Bradykinin–evoked sensitization of airway sensory nerves: A mechanism for ACE–inhibitor cough

  title={Bradykinin–evoked sensitization of airway sensory nerves: A mechanism for ACE–inhibitor cough},
  author={Alyson J. Fox and Umesh G. Lalloo and Maria G. Belvisi and Micaela Maria Bernareggi and Kian Fan Chung and Peter John Barnes},
  journal={Nature Medicine},
Cough accompanied by an increased sensitivity of the cough reflex is the most common symptom of inflammatory airway disease1,5. This symptom is also frequently reported in patients receiving angiotensin–converting enzyme (ACE) inhibitors as therapy for heart failure or hypertension2–4, although the underlying mechanism is unknown. We have investigated the possibility that the inflammatory peptide bradykinin, normally degraded by ACE, causes sensitization of airway sensory nerves and an… 

Pharmacology of Bradykinin-Evoked Coughing in Guinea Pigs

The data suggest that bradykinin induces coughing in guinea pigs by activating B2 receptors on bronchopulmonary C-fibers, and it is speculated that therapeutics targeting the actions of bradykinsin may prove useful in the treatment of cough.

Role of bradykinin and tachykinins in the potentiation by enalapril of coughing induced by citric acid in pigs

Data suggest that ACE‐inhibitor‐induced enhancement of the cough reflex is mainly due to tachykinins and not to bradykinin in the authors' pig model, suggesting that Bradykinin plays a major role in coughing induced by citric acid alone.

Interaction of noscapine with the bradykinin mediation of the cough response.

Noscapine is shown to be a non-competitive inhibitor of bradykinin in guinea pig ileum and it is possible that noscapine suppresses cough by blocking the effect of bradaykinin receptor activation in the airways.

Protease-activated receptor-2 activation exaggerates TRPV1-mediated cough in guinea pigs.

Par2 activation, by sensitizing TRPV1 in primary sensory neurons, may play a role in the exaggerated cough observed in certain airways inflammatory diseases such as asthma and chronic obstructive pulmonary disease.

Bradykinin‐evoked sensitization of neuropeptide release from afferent neurons in the guinea‐pig lung

The results suggest that BK‐induced stimulation of prostaglandin synthesis results in facilitation of histamine–evoked release of pro‐inflammatory neuropeptides from afferent neurons, a mechanism that probably becomes relevant during inflammation, and that can be blocked by a bradykinin B2 receptor antagonist.

Mechanistic studies of acid-evoked coughing in anesthetized guinea pigs.

  • B. CanningD. FarmerN. Mori
  • Biology, Medicine
    American journal of physiology. Regulatory, integrative and comparative physiology
  • 2006
The mechanisms of citric acid-evoked coughing in anesthetized guinea pigs are characterized and data indicate that coughing evoked by acid is mediated by direct activation of capsaicin-insensitive vagal afferent nerves, perhaps through sequential activation of acid-sensing ion channels and chloride channels.

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

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.

Activation of large conductance potassium channels inhibits the afferent and efferent function of airway sensory nerves in the guinea pig.

Data show that BK Ca channel activation inhibits sensory nerve activity, resulting in a reduction of both afferent and efferent function, and BKCa channel openers may be of potential benefit in reducing neurogenic inflammation and central reflexes seen during inflammatory conditions of the airways.



Capsazepine inhibits cough induced by capsaicin and citric acid but not by hypertonic saline in guinea pigs.

The data show that capsazepine is a specific inhibitor of Cap- and CA-induced cough in guinea pigs, and suggest that low pH stimuli evoke cough and nasal irritation by an action at the Cap receptor, either directly or through the release of an intermediate agent.

Neurophysiology of the cough reflex.

  • J. Widdicombe
  • Biology, Medicine
    The European respiratory journal
  • 1995
The sensitivity of the cough reflex and its pattern of response is due to a complex interaction between C-fibre receptors and rapidly adapting receptors, with peripheral and central nervous interactions.

Effects of aerosol‐applied capsaicin, histamine and prostaglandin E2 on airway sensory receptors of anaesthetized cats.

It is concluded that solutions of capsaicin and PGE2, when delivered by aerosol to the airway epithelial surface, are not selective stimulants of C fibres, and Stimulation of airway RARs by a range of pharmacologically active agents released by airway inflammation may contribute to reflex coughing and bronchoconstriction in man.

Bronchial hyperreactivity in patients who cough after receiving angiotensin converting enzyme inhibitors

Cough associated with converting enzyme inhibitors may be a variant of the cough in asthma and bronchial hyperactivity increased after rechallenge with the inhibitors.

Abnormal intraepithelial airway nerves in persistent unexplained cough?

Abnormal intraepithelial airway nerves containing increased quantities of CGRP are present in patients with idiopathic PNPC, and total nerve density (PGP-9.5 immunoreactivity) was greater in P than C, although this was not significant.

Afferent neural pathways in cough and reflex bronchoconstriction.

Cough and bronchoconstriction are airway reflexes that protect the lung from inspired noxious agents and may be mediated by the same type of receptor, they seem to have separate afferent neural pathways.