TIME-COURSE OF CHANGES IN ADENOSINE 5'-MONOPHOSPHATE AIRWAY RESPONSIVENESS WITH INHALED HEPARIN IN ALLERGIC-ASTHMA

Background: Recent studies have shown that inhaled heparin exerts a pr otective effect against various bronchoconstrictor stimuli in asthma, possible through an inhibition of mast cell activation. Objective: Bec ause adenosine 5'-monophosphate (AMP) elicits bronchoconstriction by a ugmenting mast cell mediator release, we have investigated the effect of inhaled heparin (15,000 units USP/ml, 4 mi) on the bronchoconstrict or response to this agonist and to methacholine in a randomized, doubl e-blind, placebo-controlled study of 10 subjects with asthma. We also carried out a separate randomized, double-blind study in seven additio nal volunteers with asthma to examine in more detail the time-course o f change in bronchial reactivity to inhaled AMP after treatment with n ebulized heparin. Results: Inhaled heparin significantly increased the provocative concentration of AMP causing a 20% decrease in forced exp iratory volume in 1 second (PC(20)FEV(1)-AMP) from the postplacebo tre atment value of 22.3 mg/ml (range, 5.7 to 68.9 mg/ml) to 48.1 mg/ml (r ange, 5.1 196.8 mg/ml) (p < 0.01). When compared with placebo, inhaled heparin failed to alter the airway responsiveness to methacholine; th e 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 placeb o administration, the PC20 AMP values at 15, 60, and 180 minutes did n ot 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 m g/ml) and to 52.7 mg/ml (13.9 to 90.8 mg/ml) at 15 minutes and 60 minu tes, respectively. At 180 minutes, inhaled heparin failed to affect AM P 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). Conclusion: Heparin administered by inhalation is effective in attenua ting the airway response to AMP but not to methacholine. The time cour se of change in bronchial reactivity to AMP has a peak effect at 15 mi nutes 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.