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The article discusses the potential of 8-aminopurines, specifically those containing the nucleobase guanine, as a new direction for purine-based therapeutics. Research has shown promising results in using 8-aminopurines to develop treatments for cardiovascular diseases, renal diseases, and age-related disorders. The mechanism of action involves rebalancing the purine metabolome by increasing levels of protective purines while reducing tissue-damaging purines. The study is funded by the National Institutes of Health and the Richard King Mellon Foundation, and the authors have patents related to medical uses of 8-aminopurines. [Extracted from the article]

Background Lower urinary tract syndrome (LUTS) is a group of urinary tract symptoms and signs that can include urinary incontinence. Advancing age is a major risk factor for LUTS; however, the underlying biochemical mechanisms of age-related LUTS remain unknown. Hypoxanthine (HX) is a purine metabolite associated with generation of tissue-damaging reactive oxygen species (ROS). This study tested the hypothesis that exposure of the adult bladder to HX–ROS over time damages key LUT elements, mimicking qualitatively some of the changes observed with aging. Methods Adult 3-month-old female Fischer 344 rats were treated with vehicle or HX (10 mg/kg/day; 3 weeks) administered in drinking water. Targeted purine metabolomics and molecular approaches were used to assess purine metabolites and biomarkers for oxidative stress and cellular damage. Biomechanical approaches assessed LUT structure and measurements of LUT function (using custom-metabolic cages and cystometry) were also employed. Results HX exposure increased biomarkers indicative of oxidative stress, pathophysiological ROS production, and depletion of cellular energy with declines in NAD+ levels. Moreover, HX treatment caused bladder remodeling and decreased the intercontraction interval and leak point pressure (surrogate measure to assess stress urinary incontinence). Conclusions These studies provide evidence that in adult rats chronic exposure to HX causes changes in voiding behavior and in bladder structure resembling alterations observed with aging. These results suggest that increased levels of uro-damaging HX were associated with ROS/oxidative stress-associated cellular damage, which may be central to age-associated development of LUTS, opening up potential opportunities for geroscience-guided interventions. [ABSTRACT FROM AUTHOR]

Screening of compounds comprising 8-substituted guanine revealed that 8-aminoguanosine and 8-aminoguanine cause diuresis/natriuresis/glucosuria, yet decrease potassium excretion. Subsequent investigations demonstrated that 8-aminoguanosine's effects are mediated by its metabolite 8-aminoguanine. The mechanism by which 8-aminoguanine causes diuresis/natriuresis/glucosuria involves inhibition of PNPase (purine nucleoside phosphorylase), which increases renal interstitial inosine levels. Additional evidence suggests that inosine, via indirect or direct adenosine A2B receptor activation, increases renal medullary blood flow which enhances renal excretory function. Likely, 8-aminoguanine has pleiotropic actions that also alter renal excretory function. Indeed, the antikaliuretic effects of 8-aminoguanine are independent of PNPase inhibition. 8-Aminoguanine is an endogenous molecule; nitrosative stress leads to production of biomolecules containing 8-nitroguanine moieties. Degradation of these biomolecules releases 8-nitroguanosine and 8-nitro-2'-deoxyguanosine which are converted to 8-aminoguanine. Also, guanosine and guanine per se may contribute to 8-aminoguanine formation. 8-Aminoinosine, 8-aminohypoxanthine, and 8-aminoxanthine likewise induce diuresis/natriuresis/glucosuria, yet do not reduce potassium excretion. Thus, there are several pharmacologically active 8-aminopurines with nuanced effects on renal excretory function. Chronic treatment with 8-aminoguanine attenuates hypertension in deoxycorticosterone/salt rats, prevents strokes, and increases lifespan in Dahl salt-sensitive rats on a high salt diet and attenuates the metabolic syndrome in rats; 8-aminoguanosine retards progression of pulmonary hypertension in rats and anemia and organ damage in sickle cell mice. 8-Aminoguanine reverses age-associated lower urinary tract dysfunction and retinal degeneration. 8-Aminopurines represent a new class of agents (and potentially endogenous factors) that have beneficial effects on the cardiovascular system and kidneys and may turn back the clock in age-associated diseases. [ABSTRACT FROM AUTHOR]