Open AccessSepiapterin reductase gene‐disrupted mice suffer from hypertension with fluctuation and bradycardia
Author(s) -
SumiIchinose Chiho,
Suganuma Yui,
Kano Taiki,
Ihira Noriko,
Nomura Hiroko,
Ikemoto Kazuhisa,
Hata Tadayoshi,
Katoh Setsuko,
Ichinose Hiroshi,
Kondo Kazunao
Publication year - 2017
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.13196
Subject(s) - medicine , endocrinology , bradycardia , tetrahydrobiopterin , nitric oxide , enos , nitric oxide synthase , chemistry , heart rate , blood pressure
(6 R )‐ l ‐ erythro ‐5,6,7,8‐Tetrahydrobiopterin ( BH 4) is an essential cofactor for monoamine and nitric oxide ( NO ) production. Sepiapterin reductase ( SPR ) catalyzes the final step in BH 4 biosynthesis. We analyzed the cardiovascular function of adult Spr gene‐disrupted ( Spr −/− ) mice for the first time. After weaning, Spr −/− mice suffered from hypertension with fluctuation and bradycardia, while the monoamine contents in these mice were less than 10% of those in the wild‐type mice as a result of BH 4 depletion. Heart rate variability analysis indicated the sympathetic dominant state in Spr −/− mice. The endothelium‐dependent vascular relaxation in response to acetylcholine was significantly impaired in Spr −/− mice after sexual maturation (above 4 months old). Protein amounts of α 1 adrenergic receptor and eNOS in the aorta were not altered. Spr −/− mice exhibited hypoglycemia and elevation of plasma renin activity. Our results suggest that the hypertension with fluctuation and bradycardia of Spr −/− 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 BH 4 and SPR in age‐related hypertension and a possible relationship with the cardiovascular instabilities in autonomic diseases, including Parkinson's disease and spinal cord injury.