The 8-Aminopurine Hypothesis

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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.