Effects of inhaled heparin on immunologic and nonimmunologic bronchoconstrictor responses in sheep.
The glycosaminoglycan heparin has been shown to block inositol triphosphate (IP3) receptors in various tissues. Because IP3 is one of the pathways involved in stimulus-secretion coupling in mast cells, it is possible that heparin may inhibit airway anaphylaxis. Thus, the purpose of the present investigation was to study the effect of inhaled heparin on immunologically and nonimmunologically induced bronchoconstriction in allergic sheep. Specific lung resistance (SRL) was measured in 15 sheep allergic to Ascaris suum antigen, before and after inhalation challenge with the specific antigen, compound 48/80, histamine, and carbachol. On a different day, the animals were pretreated with inhaled heparin and airway challenges with the antigen and agonists were repeated. Antigen alone increased SRL by 367 +/- 119% (mean +/- SE) above baseline (p less than 0.05). Inhaled heparin had no effect on baseline SRL, but attenuated antigen-induced bronchoconstriction in a dose-dependent fashion: mean SRL increased by 313 +/- 87, 151 +/- 69, and 24 +/- 20% above baseline with 100, 300, and 1,000 U/kg of heparin, respectively. Inhaled benzyl alcohol preservative, dextran sulfate, and de-N-sulfated heparin failed to inhibit antigen-induced bronchoconstriction. The dose of heparin (1,000 U/kg) that completely blocked antigen-induced bronchoconstriction also attenuated the bronchoconstriction induced by compound 48/80 (delta SRL = 374 +/- 72 versus 35 +/- 12%), but failed to block the bronchoconstrictor effects of histamine and carbachol. These data suggest that inhaled heparin prevents bronchoconstrictor responses induced by by stimuli that produce immunologic and nonimmunologic mast-cell degranulation in sheep, without attenuating agonist-induced bronchoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)
Ahmed
T
T
Division of Pulmonary Disease, University of Miami School of Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140.
Abraham
W M
WM
D'Brot
J
J
D000280:Administration, Inhalation; D000336:Aerosols; D000403:Airway Resistance / Q000187:drug effects / Q000276:immunology; D000818:Animals; D000947:Antigens, Helminth / Q000008:administration & dosage; D001200:Ascaris / Q000276:immunology; D016084:Bronchoconstriction / Q000187:drug effects* / Q000276:immunology; D015550:Cell Degranulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006493:Heparin / Q000008:administration & dosage*; D008176:Lung Volume Measurements; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology; D012756:Sheep
D000336:Aerosols; D000947:Antigens, Helminth; D006493:Heparin