The effect of three novel thromboxane A2 receptor antagonists (S-1452, AA-2414 and ONO-3708) on the increase in pulmonary pressure caused by Forssman anaphylaxis in guinea-pigs.
The effects were studied of three novel thromboxane A2 (TXA2) receptor antagonists (S-1452, AA-2414 and ONO-3708) on the increase in pulmonary pressure caused by Forssman anaphylaxis in guinea-pigs. Three TXA2 antagonists at doses of between 1 and 10 mg/kg administered orally 1 h before the challenge clearly inhibited the pulmonary pressure increase. At a dose of 10 mg/kg, all three antagonists inhibited the pulmonary pressure increase caused by leukotriene D4 (LTD4) and U-46619, but not that caused by histamine. The decrease in peripheral platelet counts caused by Forssman anaphylaxis was also clearly inhibited by the three TXA2 antagonists. However, the decreased peripheral leukocyte counts were unaffected by the three agents. The decrease in serum complement activity (CH50) was inhibited by S-1452 and AA-2414 at a dose of 10 mg/kg. In bronchoalveolar lavage fluid (BALF), significant increases in eosinophils and neutrophils were observed after Forssman anaphylaxis. Three TXA2 antagonists at a dose of 10 mg/kg (except for AA-2414 on eosinophils) did not affect the changes of leukocyte counts in BALF. Moreover, increases in the TXB2 and 6-keto-PGF1 alpha levels of the BALF brought about by Forssman anaphylaxis were unaffected by the three TXA2 receptor antagonists. Histamine and LTD4 were not changed in the BALF after Forssman anaphylaxis. These results indicate the efficacy of TXA2 receptor antagonists on the increase in pulmonary pressure caused by Forssman anaphylaxis in guinea-pigs by direct antagonism to released TXA2.
Nagai
H
H
Department of Pharmacology, Gifu Pharmaceutical University, Japan.
Kumimoto
M
M
Yoshitake
K
K
Iwama
T
T
Arimura
A
A
Koda
A
A
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000403:Airway Resistance / Q000187:drug effects*; D000707:Anaphylaxis / Q000503:physiopathology*; D000818:Animals; D000910:Antibodies, Heterophile / Q000008:administration & dosage; D016227:Benzoquinones; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D006168:Guinea Pigs; D006538:Heptanoic Acids; D006632:Histamine / Q000378:metabolism; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D010976:Platelet Count / Q000187:drug effects; D011809:Quinones / Q000494:pharmacology*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D017482:Receptors, Thromboxane; D013189:SRS-A / Q000378:metabolism; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013929:Thromboxane B2 / Q000037:antagonists & inhibitors / Q000378:metabolism
D000910:Antibodies, Heterophile; D016227:Benzoquinones; D001643:Bridged Bicyclo Compounds; D005229:Fatty Acids, Monounsaturated; D006538:Heptanoic Acids; D011809:Quinones; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013189:SRS-A; C056566:S 145; C060230:seratrodast; D013929:Thromboxane B2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D006632:Histamine; C049855:ONO 3708