thromboxane-a2 and Cough

The aim of this study was to elucidate the role of thromboxane A(2) (TxA(2)) on asthma-related cough in guinea pigs. Animals were immunosensitized and repeatedly challenged with ovalbumin as an antigen. Coughs were induced by the inhalation of 10(-5) M capsaicin solution for 10 min. Thromboxane synthetase (TxS) inhibitor OKY-046 and thromboxane-receptor antagonist AA-2414 significantly inhibited cough responses in repeatedly challenged animals. Inhalation of TxA(2) mimic STA-2- potentiated cough responses in normal and immunosensitized animals but not in repeatedly challenged ones. Moreover, STA-2-potentiated coughs were inhibited by administration of neurokinin-receptor antagonist FK-224. In repeatedly challenged animals, concentration of TxB(2) in airway lavage fluid, expression of TxS mRNA in tracheal epithelia, and the immunostaining intensity against TxS in mucous cells of the epithelium significantly increased compared with normal and sensitized animals. These results suggest that TxA(2) derived from mucous cells potentiated cough responses to capsaicin in allergic airway inflammation.

Topics: Animals; Asthma; Base Sequence; Bronchoalveolar Lavage Fluid; Cough; DNA, Complementary; Female; Guinea Pigs; Immunohistochemistry; Lung; Respiratory Mucosa; RNA, Messenger; Thromboxane A2; Thromboxane-A Synthase; Trachea

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.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Antitussive Agents; Capsaicin; Cough; Disease Models, Animal; Dose-Response Relationship, Drug; Guinea Pigs; Male; Methacrylates; Thromboxane A2; Thromboxane-A Synthase

Based on our earlier animal study, we became interested to investigate if thromboxane A2 (TXA2) is involved in angiotensin converting enzyme (ACE) induced cough in man. To 11 patients with hypertension, who had developed cough induced by ACE inhibitors, a TXA2 synthetase inhibitor, ozagrel was given for 1 to 2 months together with the ACE inhibitors. One patient developed headache induced by ozagrel and was eliminated from the study after 3 weeks. In other 10 patients, no obvious drug attributable abnormality was observed in subjective and objective symptoms or laboratory tests. In ten patients, cough scores were taken just before and after the administration of a combination of an ACE inhibitor with ozagrel. Median values of cough scores after the combination was significantly (p=0.012) lower than before the combination. Ozagrel reduced cough scores in 5 patients, completely suppressed cough in 3 patients and in 2 of 10 patients, ozagrel did not affect cough scores. Our observations suggest that TXA2 may somehow, mediate coughing induced by the ACE inhibitors. Further, patients on ACE inhibitors who develop cough may benefit from TXA2 synthetase inhibitors.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cough; Enzyme Inhibitors; Female; Guinea Pigs; Humans; Male; Methacrylates; Middle Aged; Thromboxane A2; Thromboxane-A Synthase

We studied the effects of the thromboxane-synthetase inhibitor ozagrel in 22 patients with chronic persistent coughing who did not have airwayhyperresponsiveness. Treatment with ozagrel (400 mg/day for 2 weeks) reduced coughing in 12 patients. Sputum from the patients in whom ozagrel was effective had a higher percentage of lymphocytes and a lower percentage of neutrophils than did sputum from those in whom ozagrel was not effective. Furthermore, in the former group the capsaicin cough threshold increased but in the latter it did not change consistently. These data indicate that thromboxane A2 may contribute to coughing associated with lymphocytic airway inflammation.

Topics: Adult; Aged; Bronchial Hyperreactivity; Chronic Disease; Cough; Enzyme Inhibitors; Female; Humans; Male; Methacrylates; Middle Aged; Thromboxane A2; Thromboxane-A Synthase

A 25-year-old woman complained of coughing for over 8 weeks. The coughing was not relieved by a bronchodilator (beta 2-adrenoceptor agonist; clenbuterol), and anti-allergic agent (azelastine), or an inhaled corticosteroid. The thromboxane synthetase inhibitor ozagrel completely abolished her cough. In this case, thromboxane A2 may have contributed to the coughing.

Topics: Adult; Antitussive Agents; Chronic Disease; Cough; Female; Humans; Methacrylates; Thromboxane A2; Thromboxane-A Synthase