INHIBITION OF ANTIGEN-INDUCED AIRWAY AND CUTANEOUS RESPONSES BY HEPARIN - A PHARMACODYNAMIC STUDY

We have previously shown that heparin attenuates the acute bronchoconstrictor response and immediate cutaneous reaction (ICR) to antigen in allergic sheep. In the present investigation, we studied the pharmacodynamics of the antiallergic action of heparin. Specific lung resistance (sRL) was measured in eight sheep, allergic to Ascaris suum antigen, before and 5 min after inhalation challenge with the antigen. On different experiment days, antigen challenge was repeated after pretreatment with 1) aerosol heparin (1,000 U/kg) administered less-than-or-equal-to 20 min, 6 h, 12 h, and 24 h and 2) intravenous heparin (1,000 U/kg) administered less-than-or-equal-to 20 min, 1 h, 6 h, and 12 h before antigen challenge. sRL increased by 374 +/- 116% (SE) above baseline with antigen alone. Both aerosol and intravenous heparin attenuated the antigen effects on sRL in a time-dependent fashion. Prolonging the lag time between pretreatment and antigen challenge decreased the inhibitory effect of aerosol heparin; DELTAsRL was 31 +/- 29, 99 +/- 38, 142 +/- 40, and 306 +/- 60% for less-than-or-equal-to 20-min, 6-h, 12-h, and 24-h pretreatment protocols, respectively. In contrast, prolonging the lag time increased the inhibitory effect of intravenous heparin: DELTAsRL was 246 +/- 64, 66 +/- 26, and 76 +/- 32% for less-than-or-equal-to 20 min, 1 h, and 6 h, respectively. In seven additional sheep pretreatment with intravenous heparin (1,000 U/kg) attenuated the ICR also in a time-dependent manner; the inhibitory effect of heparin on ICR to antigen was enhanced 60% by increasing the heparin pretreatment interval from 20 to 60 min. Finally, heparin inhibited anti-immunoglobulin E-mediated histamine release and mast cell degranulation from isolated human uterine mast cells and rat peritoneal mast cells to a greater extent, after a heparin preincubation time of 60 min than after 20 min. We conclude that the antiallergic effects of heparin are time dependent and that the time dependence is influenced by the route of administration.