Biochemical pathways of 8-aminoguanine production in Sprague-Dawley and Dahl salt-sensitive rats,BIOCHEMICAL PHARMACOLOGY

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Biochemical pathways of 8-aminoguanine production in Sprague-Dawley and Dahl salt-sensitive rats
BIOCHEMICAL PHARMACOLOGY ( IF 5.3 ) Pub Date : 2022-05-10 , DOI: 10.1016/j.bcp.2022.115076
Edwin K Jackson ₁ , Elizabeth V Menshikova ₁ , Vladimir B Ritov ₁ , Delbert G Gillespie ₁ , Zaichuan Mi ₁

Affiliation

Background

8-Aminoguanine exerts natriuretic and antihypertensive activity. Whether and how “free” 8-aminoguanine exists in vivo is unclear. Because 8-nitroguanosine is naturally occurring, we tested the hypothesis that 8-aminoguanine can arise from: pathway 1, 8-nitroguanosine → 8-aminoguanosine → 8-aminoguanine; and pathway 2, 8-nitroguanosine → 8-nitroguanine → 8-aminoguanine.

Methods

8-Aminoguanine biosynthesis was explored in rats using renal microdialysis, mass spectrometry and enzyme kinetics.

Results

In Sprague-Dawley rats, 8-nitroguanosine infusions increased kidney levels of 8-nitroguanine, 8-aminoguanosine and 8-aminoguanine; 8-nitroguanine infusions increased 8-aminoguanine. Purine nucleoside phosphorylase (PNPase) converted 8-nitroguanosine to 8-nitroguanine and 8-aminoguanosine to 8-aminoguanine. Forodesine (PNPase inhibitor) reduced metabolism of 8-nitroguanosine by pathway 2 and shunted metabolism of 8-nitroguanosine to 8-aminoguanosine. In Dahl salt-sensitive rats, 8-nitroguanosine infusions increased kidney levels of 8-nitroguanine, 8-aminoguanosine and 8-aminoguanine. These results indicate that both pathways 1 and 2 participate in the biosynthesis of 8-aminoguanine in Sprague-Dawley and Dahl rats. Endogenous 8-aminoguanine in kidneys and urine were elevated many-fold in Dahl, compared to Sprague-Dawley, rats. The increased levels of 8-aminoguanine in Dahl rats were not due to alterations in pathways 1 and 2 but were associated with increased urine levels of endogenous 8-nitroguanosine suggesting that the “upstream” production of 8-nitroguanosine was increased in Dahl rats. Dahl rats are known to have high levels of peroxynitrite, and peroxynitrite is known to nitrate guanosine in biomolecules. Here we confirm that a peroxynitrite donor increases kidney levels of 8-aminoguanine.

Conclusion

8-Aminoguanine occurs naturally via two distinct pathways and kidney levels of 8-aminoguanine are increased in Dahl rats, likely due to increased production of 8-nitroguanosine, a by-product of peroxynitrite chemistry.

中文翻译：

Sprague-Dawley 和 Dahl 盐敏感大鼠 8-氨基鸟嘌呤产生的生化途径

背景

8-氨基鸟嘌呤具有利尿钠和抗高血压活性。“游离”8-氨基鸟嘌呤在体内是否存在以及如何存在尚不清楚。因为8-硝基鸟苷是天然存在的，所以我们测试了8-氨基鸟嘌呤可以来自于以下假设：途径1，8-硝基鸟苷→8-氨基鸟苷→8-氨基鸟嘌呤；途径2，8-硝基鸟苷→8-硝基鸟嘌呤→8-氨基鸟嘌呤。

方法

使用肾微透析、质谱和酶动力学研究了大鼠中的 8-氨基鸟嘌呤生物合成。

结果

在 Sprague-Dawley 大鼠中，8-硝基鸟苷输注可增加肾脏中 8-硝基鸟嘌呤、8-氨基鸟苷和 8-氨基鸟嘌呤的水平；8-硝基鸟嘌呤输注可增加8-氨基鸟嘌呤。嘌呤核苷磷酸化酶 (PNPase) 将 8-硝基鸟苷转化为 8-硝基鸟嘌呤，将 8-氨基鸟苷转化为 8-氨基鸟嘌呤。Forodesine（PNPase 抑制剂）通过途径 2减少 8-硝基鸟苷的代谢，并将 8-硝基鸟苷的代谢分流为 8-氨基鸟苷。在达尔盐敏感大鼠中，8-硝基鸟苷输注可增加肾脏中 8-硝基鸟嘌呤、8-氨基鸟苷和 8-氨基鸟嘌呤的水平。这些结果表明途径 1和2参与 Sprague-Dawley 和 Dahl 大鼠体内 8-氨基鸟嘌呤的生物合成。与 Sprague-Dawley 大鼠相比，Dahl 大鼠肾脏和尿液中的内源性 8-氨基鸟嘌呤升高了许多倍。Dahl 大鼠中 8-氨基鸟嘌呤水平的增加并不是由于途径 1和2的改变，而是与内源性 8-硝基鸟苷尿液水平增加有关，表明 Dahl 大鼠中 8-硝基鸟苷的“上游”产生增加。已知达尔大鼠具有高水平的过氧亚硝酸盐，而过氧亚硝酸盐会硝酸化生物分子中的鸟苷。在这里，我们确认过氧亚硝酸盐供体会增加肾脏中 8-氨基鸟嘌呤的水平。