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Sepiapterin reductase (<jats:styled-content style=\"fixed-case\">SPR<\/jats:styled-content>) catalyzes the final step in <jats:styled-content style=\"fixed-case\">BH<\/jats:styled-content>4 biosynthesis. We analyzed the cardiovascular function of adult <jats:italic>Spr<\/jats:italic> gene\u2010disrupted (<jats:italic>Spr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) mice for the first time. After weaning, <jats:italic>Spr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice suffered from hypertension with fluctuation and bradycardia, while the monoamine contents in these mice were less than 10% of those in the wild\u2010type mice as a result of <jats:styled-content style=\"fixed-case\">BH<\/jats:styled-content>4 depletion. Heart rate variability analysis indicated the sympathetic dominant state in <jats:italic>Spr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. The endothelium\u2010dependent vascular relaxation in response to acetylcholine was significantly impaired in <jats:italic>Spr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice after sexual maturation (above 4\u00a0months old). Protein amounts of <jats:italic>\u03b1<\/jats:italic><jats:sub>1<\/jats:sub> adrenergic receptor and <jats:styled-content style=\"fixed-case\">eNOS<\/jats:styled-content> in the aorta were not altered. <jats:italic>Spr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice exhibited hypoglycemia and elevation of plasma renin activity. Our results suggest that the hypertension with fluctuation and bradycardia of <jats:italic>Spr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice would be caused by an imbalance of sympathetic and parasympathetic input and impaired nitric oxide production in endothelial cells. We suggest an important role of <jats:styled-content style=\"fixed-case\">BH<\/jats:styled-content>4 and <jats:styled-content style=\"fixed-case\">SPR<\/jats:styled-content> in age\u2010related hypertension and a possible relationship with the cardiovascular instabilities in autonomic diseases, including Parkinson's disease and spinal cord injury.<\/jats:p>","DOI":"10.14814\/phy2.13196","type":"journal-article","created":{"date-parts":[[2017,3,21]],"date-time":"2017-03-21T01:40:41Z","timestamp":1490060441000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Sepiapterin reductase gene\u2010disrupted mice suffer from hypertension with fluctuation and bradycardia"],"prefix":"10.14814","volume":"5","author":[{"given":"Chiho","family":"Sumi\u2010Ichinose","sequence":"first","affiliation":[{"name":"Department of Pharmacology School of Medicine Fujita Health University Toyoake Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yui","family":"Suganuma","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Medicine Fujita Health University Toyoake Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taiki","family":"Kano","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Medicine Fujita Health University Toyoake Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noriko","family":"Ihira","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Medicine Fujita Health University Toyoake Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroko","family":"Nomura","sequence":"additional","affiliation":[{"name":"Graduate School of Health Science Fujita Health University Toyoake Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhisa","family":"Ikemoto","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Medicine Fujita Health University Toyoake Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tadayoshi","family":"Hata","sequence":"additional","affiliation":[{"name":"Graduate School of Health Science Fujita Health University Toyoake Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Setsuko","family":"Katoh","sequence":"additional","affiliation":[{"name":"Department of Dentistry Meikai University Sakado Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Ichinose","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology Tokyo Institute of Technology Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazunao","family":"Kondo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Medicine Fujita Health University Toyoake Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,3,21]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2003.01742.x"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-201X.1997.00177.x"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1006\/mgme.2001.3213"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(02)00065-9"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(76)90527-3"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00460-1"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-005-1857-5"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.114.03089"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2007.147686"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1311488"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22685"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(80)90336-X"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvp042"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.159426"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12287"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90615-W"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/121.9.1711"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1995.tb00038.x"},{"key":"e_1_2_7_20_1","doi-asserted-by":"crossref","first-page":"20496","DOI":"10.1016\/S0021-9258(19)47089-0","article-title":"Reduced biopterin as a cofactor in the generation of nitrogen oxides by murine macrophages","volume":"264","author":"Kown N. 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