Sumi-Ichinose Chiho, Suganuma Yui, Kano Taiki, Ihira Noriko, Nomura Hiroko, Ikemoto Kazuhisa, Hata Tadayoshi, Katoh Setsuko, Ichinose Hiroshi, Kondo Kazunao
Department of Pharmacology, School of Medicine, Fujita Health University, Toyoake, Japan
Department of Pharmacology, School of Medicine, Fujita Health University, Toyoake, Japan.
Physiol Rep. 2017 Mar;5(6). doi: 10.14814/phy2.13196.
(6)-l--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 gene-disrupted () mice for the first time. After weaning, 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 mice. The endothelium-dependent vascular relaxation in response to acetylcholine was significantly impaired in mice after sexual maturation (above 4 months old). Protein amounts of adrenergic receptor and eNOS in the aorta were not altered. mice exhibited hypoglycemia and elevation of plasma renin activity. Our results suggest that the hypertension with fluctuation and bradycardia of 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.
（6）-L-5,6,7,8-四氢生物蝶呤（BH4）是单胺和一氧化氮（NO）生成所必需的辅助因子。蝶呤还原酶（SPR）催化BH4生物合成的最后一步。我们首次分析了成年基因敲除（）小鼠的心血管功能。断奶后，小鼠出现血压波动和心动过缓的高血压症状，由于BH4缺乏，这些小鼠的单胺含量不到野生型小鼠的10%。心率变异性分析表明小鼠处于交感神经占主导的状态。性成熟后（4个月以上），小鼠对乙酰胆碱的内皮依赖性血管舒张功能明显受损。主动脉中肾上腺素能受体和内皮型一氧化氮合酶的蛋白量没有改变。小鼠出现低血糖和血浆肾素活性升高。我们的结果表明，小鼠的血压波动和心动过缓型高血压可能是由交感神经和副交感神经输入失衡以及内皮细胞中一氧化氮生成受损引起的。我们认为BH4和SPR在年龄相关性高血压中起重要作用，并且可能与包括帕金森病和脊髓损伤在内的自主神经疾病中的心血管不稳定有关。
