Time course of changes in adenosine 5'-monophosphate airway responsiveness with inhaled heparin in allergic asthma

Recent studies have shown that inhaled heparin exerts a protective effect against various bronchoconstrictor stimuli in asthma, possible through an inhibition of mast cell activation.

Because adenosine 5'-monophosphate (AMP) elicits bronchoconstriction by augmenting mast cell mediator release, we have investigated the effect of inhaled heparin (15,000 units USP/ml, 4 ml) on the bronchoconstrictor response to this agonist and to methacholine in a randomized, double-blind, placebo-controlled study of 10 subjects with asthma. We also carried out a separate randomized, double-blind study in seven additional volunteers with asthma to examine in more detail the time-course of change in bronchial reactivity to inhaled AMP after treatment with nebulized heparin.

Inhaled heparin significantly increased the provocative concentration of AMP causing a 20% decrease in forced expiratory volume in 1 second (PC20 FEV1-AMP) from the postplacebo treatment value of 22.3 mg/ml (range, 5.7 to 68.9 mg/ml) to 48.1 mg/ml (range, 5.1-196.8 mg/ml) (p < 0.01). When compared with placebo, inhaled heparin failed to alter the airway responsiveness to methacholine; the mean (range) PC20 methacholine values were 1.00 mg/ml (0.44 to 4.76 mg/ml) and 1.08 mg/ml (0.46 to 5.08 mg/ml), respectively. After placebo administration, the PC20 AMP values at 15, 60, and 180 minutes did not differ significantly from each other; their geometric mean (range) values were 26.1 mg/ml (5.9 to 85.8 mg/ml), 26.6 mg/ml (6.3 to 87.8 mg/ml), and 24.9 mg/ml (5.2 to 80.2 mg/ml), respectively. When compared with placebo, the PC20 values for AMP after administration of inhaled heparin were significantly increased up to 57.3 mg/ml (14.7 to 176.0 mg/ml) and to 52.7 mg/ml (13.9 to 90.8 mg/ml) at 15 minutes and 60 minutes, respectively. At 180 minutes, inhaled heparin failed to affect AMP airway responsiveness; the PC20 AMP was not significantly different from that of placebo, with a value of 30.6 mg/ml (4.8 to 93.3 mg/ml).

Heparin administered by inhalation is effective in attenuating the airway response to AMP but not to methacholine. The time course of change in bronchial reactivity to AMP has a peak effect at 15 minutes and lasts up to 60 minutes. It is possible that the mechanism(s) underlying the protective effects of inhaled heparin in asthma may be related to an inhibitory modulation of mast cell activation.