Agbanoma, G.; (2006) An investigation into the actions of Bradykinin receptor antagonists as inhibitors of kallikrein and the generation of kinins within the human nasal airway. Doctoral thesis , University of London.

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Abstract

Intranasal challenge of allergic individuals with allergen causes symptoms of nasal blockage and airway hyper-reactivity (AHR). A group of inflammatory peptides, known as kinins, are synthesised in the nasal airway, in response to challenge with allergen and their production coincides with symptom severity. These effects can be modelled in non-allergic individuals with the inflammatory phospholipid platelet- activating factor (PAF). Antagonism of kinin B2 receptors in vivo reduces the recovery of kinins from the nasal airway of allergic individuals challenged with allergen and non-allergic individuals challenged with PAF, and inhibits AHR in both allergic and non-allergic individuals. In this thesis, the mechanism by which, icatibant, a kinin B2 receptor antagonist, reduces the recovery of kinins from the nasal airway of non-allergic individuals challenged with PAF has been investigated. In addition, the mechanism by which PAF enhances the congestive responses to intranasal challenge with the kinin, bradykinin, and the mast cell-derived mediator, histamine, has been investigated. The effect of various kinin receptor antagonists on the recovery of albumin and kinins, by nasal lavage, from individuals challenged with PAF were determined by ELISA and radioimmunoassay respectively. The effect of various kinin receptor antagonists on the enzyme activity of tissue kallikrein, plasma kallikrein and crude nasal lavage fluid were investigated by spectrophotmetry with the chromogenic substrates S-2266 and S-2302. Nasal blockage was measured objectively using acoustic rhinometry. The data in this thesis has shown that icatibant potently inhibits the recovery of kinins from PAF challenged non-atopic individuals in vivo. This effect does not appear to be dependant on the inhibition of plasma or tissue kallikrein activity, or the antagonism of kinin B2 receptors which control the influx of prekallikrein and kininogen into the nasal airway. In addition, there is evidence to suggest that nerves within the human nasal airway may play a role in PAF-induced AHR.

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