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The mechanisms of ATP release in cough and how P2X\u2010receptor engagement produces cough hypersensitivity are not clear. It is also unclear whether P2X receptor blockade could compromise the essential defensive functions of cough regulated by the vagal A\n                      <jats:italic>\u03b4<\/jats:italic>\n                      \u2010fibres terminating in the extrapulmonary airways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>We measured ATP release from isolated human and guinea pig airways. P2X receptor\u2010dependent regulation of vagal afferent nerve discharge in vitro and respiratory reflexes in anaesthetised guinea pigs also were studied using the P2X blockers AF\u2010353 and AF\u2010454.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      ATP was released continually and metabolised by human and guinea\u2010pig airways. ATP release was augmented by mild mechanical stimulation (blocked by carbenoxolone) and hypotonic challenges (blocked by ruthenium red), dwarfing the ATP release evoked by acid or by TRPV4 activation. Epithelium removal prevented ATP release evoked by either mechanical stimulation of the airways or by hypotonic challenges. AF\u2010454 inhibited\n                      <jats:italic>\u03b1<\/jats:italic>\n                      ,\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u2010methylene ATP evoked action potential discharge in bronchopulmonary nodose C\u2010fibres, but was without effect on extrapulmonary A\n                      <jats:italic>\u03b4<\/jats:italic>\n                      \u2010fibre excitability and did not prevent acid or mechanically induced cough responses evoked in anaesthetised guinea pigs. AF\u2010454 and AF\u2010353 did, however, inhibit\n                      <jats:italic>\u03b1<\/jats:italic>\n                      ,\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u2010methylene ATP evoked increases in airway cholinergic tone and changes in respiratory patterns, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>These results predict a desirable safety profile for P2X receptor blockade and identify multiple potential biomarkers that may differentiate responders from non\u2010responders in studies evaluating P2X blockers in chronic cough patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70238","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T07:09:31Z","timestamp":1762153771000},"page":"1071-1084","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["ATP release and metabolism by human and guinea pig airways and P2X receptor\u2010dependent effects on bronchopulmonary vagal afferent nerve subtypes"],"prefix":"10.1111","volume":"183","author":[{"given":"Brendan J.","family":"Canning","sequence":"first","affiliation":[{"name":"Johns Hopkins Asthma and Allergy Center  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Midori","family":"Yoshihara","sequence":"additional","affiliation":[{"name":"Division of Dysphagia Rehabilitation Niigata University Graduate School of Medical and Dental Sciences  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanako","family":"Mori","sequence":"additional","affiliation":[{"name":"Johns Hopkins Asthma and Allergy Center  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanori","family":"Tsujimura","sequence":"additional","affiliation":[{"name":"Division of Dysphagia Rehabilitation Niigata University Graduate School of Medical and Dental Sciences  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Inoue","sequence":"additional","affiliation":[{"name":"Division of Dysphagia Rehabilitation Niigata University Graduate School of Medical and Dental Sciences  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonya","family":"Meeker","sequence":"additional","affiliation":[{"name":"Johns Hopkins Asthma and Allergy Center  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Liu","sequence":"additional","affiliation":[{"name":"Johns Hopkins Asthma and Allergy Center  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley J.","family":"Undem","sequence":"additional","affiliation":[{"name":"Johns Hopkins Asthma and Allergy Center  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,2]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0003-9993(99)90112-0"},{"issue":"2","key":"e_1_2_12_3_1","first-page":"S145","article-title":"The concise guide to PHARMACOLOGY 2023\/24: Ion channels","volume":"180","author":"Alexander S. 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