Details

Autor(en) / Beteiligte

• Sumi‐Ichinose, Chiho
• Suganuma, Yui
• Kano, Taiki
• Ikemoto, Kazuhisa
• Ihira, Noriko
• Ichinose, Hiroshi
• Kondo, Kazunao

Titel

Priapism caused by partial deficiency of tetrahydrobiopterin through hypofunction of the sympathetic neurons in sepiapterin reductase gene‐disrupted mice

Ist Teil von

• Journal of inherited metabolic disease, 2022-05, Vol.45 (3), p.621-634

Ort / Verlag

Hoboken, USA: John Wiley & Sons, Inc

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• 6R‐L‐erythro‐5,6,7,8‐tetrahydrobiopterin (BH4) is an essential cofactor for aromatic L‐amino acid hydroxylases, including tyrosine hydroxylase (TH), alkylglycerol monooxygenase, and three types of nitric oxide (NO) synthases (NOS). Sepiapterin reductase (SPR) catalyzes the third step of BH4 biosynthesis. SPR gene‐disrupted (Spr−/−) mice exhibit a dystonic posture, low body weight, hyperphenylalaninemia, and unstable hypertension with endothelial dysfunction. In this study, we found that Spr−/− mice suffered from a high incidence of severe priapism. Their erections persisted for months. The biopterin, BH4, and norepinephrine contents, and TH protein levels in the penile tissue of Spr−/− mice without and with priapism were significantly reduced compared to those of Spr+/+ mice. In contrast, their neural NOS (nNOS) protein levels were increased, and the cyclic guanosine monophosphate (cGMP) levels were remarkably elevated in the penises of Spr−/− mice with priapism. The symptoms were relieved by repeated administration of BH4. The biopterin, BH4, and norepinephrine contents were increased in penile homogenates from BH4‐supplemented Spr−/− mice, and the TH protein levels tended to increase, and their nitrite plus nitrate levels were significantly lower than those of vehicle‐treated Spr−/− mice and were approximately the same as vehicle‐ and BH4‐supplemented Spr+/+ mice. Thus, we deduced that the priapism of Spr−/− mice is primarily caused by hypofunction of the sympathetic neurons due to cofactor depletion and the loss of TH protein and, further, dysregulation of the NO/cGMP signaling pathway, which would be caused by disinhibition of nNOS‐containing neurons and/or abnormal catabolism of cyclic nucleotides is suggested.