Purine nucleoside phosphorylase as a target for the treatment of interstitial cystitis/bladder pain syndrome with and without Hunner lesions.

Chronic visceral pain disorders, such as interstitial cystitis/bladder pain syndrome (IC/BPS), are difficult to treat, and therapies are limited in number and efficacy. Emerging evidence suggests that alterations in the enzyme purine nucleoside phosphorylase (PNPase) may participate in oxidative injury and cellular damage. PNPase is important for the metabolism of 'tissue-protective' purine metabolites to 'tissue-damaging' purines that generate free radicals. The aim of this study is to test whether patients living with IC/BPS without or with Hunner lesions and irrespective of any therapies exhibit purine dysregulation with higher levels of tissue-damaging purine metabolites as measured by liquid chromatography-tandem mass spectrometry. Our results demonstrate that levels of urotoxic purine metabolites (hypoxanthine and xanthine) in IC/BPS patients with and without Hunner lesions are elevated compared to healthy controls. These findings suggest there may be pathophysiologic commonalities between patient subtypes. Furthermore, the accumulation of uroprotective purines and depletion of urodamaging purines by PNPase inhibition may be therapeutically effective in both groups of patients.

8-Aminoguanine and its actions in the metabolic syndrome.

The metabolic syndrome is characterized by obesity, insulin resistance, dyslipidemia and hypertension and predisposes to cardiorenal injury. Here, we tested our hypothesis that 8-aminoguanine, an endogenous purine, exerts beneficial effects in Zucker Diabetic-Sprague Dawley (ZDSD) rats, a preclinical model of the metabolic syndrome. ZDSD rats were instrumented for blood pressure radiotelemetry and randomized to vehicle or 8-aminoguanine (10 mg/kg/day, po). The protocol was divided into four phases: Phase 1: 17 days of tap water/normal diet; Phase 2: 30 days of 1% saline/normal diet; Phase 3: 28 days of 1% saline/diabetogenic diet; Phase 4: acute/terminal measurements. 8-Aminoguanine: (1) decreased mean arterial blood pressure (P = 0.0004; 119.5 ± 1.0 (vehicle) versus 116.3 ± 1.0 (treated) mmHg) throughout all three phases of the radiotelemetry study; (2) rebalanced the purine metabolome away from hypoxanthine (pro-inflammatory) and towards inosine (anti-inflammatory); (3) reduced by 71% circulating IL-1ß, a cytokine that contributes to hypertension-induced adverse cardiovascular events and type 2 diabetes; (4) attenuated renovascular responses to angiotensin II; (5) improved cardiac and renal histopathology; (6) attenuated diet-induced polydipsia/polyuria; and (7) reduced HbA1c. In the metabolic syndrome, 8-aminoguanine lowers blood pressure, improves diabetes and reduces organ damage, likely by rebalancing the purine metabolome leading to reductions in injurious cytokines such as IL-1ß.

GEOMETRIC CHARACTERIZATION OF RAT URINARY BLADDER WALL DURING EX-VIVO FILLING USING MICRO-COMPUTED TOMOGRAPHY (MICRO-CT).

Current mechanical models of the bladder largely idealize the bladder as spherical with uniform thickness. This present study aims to investigate this idealization using micro-CT to generate 3D reconstructed models of rat bladders at 10-20 micrometer resolution in both voided and filled states. Applied to three rat bladders, this approach identifies shape, volume, and thickness variations under different pressures. These results demonstrate the filling/voiding process is far from the idealized spherical inflation/contraction. However, the geometry idealizations may be reasonable in cases where the filled bladder geometry is of importance, such as in studies of growth and remodeling.

Quantification of Aging-Related Decreases in Sensory Innervation of the Bladder Trigone in Rats.

PURPOSE: The prevalence of lower urinary tract symptoms (LUTS), characterized by problems regarding storage and/or voiding of urine, is known to significantly increase with age. Effective communication between the lower urinary tract and the central nervous system (CNS) is essential for the optimal function of this system, and heavily relies on the efficient interaction between the bladder urothelium and the afferent nerve fibers situated in close proximity to the urothelium within the lamina propria. METHODS: We aimed to quantify aging-related differences in the expression of calcitonin gene-related peptide (CGRP, an established marker for sensory nerve fibers) in the trigonal mucosal layers of young (3-4 months) and aged (25-30 months) rats. We evaluated trigonal tissue from 3 animals per age group. Tissue was serially sectioned at 10 µm and stained for CGRP. Images were taken along the full length of the tissue. For each image we computed the total CGRP-positive area (µm2) and the median value for each animal was used for further analysis. RESULTS: Upon statistical analysis the aged rats show a significantly lower CGRP-positive area compared to young rats (P=0.0049). These results indicate that aging has a negative effect on the area of CGRP-positive signal in the trigone. CONCLUSION: The structural and functional integrity of the sensory web in the trigonum of rats is negatively affected by the aging process, potentially leading to impaired communication between the bladder urothelium the CNS. Consequently, these perturbations in the sensory system may contribute to the pathogenesis or exacerbation LUTS.

Purine nucleoside phosphorylase inhibition is an effective approach for the treatment of chemical hemorrhagic cystitis.

Hemorrhagic cystitis may be induced by infection, radiation therapy, or medications or may be idiopathic. Along with hemorrhagic features, symptoms include urinary urgency and frequency, dysuria (painful urination), and visceral pain. Cystitis-induced visceral pain is one of the most challenging types of pain to treat, and an effective treatment would address a major unmet medical need. We assessed the efficacy of a purine nucleoside phosphorylase inhibitor, 8-aminoguanine (8-AG), for the treatment of hemorrhagic/ulcerative cystitis. Lower urinary tract (LUT) function and structure were assessed in adult Sprague-Dawley rats, treated chronically with cyclophosphamide (CYP; sacrificed day 8) and randomized to daily oral treatment with 8-AG (begun 14 days prior to CYP induction) or its vehicle. CYP-treated rats exhibited multiple abnormalities, including increased urinary frequency and neural mechanosensitivity, reduced bladder levels of inosine, urothelial inflammation/damage, and activation of spinal cord microglia, which is associated with pain hypersensitivity. 8-AG treatment of CYP-treated rats normalized all observed histological, structural, biochemical, and physiological abnormalities. In cystitis 8-AG improved function and reduced both pain and inflammation likely by increasing inosine, a tissue-protective purine metabolite. These findings demonstrate that 8-AG has translational potential for reducing pain and preventing bladder damage in cystitis-associated LUT dysfunctions.

Pathophysiology, clinical presentation, and management of ketamine-induced cystitis.

Ketamine is illegally used as a recreational drug in many Asian countries. Long-term ketamine abusers often develop irritable bladder symptoms that gradually develop into more severe urinary frequency and urgency and eventually into a painful ulcerated bladder. These patients typically have reduced functional bladder capacity, increased bladder sensation, detrusor overactivity, severe urgency, urinary incontinence, and bladder contracture. Ketamine metabolites can cause severe inflammation of the urothelium, urothelial barrier deficits, vascular endothelial fibrinoid changes, increased oxidative stress, and bladder wall fibrosis. A decrease in bladder compliance, urinary tract infection, severe bladder pain with a full bladder, and painful micturition are also common symptoms. Finally, with continued abuse of ketamine, hydronephrosis, ureteral stricture, vesicoureteral reflux, and renal failure may develop. Cessation of ketamine is the mainstay of treatment. Lower urinary tract symptoms usually relapse if patients reuse ketamine after stopping. In cases of severe ketamine cystitis, only augmentation enterocystoplasty can relieve bladder pain and restore normal lower urinary tract function. This article reviews the underlying pathophysiology, clinical characteristics, and management of ketamine cystitis.

Hypoxanthine Induces Signs of Bladder Aging with Voiding dysfunction and Lower Urinary Tract Remodeling.

BACKGROUND: Lower urinary tract syndrome (LUTS) is a group of urinary tract symptoms and signs which can include urinary incontinence. Advancing age is a major risk factors for LUTS; however the underlying biochemical mechanisms of age-related LUTS remain unknown. HX (hypoxanthine) 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 (F344) 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.

8-Aminopurines in the Cardiovascular and Renal Systems and Beyond.

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.

Sensory Receptor, Inflammatory, and Apoptotic Protein Expression in the Bladder Urothelium of Patients with Different Subtypes of Interstitial Cystitis/Bladder Pain Syndrome.

The aim of this study was to investigate the expression levels of sensory receptors, inflammatory proteins, and pro-apoptotic proteins in the urothelium of non-Hunner's interstitial cystitis (NHIC) bladders of patients with different clinical and cystoscopic phenotypes. The urothelia from the bladders of 52 NHIC patients were harvested. The expression of sensory receptors, including TRPV1, TRPV4, TRPA1, H1-receptors, and sigma-1 receptors; the inflammatory proteins p38 and tryptase; and the pro-apoptotic proteins, such as caspase-3, BAD, and BAX in the urothelium, were investigated using immunohistochemistry and Western blotting. We compared the expression levels of these proteins in NHIC subtypes according to IC symptom scores, visual analog scores of bladder pain, maximal bladder capacity, glomerulation grades, and combined maximal bladder capacity and glomerulations after cystoscopic hydrodistention. The expression levels of TRPV1, TRPV4, sigma-1, P38, tryptase, caspase-3, and BAD were significantly increased in the urothelium of IC/BPS patients compared with the expression levels in the controls. TRPV1 was significantly associated with IC symptom severity. However, no significant differences in sensory receptor expression in the IC/BPS bladders with different bladder conditions were detected. Inflammatory and pro-apoptotic protein expression levels in the urothelium were similar among the IC/BPS subgroups. This study concluded that IC/BPS patients with frequency and bladder pain complaints have higher levels of urothelial sensory receptors, and inflammatory and pro-apoptotic proteins. The expression levels of these sensory receptors, inflammatory proteins, and pro-apoptotic proteins are not significantly different among IC/BPS bladders with different conditions.

Overactive Bladder and Cognitive Impairment: The American Urogynecologic Society and Pelvic Floor Disorders Research Foundation State-of-the-Science Conference Summary Report.

IMPORTANCE: Overactive bladder (OAB) is prevalent in older adults in whom management is complicated by comorbidities and greater vulnerability to the cognitive effects of antimuscarinic medications. OBJECTIVES: The aim of this study is to provide a comprehensive evidence-based summary of the 2021 State-of-the-Science (SOS) conference and a multidisciplinary expert literature review on OAB and cognitive impairment. STUDY DESIGN: The American Urogynecologic Society and the Pelvic Floor Disorders Research Foundation convened a 3-day collaborative conference. Experts from multidisciplinary fields examined cognitive function, higher neural control of the OAB patient, risk factors for cognitive impairment in older patients, cognitive effects of antimuscarinic medications for OAB treatment, OAB phenotyping, conservative and advanced OAB therapies, and the need for a multidisciplinary approach to person-centered treatment. Translational topics included the blood-brain barrier, purine metabolome, mechanotransduction, and gene therapy for OAB targets. RESULTS: Research surrounding OAB treatment efficacy in cognitively impaired individuals is limited. Short- and long-term outcomes regarding antimuscarinic effects on cognition are mixed; however, greater anticholinergic burden and duration of use influence risk. Oxybutynin is most consistently associated with negative cognitive effects in short-term, prospective studies. Although data are limited, beta-adrenergic agonists do not appear to confer the same cognitive risk. CONCLUSIONS: The 2021 SOS summary report provides a comprehensive review of the fundamental, translational, and clinical research on OAB with emphasis on cognitive impairment risks to antimuscarinic medications. Duration of use and antimuscarinic type, specifically oxybutynin when examining OAB treatments, appears to have the most cognitive impact; however, conclusions are limited by the primarily cognitively intact population studied. Given current evidence, it appears prudent to minimize anticholinergic burden by emphasizing nonantimuscarinic therapeutic regimens in the older population and/or those with cognitive impairment.

Evidence-Informed, Interdisciplinary, Multidimensional Action Plan to Advance Overactive Bladder Research and Treatment Initiatives: Directives From State-of-the-Science Conference on Overactive Bladder and Cognitive Impairment.

ABSTRACT: This article outlines an evidence-informed, interdisciplinary, multidimensional, comprehensive action plan for the American Urogynecologic Society to improve care of women with overactive bladder (OAB) while minimizing treatment-related adverse events, including cognitive impairment. It is a "call to action" to advance basic, translational, and clinical research and summarizes initiatives developed at the State-of-the-Science Conference on OAB and Cognitive Impairment to (1) develop framework for a new OAB treatment approach in women, (2) define research gaps and future research priorities, (3) champion health equity and diversity considerations in OAB treatment, (4) foster community and promote education to remove stigma surrounding OAB and urinary incontinence, and (5) elevate visibility and impact of OAB, by creating partnerships through education and engagement with health care professionals, industry, private and public payers, funding agencies, and policymakers.

Between-subject similarity of functional connectivity-based organization of the human periaqueductal gray related to autonomic processing.

The periaqueductal gray (PAG) is a brain stem area designated to play an essential role in lower urinary tract (LUT) control. Post-mortem human and animal studies have indicated that the PAG is symmetrically organized in functionally and anatomically distinct columns which are involved in sympathetic or parasympathetic autonomic control of the LUT. The current study aims to find consistency across subjects and identify homologous clusters between subjects. Here, we evaluated data from 10 female participants. During a bladder filling protocol, we ran a resting-state functional magnetic resonance imaging (fMRI) scan while participants experienced a strong desire to void. A voxel-by-voxel correlation matrix of the PAG was created and parcellated using the Louvain module detection algorithm. Resulting in a map of the PAG in which each voxel is assigned to a cluster as determined by the Louvain module detection algorithm. The spatial similarity of resulting clusters between participants was assessed by computing the Dice similarity coefficient for all cluster comparisons. Next, we designed a permutation test to create randomized parcellation maps which enabled us to statistically test the similarity values observed across participants. We observed several significantly similar clusters between subjects compared to permutations (p ≤ 0.05). These results show that the PAG can be parcellated into distinct clusters which show a similar spatial distribution at the group level. This analysis is a crucial step to determine the agreement between in vivo PAG parcellations and the functional and anatomical columnar organization of the PAG which is known from previous research. These advancements may enable us to identify the relationship between LUT symptoms, such as urgency, and activity patterns in the PAG in normal and pathological states.

Purine nucleoside phosphorylase as a target to treat age-associated lower urinary tract dysfunction.

The lower urinary tract (LUT), including the bladder, urethra and external striated muscle, becomes dysfunctional with age; consequently, many older individuals suffer from lower urinary tract disorders (LUTDs). By compromising urine storage and voiding, LUTDs degrade quality of life for millions of individuals worldwide. Treatments for LUTDs have been disappointing, frustrating both patients and their physicians; however, emerging evidence suggests that partial inhibition of the enzyme purine nucleoside phosphorylase (PNPase) with 8-aminoguanine (an endogenous PNPase inhibitor that moderately reduces PNPase activity) reverses age-associated defects in the LUT and restores the LUT to that of a younger state. Thus, 8-aminoguanine improves LUT biochemistry, structure and function by rebalancing the LUT purine metabolome, making 8-aminoguanine a novel potential treatment for LUTDs.

Aging-Associated Changes in Oxidative Stress Negatively Impacts the Urinary Bladder Urothelium.

PURPOSE: Lower urinary tract symptoms are known to significantly increase with age, negatively impacting quality of life and self-reliance. The urothelium fulfills crucial tasks, serving as a barrier protecting the underlying bladder tissue from the harsh chemical composition of urine, and exhibits signaling properties via the release of mediators within the bladder wall that affect bladder functioning. Aging is associated with detrimental changes in cellular health, in part by increasing oxidative stress in the bladder mucosa, and more specifically the urothelium. This, in turn, may impact urothelial mitochondrial health and bioenergetics. METHODS: We collected mucosal tissue samples from both young (3-4 months old) and aged (25-30 months old) rats. Tissue was evaluated for p21-Arc, nitrotyrosine, and cytochrome C expression by western immunoblotting. Urothelial cells were cultured for single-cell imaging to analyze basal levels of reactive oxygen species and the mitochondrial membrane potential. Mitochondrial bioenergetics and cellular respiration were investigated by the Seahorse assay, and measurements of adenosine triphosphate release were made using the luciferin-luciferase assay. RESULTS: Aging was associated with a significant increase in biomarkers of cellular senescence, oxidative stress, and basal levels of reactive oxygen species. The mitochondrial membrane potential was significantly lower in urothelial cell cultures from aged animals, and cultures from aged animals showed a significant decrease in mitochondrial bioenergetics. CONCLUSION: Aging-related increases in oxidative stress and excessive reactive oxygen species may be contributing factors underlying lower urinary tract symptoms in older adults. The mechanisms outlined in this study could be utilized to identify novel pharmaceutical targets to improve aging-associated bladder dysfunction.

Impact of Aging on Urinary Natriuretic Peptides in Nocturia and Nocturnal Polyuria.

PURPOSE: The pathophysiology of nocturia and nocturnal polyuria (NP), conditions that become more prevalent with aging, may in part be explained by changes in hormones involved in water homeostasis. The purpose of this study was to analyze the impact of aging on urinary natriuretic peptides in nocturia and NP. METHODS: Patients aged ≥18 years completed 24-hour bladder diaries for assessment of nocturia and NP. They were divided into subgroups of ≥65 years old and <65 years old. Urine samples were collected and analyzed for natriuretic peptide (NT-proANP, NT-proBNP, and NT-proCNP) levels. Peptide levels were compared between patients with and without nocturia/NP and within age subgroups; correlation to the NP index (NPi) was determined. RESULTS: Compared to patients without nocturia (N=15), patients with nocturia (N=36) had higher median levels of urinary NT-proANP (15.8 pmol/mmol Cr vs. 10.9 pmol/mmol Cr, P=0.016) and NT-proBNP (6.3 pmol/mmol Cr vs. 4.5 pmol/mmol Cr, P=0.021), but showed no differences in NT-proCNP (2.4 pmol/mmol Cr vs. 2.5 pmol/mmol Cr, P=0.967). Patients ≥65 years old with nocturia had higher NT-proANP (29.8 pmol/mmol Cr vs. 11.0 pmol/mmol Cr, P<0.001) and NT-proBNP (9.6 pmol/mmol Cr vs. 5.0 pmol/mmol Cr, P<0.001) than patients <65 years old. Additionally, patients with NP (N=30) showed higher urinary NT-proANP (19.6 pmol/mmol Cr vs. 10.5 pmol/mmol Cr, P<0.001) and NT-proBNP (6.7 pmol/mmol Cr vs. 4.7 pmol/mmol Cr, P=0.020) compared to patients without NP (N=21). NP patients ≥65 years had higher NT-proANP (29.8 pmol/mmol Cr vs. 12.5 pmol/mmol Cr, P<0.001) and NT-proBNP (9.6 pmol/mmol Cr vs. 4.4 pmol/mmol Cr, P=0.004) than patients <65 years old. NPi positively correlated with urinary NT-proANP (RS=0.417, P=0.002) and NT-proBNP (RS=0.303, P=0.031), but not with NT-proCNP (RS=-0.094, P=0.510). CONCLUSION: Since urinary NT-proANP and NT-proBNP were greater in aged patients with nocturia and NP, natriuretic peptides may contribute to the pathophysiology of these conditions and further research should aim to explore them as targets for management.

8-Aminoinosine and 8-Aminohypoxanthine Inhibit Purine Nucleoside Phosphorylase and Exert Diuretic and Natriuretic Activity.

8-Aminoguanine and 8-aminoguanosine (via metabolism to 8-aminoguanine) are endogenous 8-aminopurines that induce diuresis, natriuresis, and glucosuria by inhibiting purine nucleoside phosphorylase (PNPase); moreover, both 8-aminopurines cause antikaliuresis by other mechanisms. Because 8-aminoinosine and 8-aminohypoxanthine are structurally similar to 8-aminoguanosine and 8-aminoguanine, respectively, we sought to define their renal excretory effects. First, we compared the ability of 8-aminoguanine, 8-aminohypoxanthine, and 8-aminoinosine to inhibit recombinant PNPase. These compounds inhibited PNPase with a potency order of 8-aminoguanine > 8-aminohypoxanthine = 8-aminoinosine. Additional studies showed that 8-aminoinosine is a competitive substrate that is metabolized to a competitive PNPase inhibitor, namely 8-aminohypoxanthine. Administration of each 8-aminopurine (33.5 µmol/kg) reduced the guanine-to-guanosine and hypoxanthine-to-inosine ratios in urine, a finding confirming their ability to inhibit PNPase in vivo. All three 8-aminopurines induced diuresis, natriuresis, and glucosuria; however, the glucosuric effects of 8-aminohypoxanthine and 8-aminoinosine were less pronounced than those of 8-aminoguanine. Neither 8-aminohypoxanthine nor 8-aminoinosine altered potassium excretion, whereas 8-aminoguanine caused antikaliuresis. In vivo administration of 8-aminoinosine increased 8-aminohypoxanthine excretion, indicating that 8-aminohypoxanthine mediates, in part, the effects of 8-aminoinosine. Finally, 8-aminohypoxanthine was metabolized to 8-aminoxanthine by xanthine oxidase. Using ultraperformance liquid chromatography-tandem mass spectrometry, we identified 8-aminoinosine as an endogenous 8-aminopurine. In conclusion, 8-aminopurines have useful pharmacological profiles. To induce diuresis, natriuresis, glucosuria, and antikaliuresis, 8-aminoguanine (or its prodrug 8-aminoguanosine) would be preferred. If only diuresis and natriuresis, without marked glucosuria or antikaliuresis, is desired, 8-aminohypoxanthine or 8-aminoinosine might be useful. Finally, here we report the in vivo existence of another pharmacologically active 8-aminopurine, namely 8-aminoinosine. SIGNIFICANCE STATEMENT: Here, we report that a family of 8-aminopurines affects renal excretory function: effects that may be useful for treating multiple diseases including hypertension, heart failure, and chronic kidney disease. For diuresis and natriuresis accompanied by glucosuria and antikaliuresis, 8-aminoguanine (or its prodrug 8-aminoguanosine) would be useful; if only diuresis and natriuresis is called for, 8-aminohypoxanthine or 8-aminoinosine would be useful. Previously, we identified 8-aminoguanine and 8-aminoguanosine as endogenous 8-aminopurines; here, we extend the family of endogenous 8-aminopurines to include 8-aminoinosine.