Participation of thromboxane A(2) in the cough response in guinea-pigs: antitussive effect of ozagrel.
1. The purpose of this study was to investigate the involvement of thromboxane A(2) (TXA(2)) in the cough response in a guinea-pig cough model. Here, we describe results obtained using a selective TXA(2) synthetase inhibitor, ozagrel, and a selective TXA(2) agonist, U-46619. 2. Guinea-pigs were anaesthetized and exposed to an aerosol of capsaicin (100 microM) to elicit coughing. The number of coughs was 20.0+/-5.8 during capsaicin provocation (5 min), but only 2. 8+/-0.4 during a 5-min inhalation of phosphate-buffered saline (PBS) (P:<0.05). 3. TXB(2) levels in BAL were 101.4+/-8.0 and 58.4+/-8.7 pg ml(-1) following capsaicin and PBS inhalation, respectively (P:<0. 01), but there was no intergroup difference in the cell populations in BAL. 4. Inhalation of U-46619 did not induce a cough response by itself at concentrations of 100 ng ml(-1) to 10 microg ml(-1). However, it caused a 2 fold increase in the number of capsaicin-induced coughs. 5. To explore the source of the TXA(2), BAL cells were stimulated with capsaicin and the supernatants collected for analysis. The TXB(2) concentration in BAL was increased dose-dependently, indicating that TXA(2) is released from BAL cells in response to capsaicin. 6. Ozagrel was administered orally 1 h before a 5 min capsaicin provocation and the number of coughs was counted during the capsaicin inhalation. Ozagrel decreased the number of coughs dose-dependently (ED(50) value, 26.3 mg kg(-1)). 7. These results show that TXA(2) modulates the capsaicin-induced cough response by increasing capsaicin-sensitivity.
Shinagawa
K
K
Pharmacology Laboratory, Kissei Pharmaceutical Co. Ltd., 4365-1, Kashiwabara, Hotaka, Minamiazumi, Nagano, 399-8304, Japan. kazuhiko_shinagawa@pharm.kissei.co.jp
Kojima
M
M
Ichikawa
K
K
Hiratochi
M
M
Aoyagi
S
S
Akahane
M
M
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D000996:Antitussive Agents / Q000494:pharmacology / Q000627:therapeutic use; D002211:Capsaicin; D003371:Cough / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D008689:Methacrylates / Q000494:pharmacology / Q000627:therapeutic use; D013928:Thromboxane A2 / Q000378:metabolism / Q000502:physiology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism
D000996:Antitussive Agents; D008689:Methacrylates; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013930:Thromboxane-A Synthase; C034364:ozagrel; D002211:Capsaicin