# The 8-Aminopurine Hypothesis

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $501,758

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10192785
- **Project number:** 5R01HL109002-10
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** EDWIN Kerry JACKSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $501,758
- **Award type:** 5
- **Project period:** 2012-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10192785

## Citation

> US National Institutes of Health, RePORTER application 10192785, The 8-Aminopurine Hypothesis (5R01HL109002-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10192785. Licensed CC0.

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