{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T09:17:42Z","timestamp":1777972662202,"version":"3.51.4"},"reference-count":33,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T00:00:00Z","timestamp":1613606400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Organic nitrates such as nitroglycerin (NTG) or pentaerythritol tetranitrate (PETN) have been used for over a century in the treatment of angina or ischaemic heart disease. These compounds are prodrugs which release their nitrovasodilators upon enzymic bioactivation by aldehyde dehydrogenase (ALDH2) or cytochromes P450 (CYP). Whereas ALDH2 is known to directly activate organic nitrates in vessels, the contribution of vascular CYPs is unknown and was studied here.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>As all CYPs depend on cytochrome P450 reductase (POR) as electron donor, we generated a smooth muscle cell\u2010specific, inducible knockout mouse of POR (smcPOR<jats:sup>\u2212\/\u2212<\/jats:sup>) to investigate the contribution of POR\/CYP to vascular biotransformation of organic nitrates.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Microsomes containing recombinant CYPs expressed in human vascular tissues released nitrite from NTG and PETN with CYP2C9 and CYP2C8 being most efficient. SFK525, a CYP suicide inhibitor, blocked this effect. smcPOR<jats:sup>\u2212\/\u2212<\/jats:sup> mice exhibited no obvious cardiovascular phenotype (normal cardiac weight and endothelium\u2010dependent relaxation) and plasma and vascular nitrite production was similar to control (CTL) animals. NTG\u2010 and PETN\u2010induced relaxation of isolated endothelium\u2010intact or endothelium\u2010denuded vessels were identical between CTL and smcPOR<jats:sup>\u2212\/\u2212<\/jats:sup>. Likewise, nitrite release from organic nitrates in aortic rings was not affected by deletion of POR in smooth muscle cells (SMCs). In contrast, inhibition of ALDH2 by benomyl (10 \u03bcM) inhibited NTG\u2010induced nitrite production and relaxation. Deletion of POR did not modulate this response.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Our data suggest that metabolism by vascular CYPs does not contribute to the pharmacological function of organic nitrates.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15362","type":"journal-article","created":{"date-parts":[[2021,1,16]],"date-time":"2021-01-16T00:35:43Z","timestamp":1610757343000},"page":"1495-1506","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Vascular biotransformation of organic nitrates is independent of cytochrome P450 monooxygenases"],"prefix":"10.1111","volume":"178","author":[{"given":"Melina","family":"Lopez","sequence":"first","affiliation":[{"name":"Institute for Cardiovascular Physiology, Faculty of Medicine Goethe University  Frankfurt am Main Germany"},{"name":"German Center for Cardiovascular Research (DZHK) Partner site Rhein Main  Frankfurt am Main Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro F.","family":"Malacarne","sequence":"additional","affiliation":[{"name":"Institute for Cardiovascular Physiology, Faculty of Medicine Goethe University  Frankfurt am Main Germany"},{"name":"German Center for Cardiovascular Research (DZHK) Partner site Rhein Main  Frankfurt am Main Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6253-3329","authenticated-orcid":false,"given":"Anna","family":"Gajos\u2010Draus","sequence":"additional","affiliation":[{"name":"Department of Clinical Physiology National Science Centre  Krak\u00f3w Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinxin","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy The University of Arizona  Tucson Arizona USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2769-0094","authenticated-orcid":false,"given":"Andreas","family":"Daiber","sequence":"additional","affiliation":[{"name":"German Center for Cardiovascular Research (DZHK) Partner site Rhein Main  Frankfurt am Main Germany"},{"name":"Zentrum f\u00fcr Kardiologie \u2010 Kardiologie 1, Labor f\u00fcr Moleculare Kardiologie Johannes Gutenberg University  Mainz Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jon O.","family":"Lundberg","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology Karolinska Institute  Stockholm Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Offermanns","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Max Planck Institute for Heart and Lung Research  Bad Nauheim Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ralf P.","family":"Brandes","sequence":"additional","affiliation":[{"name":"Institute for Cardiovascular Physiology, Faculty of Medicine Goethe University  Frankfurt am Main Germany"},{"name":"German Center for Cardiovascular Research (DZHK) Partner site Rhein Main  Frankfurt am Main Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fl\u00e1via","family":"Rezende","sequence":"additional","affiliation":[{"name":"Institute for Cardiovascular Physiology, Faculty of Medicine Goethe University  Frankfurt am Main Germany"},{"name":"German Center for Cardiovascular Research (DZHK) Partner site Rhein Main  Frankfurt am Main Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,2,18]]},"reference":[{"issue":"1","key":"e_1_2_12_2_1","first-page":"S297","article-title":"The Concise Guide to PHARMACOLOGY 2019\/20: Enzymes","volume":"176","author":"Alexander S. 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