Bradykinin-evoked sensitization of airway sensory nerves: a mechanism for ACE-inhibitor cough.
Cough accompanied by an increased sensitivity of the cough reflex is the most common symptom of inflammatory airway disease. This symptom is also frequently reported in patients receiving angiotensin-converting enzyme (ACE) inhibitors as therapy for heart failure or hypertension, 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 enhancement of the cough reflex in conscious guinea pigs. Treatment of guinea pigs for two weeks with captopril led to an increased cough response to inhaled citric acid, which was prevented by concomitant treatment with the bradykinin receptor antagonist icatibant. A similar icatibant-sensitive enhancement of citric acid-evoked cough was seen in untreated animals after prior inhalation of bradykinin, although cough evoked by hypertonic saline was unaffected. In electrophysiological studies performed in vitro, responses of single vagal C fibers to capsaicin, applied to receptive fields of single-fiber units in the trachea, were also markedly increased after perfusion with bradykinin, whereas A delta fiber responses to hypertonic saline were unaffected. These results indicate that bradykinin-evoked sensitization of airway sensory nerves may underlie the pathogenesis of ACE-inhibitor cough. Bradykinin receptor antagonists may be of benefit in treating chronic cough seen with this and other inflammatory conditions.
Fox
A J
AJ
Department of Thoracic Medicine, National Heart & Lung Institute, London, UK.
Lalloo
U G
UG
Belvisi
M G
MG
Bernareggi
M
M
Chung
K F
KF
Barnes
P J
PJ
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000187:drug effects / Q000494:pharmacology / Q000502:physiology*; D065168:Bradykinin Receptor Antagonists; D002216:Captopril / Q000009:adverse effects* / Q000494:pharmacology; D003371:Cough / Q000139:chemically induced* / Q000517:prevention & control; D006168:Guinea Pigs; D008297:Male; D043782:Receptor, Bradykinin B2; D014132:Trachea / Q000187:drug effects / Q000294:innervation* / Q000502:physiology
D000806:Angiotensin-Converting Enzyme Inhibitors; D065168:Bradykinin Receptor Antagonists; D043782:Receptor, Bradykinin B2; C065679:icatibant; D002216:Captopril; D001920:Bradykinin