Aminoguanidine inhibits albuminuria, but not the formation of advanced glycation end-products in skin collagen of diabetic rats.
Aminoguanidine, an inhibitor of advanced glycation reactions in vitro, inhibits the development of diabetic complications in animal models of diabetes, suggesting that it acts by inhibition of advanced glycation reactions in vivo. However, effects of aminoguanidine on the formation of specific advanced glycation end-products (AGEs) in vivo have not been rigorously examined. Therefore, we studied the effects of aminoguanidine on the formation of pentosidine and N(epsilon)-(carboxymethyl)lysine (CML), measured by analytical chemical methods, in collagen of streptozotocin-diabetic Lewis rats at doses which ameliorated urinary albumin excretion, an index of diabetic nephropathy. At 12 weeks, diabetic animals had fivefold higher blood glucose, threefold higher glycated hemoglobin and fivefold higher collagen glycation, compared to metabolically healthy controls; pentosidine and CML in skin collagen were increased by approximately 30 and 150%, respectively. Administration of aminoguanidine, 50 mg/kg by daily intraperitoneal injection, significantly inhibited the development of albuminuria (approximately 60%, P < 0.01) in diabetic rats, without an effect on blood glucose or glycation of hemoglobin or collagen. Surprisingly, aminoguanidine failed to inhibit the increase in pentosidine and CML in diabetic rat skin collagen. Similar results were obtained in an independent experiment in which aminoguanidine was administered in drinking water at a dose of 0.5 g/l. We conclude that the therapeutic benefits of aminoguanidine on albuminuria may not be the result of inhibition of AGE formation.
Degenhardt
T P
TP
Department of Chemistry and Biochemistry, University of South Carolina, Columbia 29208, USA.
Fu
M X
MX
Voss
E
E
Reiff
K
K
Neidlein
R
R
Strein
K
K
Thorpe
S R
SR
Baynes
J W
JW
Reiter
R
R
D000419:Albuminuria / Q000517:prevention & control*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000032:analysis; D001786:Blood Glucose / Q000378:metabolism; D003094:Collagen / Q000187:drug effects / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000652:urine; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006442:Glycated Hemoglobin / Q000032:analysis; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006146:Guanidines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D007700:Kinetics; D008239:Lysine / Q000031:analogs & derivatives / Q000032:analysis; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D011917:Rats, Inbred Lew; D012016:Reference Values; D012867:Skin / Q000187:drug effects / Q000378:metabolism*
D001120:Arginine; D001786:Blood Glucose; D003094:Collagen; D004791:Enzyme Inhibitors; D006442:Glycated Hemoglobin; D017127:Glycation End Products, Advanced; D006146:Guanidines; D008239:Lysine; C067242:N(epsilon)-(carboxymethyl)hydroxylysine; C062187:pentosidine; C004479:pimagedine