Background 8-Aminoguanosine and 8-aminoguanine are K+-sparing natriuretics that increase glucose excretion. Most effects of 8-aminoguanosine are due to its metabolism to 8-aminoguanine. However, the mechanism by which 8-aminoguanine affects renal function is unknown and is the focus of this investigation. Methods and Results Because 8-aminoguanine has structural similarities with inhibitors of the epithelial sodium channel (ENaC), Na+/H+ exchangers, and adenosine A1 receptors, we examined the effects of 8-aminoguanine on EN aC activity in mouse collecting duct cells, on intracellular pH of human proximal tubular epithelial cells, on responses to a selective A1-receptor agonist in vivo, and on renal excretory function in A1-receptor knockout rats. These experiments showed that 8-aminoguanine did not block EN aC, Na+/H+ exchangers, or A1 receptors. Because Rac1 enhances activity of mineralocorticoid receptors and some guanosine analogues inhibit Rac1, we examined the effects of 8-aminoguanine on Rac1 activity in mouse collecting duct cells. Rac1 activity was significantly inhibited by 8-aminoguanine. Because in vitro 8-aminoguanine is a purine nucleoside phosphorylase ( PNP ase) inhibitor, we examined the effects of a natriuretic dose of 8-aminoguanine on urinary excretion of PNP ase substrates and products. 8-Aminoguanine increased and decreased, respectively, urinary excretion of PNP ase substrates and products. Next we compared in rats the renal effects of intravenous doses of 9-deazaguanine ( PNP ase inhibitor) versus 8-aminoguanine. 8-Aminoguanine and 9-deazaguanine induced similar increases in urinary Na+ and glucose excretion, yet only 8-aminoguanine reduced K+ excretion. Nsc23766 (Rac1 inhibitor) mimicked the effects of 8-aminoguanine on K+ excretion. Conclusions 8-Aminoguanine increases Na+ and glucose excretion by blocking PNP ase and decreases K+ excretion by inhibiting Rac1.
Keywords: 8‐aminoguanine; 8‐aminoguanosine; Rac1; diuretic; natriuretic; purine nucleoside phosphorylase.