Sequential histamine inhalations cause increased bronchial histamine reactivity in guinea pigs: role of platelets, thromboxanes and prostacyclin.
Groups of 6-15 guinea pigs sensitized to ovalbumin were challenged by repeated inhalations of a constant histamine dose at time 0, 10, 20, 60 and 70 min. Bronchial obstruction was measured by whole body plethysmography. The degree of bronchial obstruction increased from one challenge to the other reaching maximal values after 70 min. This increase of bronchial responsiveness to histamine after repeated histamine challenges was reduced by pretreatment with clemastine (histamine H1-receptor antagonist, 0.12 mg/kg i.p., n = 7, P less than 0.05) and more effectively by combined clemastine/cimetidine pretreatment (combined H1-H2-receptor antagonists, 0.12 resp. 10 mg/kg, n = 7, P less than 0.001); pretreatment with acetylsalicylic acid (10 mg/kg orally) accelerated the increase of bronchial responsiveness to histamine (n = 9, P less than 0.01 at the second challenge), inhalation of prostacyclin (1 microgram) prior to each histamine inhalation prevented the increase of bronchial histamine sensitivity totally (n = 10, P less than 0.001), whereas inhibition of thromboxane biosynthesis (imidazol, 10 mg/kg i.p., n = 6; 4-[2-(1H-imidazol-1-yl)ethoxy]benzoic acid, 10 mg/kg i.p., n = 9; imidazo(1,5-a)pyridine-5-hexanoic acid, 1 mg/kg i.p., n = 8) as well as immunologic platelet depletion were ineffective in our test system. We conclude that prostacyclin inhibits the increase of bronchial responsiveness to histamine after sequential histamine inhalation challenges by a platelet independent mechanism. 1-(3-phenyl-2-propenyl)-1H-imidazol, the fourth type of thromboxane synthetase inhibitor tested (10 mg/kg i.p., n = 15) showed specific effects which may be attributed to antihistamine functions.
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000502:physiology*; D001980:Bronchi / Q000187:drug effects / Q000502:physiology*; D001985:Bronchial Provocation Tests; D055598:Chemical Phenomena; D002621:Chemistry; D002927:Cimetidine / Q000494:pharmacology; D011464:Epoprostenol / Q000502:physiology*; D006168:Guinea Pigs; D006632:Histamine / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011969:Receptors, Histamine H1 / Q000187:drug effects; D011970:Receptors, Histamine H2 / Q000187:drug effects; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D013931:Thromboxanes / Q000502:physiology*
D007093:Imidazoles; D011725:Pyridines; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D013931:Thromboxanes; C029166:dazoxiben; C025092:1-(3-phenyl-2-propenyl)-1H-imidazole; C029899:imidazole; D002927:Cimetidine; D006632:Histamine; C037787:pirmagrel; D011464:Epoprostenol; D013930:Thromboxane-A Synthase; D001241:Aspirin