The 8-Aminopurine Hypothesis

8-氨基嘌呤假说

• 批准号: 10650178
• 负责人: EDWIN Kerry JACKSON
• 金额: $ 50.96万
• 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/10650178
• 关键词: 2-Aminopurine; Anabolism; Animals; Antihypertensive Agents; Biochemical; Biological; Blood Pressure; Brain Injuries; Cardiovascular Diseases; Cessation of life; Chemical Structure; Circulation; Dahl Hypertensive Rats; Deoxycorticosterone; Diet; Diuretics; Excess Dietary Salt; Excretory function; Funding; Heart; Hypertension; Hypoxanthines; Inbred SHR Rats; Inosine; Kidney; Longevity; Mediating; Metabolic syndrome; Metabolism; Modeling; Oral; Oral Administration; Organ; 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; hypertensive; improved; in vivo; inhibitor; interstitial; mortality; pharmacologic; premature; prevent; protective effect; salt intake; salt sensitive hypertension; saluretic; translational potential

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-氨基瓜氨酸（8a-瓜氨酸）是一种天然的8-氨基嘌呤，具有独特的 药理学特征，即，它导出利尿剂，脂肪尿剂，葡萄糖尿疗法，抗红血药和降压活性。 此外，8A-瓜氨酸可以防止目标器官损害，并增加了Dahl SS大鼠的寿命 高盐饮食，由于预防盐引起的中风而产生的作用。因为8-aminoguanosine（8a-- 在全身循环中，鸟嘌呤被转化为8a-瓜氨酸，这种8-氨基嘌呤的作用与 8a-瓜氨酸。 8a-瓜氨酸的作用机理（和8A-瓜氨酸通过其代谢为8a-瓜氨酸）是 主要是通过抑制嘌呤核磷酸化酶（PNPase）。重要的是，在初步实验中 观察到，在达尔SS中，高盐饮食（4％）降低了8a-的内源性肾脏间质水平 鸟嘌呤和8A-瓜氨酸分别为85％和100％。这些初步研究表明 盐摄入至少在DAHL SS大鼠中诱导8-氨基尿素缺乏症；但是这一发现必须在 DAHL SS大鼠并在其他高血压模型中进行了测试。我们发生了8-氨基氨氨酸（8a-ino）和 8-氨基黄嘌呤（8A-HX）的化学结构非常类似于8a-瓜氨酸和8A-瓜氨酸， 分别是天然肌苷和甲黄嘌呤的类似物。因此我们 有理由认为这些化合物也可能是具有有益的生物学活性的内源性8-氨基尿素。 因为没有人检查过8A-ino或8a-hx的生物学效应，所以我们进行了初步 这些化合物的肾脏研究。这些初步研究表明，8a-ino和8a-hx可能具有 对肾功能的影响类似于8A-瓜氨酸和8A-瓜氨酸的影响，但可能更有效 在这方面。但是，必须确认这些发现。另外，这是未知的：1）8a-ino的影响是否 通过其代谢介导至8A-HX； 2）8a-ino和8a-hx是否具有降压和器官 保护作用； 3）8a-ino和8a-hx（例如8a-瓜氨酸和8a-瓜氨酸）是否自然存在； 4）高盐饮食是否也抑制了它们的生物合成。一起，我们出版了 初步发现激发了我们的“ 8-氨基尿假设假设”，该假设假设：1）8a-瓜氨酸， 8a-瓜氨酸，8A-ino和8a-hx包括一个天然的8-氨基嘌呤系统 纳特里尔特，降压和器官保护； 2）8-氨基嘌呤缺乏症有助于盐 - 敏感的高血压，目标器官损伤和死亡率； 3）8-氨基嘌呤缺乏症可能是 通过用8-氨基嘌呤的口服治疗纠正。在这里，我们建议通过：1）进一步检验此假设 阐明8a-ino和8a-hx的肾脏效应； 2）确定高盐饮食是否诱发缺乏症 在所有4个8-氨基尿素中； 3）确定8a-ino和8a-hx，例如8a-瓜氨酸和8a-瓜氨酸， 具有降压活性并防止目标器官损伤。最后，我们将探索是否 8A-INO和8A-HX的作用机理不仅涉及PNPase的抑制，而且还涉及氧化黄氨酸的抑制作用。