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8-Aminoguanine and 8-aminoguanosine (via metabolism to 8-aminoguanine) are endogenous 8-aminopurines that induce diuresis, natriuresis, and glucosuria by inhibiting purine nucleoside phosphorylase (PNPase); moreover, both 8-aminopurines cause antikaliuresis by other mechanisms. Because 8-aminoinosine and 8-aminohypoxanthine are structurally similar to 8-aminoguanosine and 8-aminoguanine, respectively, we sought to define their renal excretory effects. First, we compared the ability of 8-aminoguanine, 8-aminohypoxanthine, and 8-aminoinosine to inhibit recombinant PNPase. These compounds inhibited PNPase with a potency order of 8-aminoguanine > 8-aminohypoxanthine = 8-aminoinosine. Additional studies showed that 8-aminoinosine is a competitive substrate that is metabolized to a competitive PNPase inhibitor, namely 8-aminohypoxanthine. Administration of each 8-aminopurine (33.5 µmol/kg) reduced the guanine-to-guanosine and hypoxanthine-to-inosine ratios in urine, a finding confirming their ability to inhibit PNPase in vivo. All three 8-aminopurines induced diuresis, natriuresis, and glucosuria; however, the glucosuric effects of 8-aminohypoxanthine and 8-aminoinosine were less pronounced than those of 8-aminoguanine. Neither 8-aminohypoxanthine nor 8-aminoinosine altered potassium excretion, whereas 8-aminoguanine caused antikaliuresis. In vivo administration of 8-aminoinosine increased 8-aminohypoxanthine excretion, indicating that 8-aminohypoxanthine mediates, in part, the effects of 8-aminoinosine. Finally, 8-aminohypoxanthine was metabolized to 8-aminoxanthine by xanthine oxidase. Using ultraperformance liquid chromatography-tandem mass spectrometry, we identified 8-aminoinosine as an endogenous 8-aminopurine. In conclusion, 8-aminopurines have useful pharmacological profiles. To induce diuresis, natriuresis, glucosuria, and antikaliuresis, 8-aminoguanine (or its prodrug 8-aminoguanosine) would be preferred. If only diuresis and natriuresis, without marked glucosuria or antikaliuresis, is desired, 8-aminohypoxanthine or 8-aminoinosine might be useful. Finally, here we report the in vivo existence of another pharmacologically active 8-aminopurine, namely 8-aminoinosine. SIGNIFICANCE STATEMENT: Here, we report that a family of 8-aminopurines affects renal excretory function: effects that may be useful for treating multiple diseases including hypertension, heart failure, and chronic kidney disease. For diuresis and natriuresis accompanied by glucosuria and antikaliuresis, 8-aminoguanine (or its prodrug 8-aminoguanosine) would be useful; if only diuresis and natriuresis is called for, 8-aminohypoxanthine or 8-aminoinosine would be useful. Previously, we identified 8-aminoguanine and 8-aminoguanosine as endogenous 8-aminopurines; here, we extend the family of endogenous 8-aminopurines to include 8-aminoinosine.

8-氨基鸟嘌呤和 8-氨基鸟苷（通过代谢为 8-氨基鸟嘌呤）是内源性 8-氨基嘌呤，通过抑制嘌呤核苷磷酸化酶（PNPase）诱导利尿、利钠和糖尿；此外，这两种 8-氨基嘌呤还通过其他机制引起抗钾利尿。由于 8-氨基肌苷和 8-氨基次黄嘌呤分别与 8-氨基鸟苷和 8-氨基鸟嘌呤结构相似，我们试图确定它们的肾脏排泄作用。首先，我们比较了 8-氨基鸟嘌呤、8-氨基次黄嘌呤和 8-氨基肌苷抑制重组 PNPase 的能力。这些化合物抑制 PNPase 的效力顺序为 8-氨基鸟嘌呤>8-氨基次黄嘌呤=8-氨基肌苷。进一步的研究表明，8-氨基肌苷是一种竞争性底物，可代谢为竞争性 PNPase 抑制剂，即 8-氨基次黄嘌呤。给予每种 8-氨基嘌呤（33.5 µmol/kg）可降低尿中鸟嘌呤与鸟苷的比值和次黄嘌呤与肌苷的比值，证实了它们在体内抑制 PNPase 的能力。三种 8-氨基嘌呤均诱导利尿、利钠和糖尿；然而，8-氨基次黄嘌呤和 8-氨基肌苷的糖尿作用不如 8-氨基鸟嘌呤明显。8-氨基次黄嘌呤和 8-氨基肌苷均不改变钾排泄，而 8-氨基鸟嘌呤引起抗钾利尿。体内给予 8-氨基肌苷可增加 8-氨基次黄嘌呤的排泄，表明 8-氨基次黄嘌呤部分介导了 8-氨基肌苷的作用。最后，黄嘌呤氧化酶将 8-氨基次黄嘌呤代谢为 8-氨基黄嘌呤。使用超高效液相色谱-串联质谱法，我们鉴定出 8-氨基肌苷为内源性 8-氨基嘌呤。总之，8-氨基嘌呤具有有用的药理学特性。为了诱导利尿、利钠、糖尿和抗钾利尿，8-氨基鸟嘌呤（或其前药 8-氨基鸟苷）将是首选。如果仅需要利尿和利钠，而没有明显的糖尿和抗钾利尿，则可以使用 8-氨基次黄嘌呤或 8-氨基肌苷。最后，在这里我们报告了另一种具有药理活性的内源性 8-氨基嘌呤，即 8-氨基肌苷的体内存在。

意义陈述

在这里，我们报告了一组 8-氨基嘌呤会影响肾脏的排泄功能：这些作用可能对治疗多种疾病有用，包括高血压、心力衰竭和慢性肾病。对于利尿、利钠伴有糖尿和抗钾利尿，8-氨基鸟嘌呤（或其前药 8-氨基鸟苷）将是有用的；如果仅需要利尿和利钠，则可以使用 8-氨基次黄嘌呤或 8-氨基肌苷。此前，我们已将 8-氨基鸟嘌呤和 8-氨基鸟苷鉴定为内源性 8-氨基嘌呤；在这里，我们将内源性 8-氨基嘌呤家族扩展到包括 8-氨基肌苷。