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The present study focused on whether this phosphodiesterase 4 inhibitor and its active metabolite roflumilast N\u2010oxide affect the tone of human bronchial rings. We also investigated the interactions between roflumilast, roflumilast N\u2010oxide and the long\u2010acting \u03b2<jats:sub>2<\/jats:sub>\u2010agonist formoterol with regard to the relaxation of isolated human bronchial rings at basal tone or pre\u2010contracted with histamine. Our results demonstrated for the first time that at a clinically relevant concentration (1\u00a0n<jats:sc>m<\/jats:sc>), roflumilast N\u2010oxide and roflumilast induce a weak relaxation of the isolated human bronchus either at resting tone (22% and 16%, respectively) or even weaker on pre\u2010contracted bronchus with histamine (7% and 5%, respectively). In addition, the combination of formoterol with roflumilast or roflumilast N\u2010oxide is more potent than each component alone for relaxing pre\u2010contracted isolated bronchi \u2010 the apparent pD2 of formoterol was significantly reduced for the threshold concentration of 1\u00a0n<jats:sc>m<\/jats:sc> of the phosphodiesterase 4 inhibitors by a factor of 2.4 for roflumilast N\u2010oxide and 1.9 for roflumilast. The full inhibition of phosphodiesterase 4 activity is achieved at 100\u00a0n<jats:sc>m<\/jats:sc> but this high concentration only caused partial relaxations of the human bronchi. At a clinically relevant concentration, these oral phosphodiesterase 4 inhibitors are not effective direct bronchodilators but could enhance the efficacy of inhaled long\u2010acting \u03b22\u2010agonists.<\/jats:p>","DOI":"10.1111\/fcp.12626","type":"journal-article","created":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T09:25:35Z","timestamp":1604481935000},"page":"725-731","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Clinical relevance of the relaxant effects of roflumilast on human bronchus: potentiation by a long\u2010acting beta\u20102\u2010agonist"],"prefix":"10.1111","volume":"35","author":[{"given":"H\u00e9l\u00e8ne","family":"Salvator","sequence":"first","affiliation":[{"name":"Laboratory of Research in Respiratory Pharmacology V2I \u2010 UMR\u20100092 Universit\u00e9 Paris Saclay  Suresnes France"},{"name":"Department of Airway Diseases Respiratory Pharmacology Unit H\u00f4pital Foch  Suresnes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Naline","sequence":"additional","affiliation":[{"name":"Laboratory of Research in Respiratory Pharmacology V2I \u2010 UMR\u20100092 Universit\u00e9 Paris Saclay  Suresnes France"},{"name":"Department of Airway Diseases Respiratory Pharmacology Unit H\u00f4pital Foch  Suresnes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Brollo","sequence":"additional","affiliation":[{"name":"Laboratory of Research in Respiratory Pharmacology V2I \u2010 UMR\u20100092 Universit\u00e9 Paris Saclay  Suresnes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermann","family":"Tenor","sequence":"additional","affiliation":[{"name":"TOPADUR Pharma AG  Schlieren Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanislas","family":"Grassin\u2010Delyle","sequence":"additional","affiliation":[{"name":"Department of Airway Diseases Respiratory Pharmacology Unit H\u00f4pital Foch  Suresnes France"},{"name":"INSERM U1173 Infection &amp; Inflammation D\u00e9partement de Biotechnologie de la Sant\u00e9 Universit\u00e9 Paris\u2010Saclay  Montigny\u2010le\u2010Bretonneux France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6054-1886","authenticated-orcid":false,"given":"Philippe","family":"Devillier","sequence":"additional","affiliation":[{"name":"Laboratory of Research in Respiratory Pharmacology V2I \u2010 UMR\u20100092 Universit\u00e9 Paris Saclay  Suresnes France"},{"name":"Department of Airway Diseases Respiratory Pharmacology Unit H\u00f4pital Foch  Suresnes France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,11,20]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2019.02.002"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pupt.2015.10.002"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pupt.2015.10.006"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2015.11.035"},{"key":"e_1_2_6_6_1","first-page":"CD002309","article-title":"Phosphodiesterase\u20104 inhibitors for chronic obstructive pulmonary disease","volume":"5","author":"Janjua S.","year":"2020","journal-title":"Cochrane Database Syst. 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