The combined effects of two pairs of mediators, adenosine with methacholine and prostaglandin D2 with histamine, on airway calibre in asthma

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Abstract
1. Mediators released from mast cells and secondary effector cells in the airways contribute to bronchoconstriction of allergic asthma. This study investigates methods for defining the effect of two inflammatory mediators on airway calibre in asthma. 2. In an initial study on three asthmatic subjects, subconstrictor (subthreshold) concentrations of two mast cell derived mediators, histamine and prostaglandin (PG) D2, produced similar displacement to the left of a histamine concentration-specific airways conductance (sGaw) response curve. With both agonists enhancement of histamine-induced bronchoconstriction was greater at low histamine concentrations. Since potentiation of histamine-induced bronchoconstriction was independent of the class of subconstrictor agent given, it is likely to represent a physiological rather than a pharmacological interaction. 3. During provoked asthma different constrictor mediators are likely to be released simultaneously into the airways. A method was therefore devised to investigate the combined effect of equiconstrictor concentrations of two mediators on airway calibre. 4. Two pairs of inhaled bronchoconstrictor agonists were chosen for study: adenosine with methacholine and PGD2 with histamine. For each agonist, concentration-sGaw response curves were constructed, from which were derived the provocation concentrations of agonist causing a 25% fall in sGaw from baseline (PC25) and required to further this to 50% (PC50-25). 5. On separate days, eight subjects received paired inhalations of methacholine-adenosine, methacholine-methacholine and adenosine-adenosine. The concentration used for the first inhalation was the PC25 value and for the sec and inhalation the PC50-25 value. Before immediately after the first inhalation, and at regular intervals after the second inhalation, sGaw was followed for 30 min. In seven subjects the study was repeated, replacing methacholine with PGD2 and adenosine with histamine. 6. When methacholine was combined with adenosine, and PGD2 was combined with histamine the maximum falls in sGaw and rates of recovery after inhalation of the second mediator were not statistically different from those values observed with paired inhalations of the same mediators. 7. Thus, employing pharmacologically active concentrations of two pairs of constrictor mediators, which act through separate receptor mechanisms, we have been unable to demonstrate any pharmacological interaction on airway calibre in asthma.