期刊
JOURNAL OF THE AMERICAN HEART ASSOCIATION
卷 7, 期 21, 页码 -出版社
WILEY
DOI: 10.1161/JAHA.118.010085
关键词
8-aminoguanine; 8-aminoguanosine; diuretic; natriuretic; purine nucleoside phosphorylase; Rac1
资金
- National Institutes of Health [DK091190, HL069846, DK068575, HL109002, DK079307]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL109002] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK079307] Funding Source: NIH RePORTER
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 A(1) receptors, we examined the effects of 8-aminoguanine on ENaC activity in mouse collecting duct cells, on intracellular pH of human proximal tubular epithelial cells, on responses to a selective A(1)-receptor agonist in vivo, and on renal excretory function in A(1)-receptor knockout rats. These experiments showed that 8-aminoguanine did not block ENaC, Na+/H+ exchangers, or A(1) receptors. Because Rac1 enhances activity of mineralocorticoid receptors and some guanosine analogues inhibit Rac 1, 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 (PNPase) inhibitor, we examined the effects of a natriuretic dose of 8-aminoguanine on urinary excretion of PNPase substrates and products. 8-Aminoguanine increased and decreased, respectively, urinary excretion of PNPase substrates and products. Next we compared in rats the renal effects of intravenous doses of 9-deazaguanine (PNPase inhibitor) versus 8-aminoguanine. 8-Aminoguanine and 9deazaguanine 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 Nal and glucose excretion by blocking PNPase and decreases Kl excretion by inhibiting Racl.
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