both sensitize and induce cough but whether BK can centrally sensitize the cough reflex is not fully established. In this study, using a conscious guinea-pig model of cough, we investigated the role of BK in the central sensitization of the cough reflex and in airway obstruction. Methods: Drugs were administered, to guinea pigs, by the intracerebroventricular (i.c.v.) route. Aerosolized citric acid (0.2 M) was used to induce cough in a whole-body plethysmograph box, following i.c.v. infusion of drugs. An automated analyser recorded both cough and airway obstruction simultaneously. Results: BK, administered by the i.c.v. route, dose-dependently enhanced the citric acid-induced cough and airway obstruction. This effect was inhibited following i.c.v. pretreatment with a B2 receptor antagonist, TRPV1 and TRPA1 channels antagonists and cyclooxygenase (COX) and 12-lipoxygenase (12-LOX) inhibitors. Furthermore, co-administration of submaximal doses of the TRPV1 and TRPA1 antagonists or the COX and 12-LOX inhibitors resulted in a greater inhibition of both cough reflex and airway obstruction. Conclusions: Our findings show that central BK administration sensitizes cough and enhances airway obstruction via a B2 receptor/TRPV1 and/or TRPA1 channels which are coupled via metabolites of COX and/or 12-LOX enzymes. In addition, combined blockade of TRPV1 and TRPA1 or COX and 12-LOX resulted in a greater inhibitory effect of both cough and airway obstruction. These results indicate that central B2 receptors, TRPV1/TRPA1 channels and COX/12-LOX enzymes may represent potential therapeutic targets for the treatment of cough hypersensitivity. Graphical abstract: [Figure not available: see fulltext.]

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APA

Al-Shamlan, F., & El-Hashim, A. Z. (2019). Bradykinin sensitizes the cough reflex via a B2 receptor dependent activation of TRPV1 and TRPA1 channels through metabolites of cyclooxygenase and 12-lipoxygenase. Respiratory Research, 20(1). https://doi.org/10.1186/s12931-019-1060-8

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