The 8-Aminopurine Hypothesis

我们发现，8-氨基鸟嘌呤(8A-guanine)是一种天然存在的8-氨基嘌呤，具有独特的 药理概况，即它发挥利尿、利钠、葡萄糖、抗钾和抗高血压活性。 此外，8A-鸟嘌呤还可预防靶器官损伤，延长Dahl SS大鼠的寿命。 高盐饮食，对预防盐性中风有一定效果。因为8-氨基鸟苷(8A- 8-氨基嘌呤)在体循环中转化为8A-鸟氨酸，这种8-氨基嘌呤的作用类似于 8A-鸟嘌呤。8A-鸟嘌呤的作用机理为： 主要通过抑制嘌呤核苷磷酸化酶(PNPase)。重要的是，在初步实验中，我们 观察到Dahl SS大鼠高盐饮食(4%)可降低内源性肾间质8A- 鸟苷和8A-鸟氨酸分别增加85%和100%。这些初步研究表明， 盐摄入导致8-氨基嘌呤缺乏，至少在Dahl SS大鼠中是这样；但这一发现必须在 Dahl SS大鼠，并在其他高血压模型中进行测试。我们想到了8-氨基肌苷(8A-INO)和 8-氨基次黄嘌呤(8A-HX)具有与8A-鸟苷和8A-鸟氨酸非常相似的化学结构， 分别是天然肌苷和次黄嘌呤的类似物；因此我们 推测这些化合物也可能是具有有益生物活性的内源性8-氨基嘌呤。 由于还没有人研究8A-Ino或8A-HX的生物学效应，我们进行了初步的 用这些化合物进行肾脏研究。这些初步研究表明，8A-Ino和8A-Hx可能都有 对肾功能的影响与8A-鸟苷和8A-鸟苷相似，但可能更有效 在这方面。然而，这些发现必须得到证实。此外，尚不清楚：1)8A-Ino的作用是否 2)8A-Ino和8A-HX是否具有降压和器官保护作用。 保护作用；3)8A-Ino和8A-HX是否像8A-鸟苷和8A-鸟氨酸一样是自然产生的； 以及4)它们的生物合成是否也受到高盐饮食的抑制。总而言之，我们出版的和 初步发现支持我们的“8-氨基嘌呤假说”，即：1)8A-鸟苷， 8A-鸟嘌呤、8A-Ino和8A-HX组成了自然产生的8-氨基嘌呤系统，该系统 利钠、降压和器官保护；2)8-氨基嘌呤缺乏导致盐缺乏。 敏感性高血压、靶器官损害和死亡率；以及3)8-氨基嘌呤缺乏症 经口服8-氨基嘌呤纠正。在这里，我们建议通过以下方式进一步检验这一假设：1) 阐明8A-Ino和8A-HX对肾脏的影响；2)确定高盐饮食是否会导致缺盐 以及3)确定8A-Ino和8A-Hx是否像8A-鸟苷和8A-鸟氨酸一样， 具有抗高血压活性，防止靶器官损伤。最后，我们将探讨 8A-Ino和8A-HX的作用机制不仅涉及对PNPase的抑制，而且还涉及对黄嘌呤氧化酶的抑制。

We have discovered that 8-aminoguanine (8A-Guanine), a naturally-occurring 8-aminopurine, has a unique pharmacological profile, i.e., it exerts diuretic, natriuretic, glucosuric, antikaluretic and antihypertensive activity. In addition, 8A-Guanine protects against target-organ damage and increases the lifespan of Dahl SS rats on a high salt diet, an effect due to prevention of salt-induced strokes. Because 8-aminoguanosine (8A- Guanosine) is converted to 8A-Guanine in the systemic circulation, this 8-aminopurine has similar effects to 8A-Guanine. The mechanism of action of 8A-Guanine (and 8A-Guanosine via its metabolism to 8A-Guanine) is mostly via inhibition of purine nucleoside phosphorylase (PNPase). Importantly, in preliminary experiments we observed that in Dahl SS rats a high salt diet (4%) reduced endogenous renal interstitial levels of 8A- Guanosine and 8A-Guanine by 85% and 100%, respectively. These preliminary studies suggest that a high salt intake induces 8-aminopurine deficiency, at least in Dahl SS rats; but this finding must be confirmed in Dahl SS rats and tested in other models of hypertension. It occurred to us that 8-aminoinosine (8A-Ino) and 8-aminohypoxanthine (8A-HX) have chemical structures very similar to 8A-Guanosine and 8A-Guanine, respectively, and are analogues of naturally-occurring inosine and hypoxanthine, respectively; therefore we reasoned that these compounds too may be endogenous 8-aminopurines with beneficial biological activities. Because no one has ever examined the biological effects of either 8A-Ino or 8A-HX, we conducted preliminary renal studies with these compounds. These preliminary studies suggest that both 8A-Ino and 8A-HX may have effects on renal function similar to those of 8A-Guanosine and 8A-Guanine, but may be even more efficacious in this regard. However, these findings must be confirmed. Also, it is unknown: 1) whether the effects of 8A-Ino are mediated via its metabolism to 8A-HX; 2) whether 8A-Ino and 8A-HX have antihypertensive and organ- protective effects; 3) whether 8A-Ino and 8A-HX, like 8A-Guanosine and 8A-Guanine, are naturally-occurring; and 4) whether their biosynthesis is also suppressed by a high salt diet. Together, our published and preliminary findings motivate our “8-AMINOPURINE HYPOTHESIS”, which postulates that: 1) 8A-Guanosine, 8A-Guanine, 8A-Ino and 8A-HX comprise a naturally-occurring 8-aminopurine system that is natriuretic, antihypertensive and organ-protective; 2) 8-aminopurine deficiency contributes to salt- sensitive hypertension, target-organ damage and mortality; and 3) 8-aminopurine deficiency can be corrected by oral treatment with 8-aminopurines. Here we propose to further test this hypothesis by: 1) elucidating the renal effects of 8A-Ino and 8A-HX; 2) determining whether a high salt diet induces a deficiency in all 4 8-aminopurines; and 3) determining whether 8A-Ino and 8A-HX, like 8A-Guanosine and 8A-Guanine, have antihypertensive activity and prevent target organ damage. Finally, we will explore whether the mechanism of action of 8A-Ino and 8A-HX involves not only inhibition of PNPase, but also of xanthine oxidase.