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 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 a1 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.