Sepiapterin reductase gene-disrupted mice suffer from hypertension with fluctuation and bradycardia.
(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 adultSprgene-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 inSpr-/-mice. The endothelium-dependent vascular relaxation in response to acetylcholine was significantly impaired inSpr-/-mice after sexual maturation (above 4 months old). Protein amounts ofα1adrenergic 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 ofSpr-/-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.
Department of Pharmacology, School of Medicine, Fujita Health University, Toyoake, Japan csichino@fujita-hu.ac.jp.
Chiho
C
Sumi-Ichinose
Department of Pharmacology, School of Medicine, Fujita Health University, Toyoake, Japan.
Yui
Y
Suganuma
Department of Pharmacology, School of Medicine, Fujita Health University, Toyoake, Japan.
Taiki
T
Kano
Department of Pharmacology, School of Medicine, Fujita Health University, Toyoake, Japan.
Noriko
N
Ihira
Graduate School of Health Science, Fujita Health University, Toyoake, Japan.
Hiroko
H
Nomura
Department of Pharmacology, School of Medicine, Fujita Health University, Toyoake, Japan.
Kazuhisa
K
Ikemoto
Graduate School of Health Science, Fujita Health University, Toyoake, Japan.
Tadayoshi
T
Hata
Department of Dentistry, Meikai University, Sakado, Japan.
Setsuko
S
Katoh
School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan.
Hiroshi
H
Ichinose
Department of Pharmacology, School of Medicine, Fujita Health University, Toyoake, Japan.
Kazunao
K
Kondo
D000367:Age Factors; D000429:Alcohol Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000235:genetics*; D001919:Bradycardia / Q000235:genetics* / Q000378:metabolism; D005247:Feeding Behavior / Q000502:physiology; D006339:Heart Rate / Q000235:genetics*; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism
D001786:Blood Glucose; D018340:Receptors, Adrenergic, alpha-1; D009569:Nitric Oxide; D000429:Alcohol Oxidoreductases; C022630:sepiapterin reductase; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse
Autonomic failure; endothelial dysfunction; hypertension; tetrahydrobiopterin