Heparin has been shown to act as a competitive inhibitor of inositol 1,4,5-triphosphate (InsP3) receptors in various cell types. Because InsP3 is one of the second messengers involved in stimulus-secretion coupling in mast cells, it is possible that heparin may inhibit mast cell-mediated reactions. Therefore, in allergic sheep, we tested this hypothesis in two mast cell-mediated reactions induced by immunologic and nonimmunologic stimuli: immediate cutaneous reaction (ICR) and acute bronchoconstrictor response (ABR). In 12 sheep allergic to Ascaris suum antigen, the surface area of the skin wheal was determined 20 min after intradermal injection (0.05 ml) of increasing concentrations of specific antigen, compound 48/80, and histamine, without and after pretreatment with heparin (100, 300, or 1,000 U/kg i.v.). Antigen, compound 48/80, and histamine produced concentration-dependent increases in ICR. Heparin "partially" inhibited the ICR to antigen and compound 48/80 in a dose-dependent manner without modifying the ICR to histamine. The heparin preservative benzyl alcohol was ineffective. In 11 additional sheep, specific lung resistance was measured before and after inhalation challenges with antigen, compound 48/80, and histamine without and with aerosol heparin pretreatment (1,000 U/kg). Heparin blocked the antigen- and compound 48/80-induced bronchoconstriction without modifying the airway effects of histamine. In isolated human uterine mast cells, heparin inhibited the anti-immunoglobulin E- but not the calcium ionophore- (A23187) induced histamine release. These data suggest that heparin inhibits the ICR and ABR induced by stimuli that produce immunologic and nonimmunologic mast cell degranulation without attenuating the effects of histamine.(ABSTRACT TRUNCATED AT 250 WORDS)

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 < or = 20 min, 6 h, 12 h, and 24 h and 2) intravenous heparin (1,000 U/kg) administered < or = 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; delta sRL was 31 +/- 29, 99 +/- 38, 142 +/- 40, and 306 +/- 60% for < or = 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: delta sRL was 246 +/- 64, 66 +/- 26, and 76 +/- 32% for < or = 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.(ABSTRACT TRUNCATED AT 250 WORDS)

In preliminary studies we have observed that inhaled heparin blocks antigen-induced airway responses in sheep that develop only acute responses to inhaled antigen (acute responders), but not in sheep that develop both acute and later responses (dual responders). Because heparin is an antagonist of inositol triphosphate (IP3) (one of the pathways involved in stimulus-secretion-coupling in mast cells), the differential effect of inhaled heparin in acute responders and dual responders might indicate the involvement of different signaling pathways during IgE-mediated mast cell reactions. Therefore, in this study we compared the effects of heparin on antigen-induced bronchconstriction, allergic cutaneous reaction, and histamine release into bronchoalveolar lavage fluid (BAL) in sheep that develop only acute responses or dual responses to inhaled Ascaris suum antigen. Specific lung resistance (SRL) was measured in 21 sheep (eight acute responders; 13 dual responders) before and after inhalation challenge with antigen, without and after pretreatment with inhaled heparin (1,000 units/kg). Histamine in BAL was measured by RIA before and after segmental antigen challenge, without and after pretreatment with inhaled heparin (eight acute responders; eight dual responders). In acute responders, mean +/- SE SRL increased by 197 +/- 21% with antigen; this was prevented by inhaled heparin (deltaSRL = 15 +/- 7%; p < 0.05). In dual responders, inhaled heparin had no effect on antigen-induced early (deltaSRL = 328 +/- 51% versus 305 +/- 76%) or late (deltaSRL = 201 +/- 33% versus 163 +/- 15%) responses. After segmental antigen challenge, BAL mean +/- SE histamine increased from 2.09 +/- 0.8 nM to 75.4 +/- 21.1 nM in acute responders and 1.58 +/- 0.7 nM to 66.8 +/- 27.3 nM in dual responders (p < 0.01). Inhaled heparin inhibited the increase in BAL histamine by 81% in acute responders (p < 0.05) and by only 19% in dual responders (p = NS). As was seen in the airways, heparin attenuated the allergic cutaneous reaction in acute responders by 46% (p < 0.05), but it was ineffective in dual responders. In contrast, H-7, a nonspecific protein kinase C inhibitor, attenuated the cutaneous reaction in dual responders by 28% (p < 0.05), but it was ineffective in acute responders. These data suggest that heterogeneity of allergic airway response is related to difference in mast cell signal transduction; IP3 is the predominant second messenger in acute responders, whereas non-IP3 pathways may be involved in dual responders.

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