The 8-Aminopurine Hypothesis

8-氨基嘌呤假说

• 批准号: 10038684
• 负责人: EDWIN Kerry JACKSON
• 金额: $ 50.18万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10038684
• 关键词: 2-Aminopurine; Anabolism; Animals; Antihypertensive Agents; Biochemical; Biological; Blood Circulation; Blood Pressure; Brain Injuries; Cardiovascular Diseases; Cessation of life; Chemical Structure; Dahl Hypertensive Rats; Deoxycorticosterone; Diet; Diuretics; Excess Dietary Salt; Excretory function; Funding; Guanine; Guanosine; Heart; Hypertension; Hypoxanthines; Inbred SHR Rats; Inosine; Kidney; Lead; Longevity; Mediating; Metabolic syndrome; Metabolism; Modeling; Oral; Oral Administration; Organ; Pharmacology; Prevention; Publishing; Purine-Nucleoside Phosphorylase; Rattus; Renal function; Sodium Chloride; Stroke; System; Testing; Work; Xanthine Oxidase; analog; blood pressure reduction; dietary salt; experimental study; high salt diet; improved; in vivo; inhaled nitric oxide; inhibitor/antagonist; interstitial; mortality; premature; prevent; protective effect; salt intake; salt sensitive hypertension; saluretic

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.

我们发现8-氨基鸟嘌呤（8A-鸟嘌呤）是一种天然存在的8-氨基嘌呤，具有独特的 药理学特征，即它发挥利尿、利尿钠、糖尿、抗钾尿和抗高血压活性。 此外，8A-鸟嘌呤可防止靶器官损伤并延长 Dahl SS 大鼠的寿命 高盐饮食，有预防盐引起的中风的作用。因为8-氨基鸟苷（8A- 鸟苷）在体循环中转化为 8A-鸟嘌呤，这种 8-氨基嘌呤具有与 8A-鸟嘌呤。 8A-鸟嘌呤（以及 8A-鸟苷通过代谢为 8A-鸟嘌呤）的作用机制是 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，在 Dahl SS 大鼠中，高盐饮食 (4%) 降低了 8A- 的内源性肾间质水平 鸟苷和 8A-鸟嘌呤分别减少 85% 和 100%。这些初步研究表明，高 盐摄入会导致 8-氨基嘌呤缺乏，至少在 Dahl SS 大鼠中是如此；但这一发现必须得到证实 Dahl SS 大鼠并在其他高血压模型中进行了测试。我们想到 8-氨基肌苷 (8A-Ino) 和 8-氨基次黄嘌呤 (8A-HX) 的化学结构与 8A-鸟苷和 8A-鸟嘌呤非常相似， 分别是天然存在的肌苷和次黄嘌呤的类似物；因此我们 推断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。 由于没有人检查过 8A-Ino 或 8A-HX 的生物学效应，我们进行了初步研究 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 可能具有 对肾功能的影响与 8A-鸟苷和 8A-鸟嘌呤相似，但可能更有效 在这方面。然而，这些发现必须得到证实。另外，尚不清楚：1）8A-Ino是否有效果 通过其代谢介导为 8A-HX； 2）8A-Ino和8A-HX是否具有降压和器官功能 保护作用； 3) 8A-Ino和8A-HX是否像8A-鸟苷和8A-鸟嘌呤一样是天然存在的； 4）高盐饮食是否也会抑制它们的生物合成。我们共同发布和 初步研究结果激发了我们的“8-氨基嘌呤假说”，该假说假设：1) 8A-鸟苷， 8A-鸟嘌呤、8A-Ino 和 8A-HX 组成天然存在的 8-氨基嘌呤系统 利钠、降压和器官保护； 2) 8-氨基嘌呤缺乏会导致盐- 敏感高血压、靶器官损伤和死亡率； 3) 8-氨基嘌呤缺乏症可能是 通过口服 8-氨基嘌呤治疗来纠正。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 的肾脏影响； 2）确定高盐饮食是否会导致缺乏症 全部 4 个 8-氨基嘌呤； 3) 确定 8A-Ino 和 8A-HX 是否像 8A-鸟苷和 8A-鸟嘌呤一样， 具有降压作用并防止靶器官损伤。最后，我们将探讨是否 8A-Ino和8A-HX的作用机制不仅涉及PNPase的抑制，还涉及黄嘌呤氧化酶的抑制。