TY - JOUR
T1 - Sepiapterin reductase gene-disrupted mice suffer from hypertension with fluctuation and bradycardia
AU - Sumi-Ichinose, Chiho
AU - Suganuma, Yui
AU - Kano, Taiki
AU - Ihira, Noriko
AU - Nomura, Hiroko
AU - Ikemoto, Kazuhisa
AU - Hata, Tadayoshi
AU - Katoh, Setsuko
AU - Ichinose, Hiroshi
AU - Kondo, Kazunao
N1 - Funding Information:
Funding information This work was supported by JSPS KAKENHI Grant Numbers JP22590250, JP25460346, JP16K08561, NEXT Grant SENRYAKU 1001034, and grants obtained from Fujita Health University (to C. S.-I.). We thank Mr. S Oikawa, Ms. M Nishio, and Ms. R Nagata for their technical assistance in the ECG recording and analysis, and we thank Mr. M Suzuki, Ms. A Uemura, and Ms. Y Murata for animal care.
Publisher Copyright:
© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.
PY - 2017/3/1
Y1 - 2017/3/1
N2 - (6R)-l-erythro-5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for monoamine and nitric oxide (NO) production. Sepiapterin reductase (SPR) catalyzes the final step in BH4 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 BH4 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 α1 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 BH4 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.
AB - (6R)-l-erythro-5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for monoamine and nitric oxide (NO) production. Sepiapterin reductase (SPR) catalyzes the final step in BH4 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 BH4 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 α1 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 BH4 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.
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U2 - 10.14814/phy2.13196
DO - 10.14814/phy2.13196
M3 - Article
C2 - 28320892
AN - SCOPUS:85016311243
SN - 2051-817X
VL - 5
JO - Physiological Reports
JF - Physiological Reports
IS - 6
M1 - e13196
ER -