ozagrel and Anaphylaxis

1-[3-(4-Benzhydryl-1-piperazinyl)propyl]-3-(1H-imidazol-1-ylmethyl )- 1H-indole-6-carboxylic acid (CAS 172544-75-1, KY-234) was characterized pharmacologically. KY-234 (10(-9)-10(-6) mol/l) and ozagrel (10(-8)-10(-5) mol/l) inhibited the production of thromboxane A2 (TXA2) in rabbit platelets. KY-234 and pyrilamine at concentrations of 10(-9)-10(-6) mol/l relaxed the isolated guinea pig trachea contracted with histamine, while neither drug attenuated the heart rate increased by histamine. Cimetidine antagonized histamine in the right atrium but not in the trachea. KY-234 (10(-8)-10(-5) mol/l) and ozagrel (10(-7)-10(-4) mol/l), but not pyrilamine, attenuated the contraction induced by leukotriene D4 (LTD4) and platelet-activating factor in the lung parenchymal strips. In anesthetized guinea pigs, KY-234 (1-10 mg/kg p.o.) inhibited the LTD4- and histamine-induced bronchoconstriction. Ozagrel and terfenadine inhibited only the LTD4- and histamine-induced constrictions. KY-234 (3-30 mg/kg p.o.) inhibited the anaphylactic bronchoconstriction continuously for 15 min after antigen-challenge. Terfenadine (3-30 mg/kg p.o.) inhibited the constriction more strongly within the first 5 min (fast phase) than it did within 5 to 15 min (slow phase) after the challenge. Ozagrel (100 mg/kg p.o.) slightly attenuated only the constriction during the slow phase. These findings demonstrated that KY-234 has a selective TXA2 synthetase-inhibitory and H1-blocking activity and protects against anaphylactic bronchospasm more effectively than a TXA2 synthetase inhibitor or H1-blocker alone.

Topics: Anaphylaxis; Animals; Bronchial Spasm; Bronchoconstriction; Enzyme Inhibitors; Guinea Pigs; Histamine H1 Antagonists; In Vitro Techniques; Indoles; Leukotriene D4; Lung; Male; Methacrylates; Platelet Activating Factor; Rabbits; Thromboxane A2; Thromboxane-A Synthase; Trachea

This study was designed to examine whether an inhaled beta 2-agonist, procaterol, inhibits thromboxane A2 (TXA2) production induced by antigen challenge in passively sensitized guinea-pigs in vivo. Antigen-induced bronchoconstriction was markedly inhibited by pre-treatment with procaterol. Inhaled procaterol significantly reduced in a dose-dependent manner the increment in TXB2 concentration in bronchoalveolar lavage fluid obtained 5 min after antigen challenge. Aerosol administration of procaterol significantly inhibited bronchoconstriction induced by inhaled histamine. These results suggest that inhalation of procaterol has an inhibitory effect on antigen-induced TXA2 production as well as a protective effect against bronchoconstriction induced by bronchoactive agents.

Topics: Administration, Inhalation; Anaphylaxis; Animals; Antigens; Bronchi; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Ethanolamines; Guinea Pigs; Histamine; Male; Methacrylates; Procaterol; Prostaglandins; Thromboxane A2; Thromboxane-A Synthase

We investigated the effects of OKY-046, a potent and selective thromboxane A2 (TxA2) synthetase inhibitor, on anaphylactic bronchoconstriction and release of chemical mediators into airway lumen in sensitized guinea pigs in vivo. OKY-046 dose-dependently inhibited antigen-induced anaphylactic bronchoconstriction with or without mepyramine, a histamine H1 antagonist. In the presence of mepyramine, OKY-046 (300 mg/kg, p.o.) elicited significant reductions in histamine (1 min) and TxB2 increases (1-15 min) in bronchoalveolar lavage (BAL) fluid but significantly increased the plasma level of 6-keto-PGF1 alpha, a stable PGI2 metabolite, after antigen challenge. On the contrary, indomethacin only significantly reduced increases in TxB2 levels. These results suggest that the antiasthmatic effect of OKY-046 is probably due to inhibition of TxA2 synthesis and suppression of histamine release via a PGI2 shunting mechanism.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Anaphylaxis; Animals; Bordetella pertussis; Cyclooxygenase Inhibitors; Guinea Pigs; Histamine Release; Immunization; Indomethacin; Male; Methacrylates; Pulmonary Alveoli; Pyrilamine; Thromboxane B2

Topics: Anaphylaxis; Animals; Antigens, Helminth; Ascaris; Blood Pressure; Dogs; Leukotriene E4; Methacrylates; SRS-A; Thromboxane B2; Trachea

To study the role of thromboxane (Tx) A2 in Forssman systemic shock (FSS) in guinea pig, the effect of (E)-3-[p-(1H-Imidazol-1-ylmethyl)phenyl]-2-propenoic acid hydrochloride (OKY-046), a specific Tx A2 synthetase inhibitor, was studied. OKY-046 administered intravenously clearly prolonged survival time and protected against fatal shock. In shocked animals, definite decreases in serum complement hemolytic activity (CH50), leucocyte counts and platelet counts and an increase in lactate dehydrogenase (LDH) activity were observed. In addition, a significant increase of Tx B2 and incoagulability of blood were observed after shock. Whereas OKY-046 had no effect on the decreases in CH50, platelet counts and leucocyte counts, it inhibited the increase of Tx B2 and increased the amount of 6-keto PG F1 alpha. When Forssman antibody (half a lethal dose) was injected, a diphasic increase in airway resistance was observed. OKY-046 inhibited this diphasic increase in airway resistance. These data suggest a pathophysiological role for Tx A2 in FSS. OKY-046 inhibited the Forssman antibody induced respiratory disorders probably due to the inhibition of Tx A2 synthesis after shock.

Topics: Acrylates; Airway Resistance; Anaphylaxis; Animals; Benzamidines; Female; Forssman Antigen; Guanidines; Guinea Pigs; Male; Methacrylates; Thromboxane A2; Thromboxane-A Synthase