Adenosine and airway calibre in man

Cushley, Michael John (1986) Adenosine and airway calibre in man. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

This thesis investigates the effect of the adenine nucleoside adenosine on airway calibre in man. Antagonism of the effects of endogenous adenosine has been proposed as one mechanism by which methylxanthines, such as theophylline, produce their bronchodilator effect in asthma. However, there have been no previous studies examining the effects of this nucleoside on the airways of man. Where possible, compounds under investigation were given by inhalation to minimise systemic effects. Airway response was measured as specific airways conductance (sGaw) and forced expiratory volume in 1 second (FEV₁). Adenosine produced concentration-dependent bronchoconstriction in asthmatic but not normal subjects. The bronchoconstriction had structural specificity in that it was shared by the adenine nucleotides, adenosine monophosphate (AMP) and adenosine diphosphate (ADP), but not by the principal metabolic product of adenosine, inosine, or a related nucleoside, guanosine. Adenosine-induced bronchoconstriction reached a peak effect within 5 minutes of inhalation of a single dose. There was a good correlation between airway responsiveness to adenosine and that to AMP (r= 0.82), but only a weak correlation between responsiveness to adenosine and histamine (r= 0.64), suggesting that bronchoconstriction induced by adenosine and AMP involves factors other than non-specific hyperreactivity. The mechanism of adenosine's constrictor effect on asthmatic airways is likely to involve a specific interaction with cell surface purinoceptors. This conclusion is drawn from the finding that dipyridamole, which blocks the facilitated uptake of adenosine, potentiated adenosine-induced bronchoconstriction, and theophylline, a competitive adenosine antagonist at external receptor sites, selectively inhibited the airway effects of adenosine. The inhibitory effect of sodium cromoglycate on adenosine-induced bronchoconstriction suggested an effect of adenosine in potentiating mast cell mediator release, but bronchoconstriction induced by adenosine was not associated with the elevation, in venous blood, of the mast cell associated mediators histamine and neutrophil chemotactic activity. The observation that isoprenaline reversed bronchoconstriction induced by adenosine in an identical way to that induced by histamine suggested that adenosine was not causing functional beta blockade. Adenosine is a newly described bronchoconstrictor stimulus in asthma. Its role in the pathogenesis of asthma and the mechanism of action of methylxanthines is discussed. (DX85731)

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