セピアプテリン還元酵素遺伝子ノックアウトマウスの持続勃起症は、一酸化窒素の過剰産生によって引き起こされるのか？

抄録

6R-L-erythro-5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for aromatic L-amino acid hydroxylases including tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine-biosynthesis, and for all types of nitric oxide synthases (NOS). Sepiapterin reductase (SPR) catalyzes the third step of BH4 biosynthesis. SPR gene-disrupted (Spr^-/-) mice (OYC32, Lexicon Pharmaceuticals Inc.) exhibit a dystonic posture, low body weight, hyperphenylalaninemia, and unstable cardiovascular control with endothelial dysfunction. Recently, we found that Spr^-/- mice suffered from severe priapism (persistent erection) at a high incidence. This priapism was relieved by repeated administration of BH4. We hypothesized that the priapism of Spr^-/- mice was primarily caused by sympathetic nerve failure due to cofactor depletion and the loss of TH protein, which caused vasodilation and relaxation of the corpus cavernosum. Its disinhibition of neuronal NOS (nNOS)-containing neurons would cause overproduction of NO and further exacerbated the priapism. To verify the possibility, we analyzed biopterin and norepinephrine content, TH protein amount and nitric oxide metabolites in the penile tissue of Spr^-/- mice with and without BH4-supplementation.