Jackson Edwin K, Tofovic Stevan P, Chen Yuanyuan, Birder Lori A
Department of Pharmacology and Chemical Biology (E.K.J., S.P.T., Y.C., L.A.B.), University of Pittsburgh School of Medicine, Pittsburgh, PA.
Department of Medicine (E.K.J., S.P.T., L.A.B.), University of Pittsburgh School of Medicine, Pittsburgh, PA.
Hypertension. 2024 Dec;81(12):2410-2414. doi: 10.1161/HYPERTENSIONAHA.124.21726. Epub 2024 Oct 21.
Research in purinergic pharmacology has yielded major advances in cardiovascular therapeutics such as adenosine for terminating atrioventricular reentrant tachycardia, regadenoson for pharmacological ischemic stress testing, and selective P2Y receptor antagonists for prevention of stroke and myocardial infarction. Mechanistically, these FDA-approved purine-based therapeutics activate or antagonize receptors having endogenous ligands containing the purine nucleobase adenine. Recent discoveries suggest a novel direction for purine-based therapeutics. An investigation of the cardiorenal effects of 8-substituted guanosine and guanine derivatives revealed that 8-aminoguanosine and 8-aminoguanine acutely trigger diuresis, natriuresis, and glucosuria, with the effects of 8-aminoguanosine being mediated by its rapid conversion to 8-aminoguanine. Mechanistic studies showed that 8-aminoguanine induces diuresis/natriuresis/glucosuria in part by inhibiting purine nucleoside phosphorylase (PNPase). Inhibition of PNPase increases its substrates (inosine and guanosine) while decreasing its products (hypoxanthine and guanine), thus “rebalancing” the purine metabolome. Additional mechanistic studies revealed that inosine activates adenosine A receptors which increases renal medullary blood flow thus enhancing renal excretory function. 8-Aminoguanine also reduces potassium excretion by an incompletely understood mechanism independent of PNPase inhibition. Emerging evidence suggests the existence of a family of endogenous and pharmacologically active 8-aminopurines that may include not only 8-aminoguanosine and 8-aminoguanine, but also 8-aminoinosine, 8-aminohypoxanthine and 8-aminoxanthine. 8-Aminopurines have beneficial effects in animal models of systemic and pulmonary hypertension, the metabolic syndrome, chronic kidney disease, strokes, and sickle cell disease. Also, 8-aminopurines reverse age-associated lower urinary tract dysfunction and retinal degeneration. 8-Aminopurines hold promise for treating cardiovascular and renal diseases and may “turning back the clock” on age-associated disorders.
嘌呤能药理学的研究在心血管治疗方面取得了重大进展，例如用于终止房室折返性心动过速的腺苷、用于药理学缺血应激试验的瑞加腺苷，以及用于预防中风和心肌梗死的选择性P2Y受体拮抗剂。从机制上讲，这些获得美国食品药品监督管理局（FDA）批准的基于嘌呤的疗法可激活或拮抗具有含嘌呤核碱基腺嘌呤的内源性配体的受体。最近的发现为基于嘌呤的疗法指明了一个新方向。一项关于8-取代鸟苷和鸟嘌呤衍生物对心肾影响的研究表明，8-氨基鸟苷和8-氨基鸟嘌呤可急性引发利尿、利钠和糖尿，8-氨基鸟苷的作用是由其迅速转化为8-氨基鸟嘌呤介导的。机制研究表明，8-氨基鸟嘌呤部分通过抑制嘌呤核苷磷酸化酶（PNPase）诱导利尿/利钠/糖尿。抑制PNPase会增加其底物（肌苷和鸟苷），同时减少其产物（次黄嘌呤和鸟嘌呤），从而“重新平衡”嘌呤代谢组。进一步的机制研究表明，肌苷激活腺苷A受体，增加肾髓质血流量，从而增强肾脏排泄功能。8-氨基鸟嘌呤还通过一种尚未完全了解的、独立于PNPase抑制的机制减少钾排泄。新出现的证据表明存在一类内源性且具有药理活性的8-氨基嘌呤，可能不仅包括8-氨基鸟苷和8-氨基鸟嘌呤，还包括8-氨基肌苷、8-氨基次黄嘌呤和8-氨基黄嘌呤。8-氨基嘌呤在系统性和肺动脉高压、代谢综合征、慢性肾病、中风和镰状细胞病的动物模型中具有有益作用。此外，8-氨基嘌呤可逆转与年龄相关的下尿路功能障碍和视网膜变性。8-氨基嘌呤有望用于治疗心血管和肾脏疾病，并可能使与年龄相关的疾病“时光倒流”。
