8-Aminoguanosine and 8-Aminoguanine Exert Diuretic, Natriuretic, Glucosuric, and Antihypertensive Activity.
In vivo, guanine moieties in DNA, RNA, guanine nucleotides, or guanosine or guanine per se can undergo nitration (for example, by peroxynitrite) or hydroxylation (for example, by superoxide anion) on position 8 of the purine ring. Subsequent catabolism of these modified biomolecules leads to the production of a diverse group of 8-nitro, 8-amino, and 8-hydroxy guanosine and guanine compounds. Indeed, studies suggest the in vivo existence of 8-nitroguanosine, 8-nitroguanine, 8-aminoguanosine, 8-aminoguanine, 8-hydroxyguanosine, 8-hydroxy-2'-deoxyguanosine, and 8-hydroxyguanine. Since a multitude of these compounds exist in vivo, and since the renal effects of 8-substituted guanosine and guanine compounds are entirely unknown, we examined the effects of guanosine, guanine, 8-nitroguanosine, 8-nitroguanine, 8-hydroxyguanosine, 8-hydroxyguanine, 8-hydroxy-2'-deoxyguanosine, 8-aminoguanosine, and 8-aminoguanine (33.5 µmol/kg/min; intravenous infusion for 115 minutes) on excretion of sodium, potassium, and glucose in rats. Guanosine, 8-nitroguanosine, and 8-hydroxy-2'-deoxyguanosine had minimal natriuretic activity. Guanine, 8-nitroguanine, 8-hydroxyguanosine, and 8-hydroxyguanine had moderate natriuretic activity (increased sodium excretion by 9.4-, 7.8-, 7.1-, and 8.6-fold, respectively). In comparison with all other compounds, 8-aminoguanosine and 8-aminoguanine were highly efficacious and increased sodium excretion by 26.6- and 17.2-fold, respectively, exceeding that of a matched dose of amiloride (13.6-fold increase). 8-Aminoguanosine and 8-aminoguanine also increased glucose excretion by 12.1- and 12.2-fold, respectively, and decreased potassium excretion by 69.1 and 71.0%, respectively. Long-term radiotelemetry studies demonstrated that oral 8-aminoguanosine and 8-aminoguanine (5 mg/kg/day) suppressed deoxycorticosterone/salt-induced hypertension. These experiments demonstrate that some naturally occurring 8-substitued guanosine and guanine compounds, particularly 8-aminoguanosine and 8-aminoguanine, are potent and efficacious potassium-sparing diuretics/natriuretics that may represent a novel class of antihypertensive diuretics.
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania edj@pitt.edu.
Edwin K
EK
Jackson
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Delbert G
DG
Gillespie
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Zaichuan
Z
Mi
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004232:Diuretics / Q000494:pharmacology* / Q000627:therapeutic use; D006029:Glycosuria / Q000188:drug therapy*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D009318:Natriuresis / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000959:Antihypertensive Agents; D004232:Diuretics; D006151:Guanosine; C033495:8-aminoguanine; C032533:8-aminoguanosine; D006147:Guanine
Biochim Biophys Acta. 2014 Feb;1840(2):768-80
23872352
Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):685-90
12522148
Antioxid Redox Signal. 2006 May-Jun;8(5-6):1033-45
16771693
Immunology. 1986 Sep;59(1):63-7
3019875
Free Radic Biol Med. 2012 May 15;52(10):2057-63
22542794
J Pharmacol Exp Ther. 1993 Aug;266(2):707-14
8355201
Hypertension. 2014 Aug;64(2):224-6
24866136
Hypertension. 2014 Sep;64(3):573-82
24935938
Nitric Oxide. 1997 Oct;1(5):373-85
9441908
J Clin Hypertens (Greenwich). 2016 Apr;18(4):342-51
26395424
Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3375-9
1565629
Hypertension. 2015 Jan;65(1):238-49
25368027
Proc Natl Acad Sci U S A. 1990 Jun;87(12):4533-7
2352934
Chem Res Toxicol. 1993 May-Jun;6(3):269-76
8318648
J Biol Chem. 2004 Jul 30;279(31):32106-15
15152004
Drugs. 2006;66(2):133-44
16451089
Semin Nephrol. 2011 Nov;31(6):542-52
22099511
Hypertension. 2014 Aug;64(2):305-14
24866139
Hypertension. 2014 Aug;64(2):384-90
24890822
FEBS Lett. 1995 Dec 4;376(3):207-10
7498543
Science. 1981 Dec 4;214(4525):1137-9
6795718