The mechanism of adenosine 5'-monophosphate (AMP)-induced bronchoconstriction in asthma
The mechanism of adenosine 5'-monophosphate (AMP)-induced bronchoconstriction in asthma
Adenosine, and its nucleotide, adenosine 5'-monophosphate (AMP), cause bronchoconstriction when inhaled by asthmatic and atopic, non-asthmatic subjects. This thesis describes a series of investigations into the mechanism whereby this effect is produced. Three drugs with mast cell membrane stabilising activity, sodium cromoglycate, nedocromil sodium and salbutamol, were found to displace the AMP dose-response curve to the right by 9.6, 22.2 and 26.6-fold respectively in asthmatic subjects. The potent, selective histamine-H1-receptor antagonist terfenadine produced a 16.2-fold rightward displacement of the AMP concentration-response curve in atopic asthmatic subjects, and inhibited the AMP FEV1-time response curve in non-atopic asthmatics by 80.8%. In this latter study, increasing the dose of terfenadine failed to increase the inhibition of the AMP response. In atopic non-asthmatic subjects, bronchoconstriction provoked by AMP and allergen was associated with approximately 2 and 2.5-fold increases respectively in venous plasma histamine concentrations. Bronchoprovocation with AMP did not provoke a late-asthmatic response or an increase in non-specific airways hyperresponsiveness. The cyclooxygenase inhibitor flurbiprofen inhibited the AMP response by 31.9% when expressed in terms of the area under the FEV1-time response curve, but failed to increase the degree of protection provided by terfenadine. Induction of tachyphylaxis to AMP potentiated rather than inhibited the subsequent allergen-provoked early asthmatic reaction. These studies suggest a central role for mast cell histamine release in mediating the AMP response, and probably a smaller contribution from newly generated mediators, notably prostanoids. The possible role of C-fibre neural reflexes is discussed. Bronchoprovocation with AMP may therefore reflect both non-specific airways hyperresponsiveness and the degree of immunological activation of bronchial mast cells.
University of Southampton
1990
Phillips, Gerrard David
(1990)
The mechanism of adenosine 5'-monophosphate (AMP)-induced bronchoconstriction in asthma.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
Adenosine, and its nucleotide, adenosine 5'-monophosphate (AMP), cause bronchoconstriction when inhaled by asthmatic and atopic, non-asthmatic subjects. This thesis describes a series of investigations into the mechanism whereby this effect is produced. Three drugs with mast cell membrane stabilising activity, sodium cromoglycate, nedocromil sodium and salbutamol, were found to displace the AMP dose-response curve to the right by 9.6, 22.2 and 26.6-fold respectively in asthmatic subjects. The potent, selective histamine-H1-receptor antagonist terfenadine produced a 16.2-fold rightward displacement of the AMP concentration-response curve in atopic asthmatic subjects, and inhibited the AMP FEV1-time response curve in non-atopic asthmatics by 80.8%. In this latter study, increasing the dose of terfenadine failed to increase the inhibition of the AMP response. In atopic non-asthmatic subjects, bronchoconstriction provoked by AMP and allergen was associated with approximately 2 and 2.5-fold increases respectively in venous plasma histamine concentrations. Bronchoprovocation with AMP did not provoke a late-asthmatic response or an increase in non-specific airways hyperresponsiveness. The cyclooxygenase inhibitor flurbiprofen inhibited the AMP response by 31.9% when expressed in terms of the area under the FEV1-time response curve, but failed to increase the degree of protection provided by terfenadine. Induction of tachyphylaxis to AMP potentiated rather than inhibited the subsequent allergen-provoked early asthmatic reaction. These studies suggest a central role for mast cell histamine release in mediating the AMP response, and probably a smaller contribution from newly generated mediators, notably prostanoids. The possible role of C-fibre neural reflexes is discussed. Bronchoprovocation with AMP may therefore reflect both non-specific airways hyperresponsiveness and the degree of immunological activation of bronchial mast cells.
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Published date: 1990
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Local EPrints ID: 462049
URI: http://eprints.soton.ac.uk/id/eprint/462049
PURE UUID: 88987dfa-046c-446a-ba10-cc816c82211a
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Date deposited: 04 Jul 2022 19:00
Last modified: 04 Jul 2022 19:00
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Author:
Gerrard David Phillips
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