Prevention of diabetic vascular dysfunction by guanidines: Inhibition of nitric oxide synthase versus advanced glycation end-product formation

Ronald Tilton, Katherine Chang, Khalid S. Hasan, Samuel R. Smith, J. Mark Petrash, Thomas P. Misko, William M. Moore, Mark G. Currie, John A. Corbett, Michael L. McDaniel, Joseph R. Williamson

Research output: Contribution to journalArticle

299 Citations (Scopus)

Abstract

This study was undertaken to compare the ability of two guanidine compounds (aminoguanidine and methylguanidine), with different in vitro effects on NO synthase activity and AGE formation, to inhibit diabetic vascular dysfunction developing early after the onset of diabetes. In rats with STZ-induced diabetes of 5-wk duration, regional vascular [125I]albumin permeation was increased about two- to threefold in ocular tissues, sciatic nerve, and aorta; in general, both guanidine compounds normalized albumin permeation in diabetic rats without affecting it in controls. Methylguanidine was only ∼7% as effective as aminoguanidine as an inhibitor of AGE formation from L-lysine and G6P; both compounds were poor inhibitors of AR. Methylguanidine was ∼1-5% as potent as aminoguanidine and L-NMMA as an inhibitor of the cytokine- and endotoxin-inducible isoform of NO synthase. In contrast, the potency of methylguanidine as an inhibitor of the constitutive isoform of NO synthase was comparable to that of aminoguanidine, and both guanidine compounds were much less effective than L-NMMA. These observations suggest a role for a relative or absolute increase in NO production in the pathogenesis of early diabetic vascular dysfunction and raise the possibility that inhibition of diabetic vascular functional changes by aminoguanidine may reflect inhibition of NO synthase activity rather than, or in addition to, prevention of AGE formation.

Original languageEnglish (US)
Pages (from-to)221-232
Number of pages12
JournalDiabetes
Volume42
Issue number2
StatePublished - 1993
Externally publishedYes

Fingerprint

Guanidines
Methylguanidine
Advanced Glycosylation End Products
Nitric Oxide Synthase
Blood Vessels
Guanidine
omega-N-Methylarginine
Albumins
Protein Isoforms
Sciatic Nerve
Endotoxins
Lysine
Aorta
pimagedine
Cytokines

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Internal Medicine

Cite this

Tilton, R., Chang, K., Hasan, K. S., Smith, S. R., Petrash, J. M., Misko, T. P., ... Williamson, J. R. (1993). Prevention of diabetic vascular dysfunction by guanidines: Inhibition of nitric oxide synthase versus advanced glycation end-product formation. Diabetes, 42(2), 221-232.

Prevention of diabetic vascular dysfunction by guanidines : Inhibition of nitric oxide synthase versus advanced glycation end-product formation. / Tilton, Ronald; Chang, Katherine; Hasan, Khalid S.; Smith, Samuel R.; Petrash, J. Mark; Misko, Thomas P.; Moore, William M.; Currie, Mark G.; Corbett, John A.; McDaniel, Michael L.; Williamson, Joseph R.

In: Diabetes, Vol. 42, No. 2, 1993, p. 221-232.

Research output: Contribution to journalArticle

Tilton, R, Chang, K, Hasan, KS, Smith, SR, Petrash, JM, Misko, TP, Moore, WM, Currie, MG, Corbett, JA, McDaniel, ML & Williamson, JR 1993, 'Prevention of diabetic vascular dysfunction by guanidines: Inhibition of nitric oxide synthase versus advanced glycation end-product formation', Diabetes, vol. 42, no. 2, pp. 221-232.
Tilton, Ronald ; Chang, Katherine ; Hasan, Khalid S. ; Smith, Samuel R. ; Petrash, J. Mark ; Misko, Thomas P. ; Moore, William M. ; Currie, Mark G. ; Corbett, John A. ; McDaniel, Michael L. ; Williamson, Joseph R. / Prevention of diabetic vascular dysfunction by guanidines : Inhibition of nitric oxide synthase versus advanced glycation end-product formation. In: Diabetes. 1993 ; Vol. 42, No. 2. pp. 221-232.
@article{5eb5715206d14d0db99285b4ad8c1d6b,
title = "Prevention of diabetic vascular dysfunction by guanidines: Inhibition of nitric oxide synthase versus advanced glycation end-product formation",
abstract = "This study was undertaken to compare the ability of two guanidine compounds (aminoguanidine and methylguanidine), with different in vitro effects on NO synthase activity and AGE formation, to inhibit diabetic vascular dysfunction developing early after the onset of diabetes. In rats with STZ-induced diabetes of 5-wk duration, regional vascular [125I]albumin permeation was increased about two- to threefold in ocular tissues, sciatic nerve, and aorta; in general, both guanidine compounds normalized albumin permeation in diabetic rats without affecting it in controls. Methylguanidine was only ∼7{\%} as effective as aminoguanidine as an inhibitor of AGE formation from L-lysine and G6P; both compounds were poor inhibitors of AR. Methylguanidine was ∼1-5{\%} as potent as aminoguanidine and L-NMMA as an inhibitor of the cytokine- and endotoxin-inducible isoform of NO synthase. In contrast, the potency of methylguanidine as an inhibitor of the constitutive isoform of NO synthase was comparable to that of aminoguanidine, and both guanidine compounds were much less effective than L-NMMA. These observations suggest a role for a relative or absolute increase in NO production in the pathogenesis of early diabetic vascular dysfunction and raise the possibility that inhibition of diabetic vascular functional changes by aminoguanidine may reflect inhibition of NO synthase activity rather than, or in addition to, prevention of AGE formation.",
author = "Ronald Tilton and Katherine Chang and Hasan, {Khalid S.} and Smith, {Samuel R.} and Petrash, {J. Mark} and Misko, {Thomas P.} and Moore, {William M.} and Currie, {Mark G.} and Corbett, {John A.} and McDaniel, {Michael L.} and Williamson, {Joseph R.}",
year = "1993",
language = "English (US)",
volume = "42",
pages = "221--232",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "2",

}

TY - JOUR

T1 - Prevention of diabetic vascular dysfunction by guanidines

T2 - Inhibition of nitric oxide synthase versus advanced glycation end-product formation

AU - Tilton, Ronald

AU - Chang, Katherine

AU - Hasan, Khalid S.

AU - Smith, Samuel R.

AU - Petrash, J. Mark

AU - Misko, Thomas P.

AU - Moore, William M.

AU - Currie, Mark G.

AU - Corbett, John A.

AU - McDaniel, Michael L.

AU - Williamson, Joseph R.

PY - 1993

Y1 - 1993

N2 - This study was undertaken to compare the ability of two guanidine compounds (aminoguanidine and methylguanidine), with different in vitro effects on NO synthase activity and AGE formation, to inhibit diabetic vascular dysfunction developing early after the onset of diabetes. In rats with STZ-induced diabetes of 5-wk duration, regional vascular [125I]albumin permeation was increased about two- to threefold in ocular tissues, sciatic nerve, and aorta; in general, both guanidine compounds normalized albumin permeation in diabetic rats without affecting it in controls. Methylguanidine was only ∼7% as effective as aminoguanidine as an inhibitor of AGE formation from L-lysine and G6P; both compounds were poor inhibitors of AR. Methylguanidine was ∼1-5% as potent as aminoguanidine and L-NMMA as an inhibitor of the cytokine- and endotoxin-inducible isoform of NO synthase. In contrast, the potency of methylguanidine as an inhibitor of the constitutive isoform of NO synthase was comparable to that of aminoguanidine, and both guanidine compounds were much less effective than L-NMMA. These observations suggest a role for a relative or absolute increase in NO production in the pathogenesis of early diabetic vascular dysfunction and raise the possibility that inhibition of diabetic vascular functional changes by aminoguanidine may reflect inhibition of NO synthase activity rather than, or in addition to, prevention of AGE formation.

AB - This study was undertaken to compare the ability of two guanidine compounds (aminoguanidine and methylguanidine), with different in vitro effects on NO synthase activity and AGE formation, to inhibit diabetic vascular dysfunction developing early after the onset of diabetes. In rats with STZ-induced diabetes of 5-wk duration, regional vascular [125I]albumin permeation was increased about two- to threefold in ocular tissues, sciatic nerve, and aorta; in general, both guanidine compounds normalized albumin permeation in diabetic rats without affecting it in controls. Methylguanidine was only ∼7% as effective as aminoguanidine as an inhibitor of AGE formation from L-lysine and G6P; both compounds were poor inhibitors of AR. Methylguanidine was ∼1-5% as potent as aminoguanidine and L-NMMA as an inhibitor of the cytokine- and endotoxin-inducible isoform of NO synthase. In contrast, the potency of methylguanidine as an inhibitor of the constitutive isoform of NO synthase was comparable to that of aminoguanidine, and both guanidine compounds were much less effective than L-NMMA. These observations suggest a role for a relative or absolute increase in NO production in the pathogenesis of early diabetic vascular dysfunction and raise the possibility that inhibition of diabetic vascular functional changes by aminoguanidine may reflect inhibition of NO synthase activity rather than, or in addition to, prevention of AGE formation.

UR - http://www.scopus.com/inward/record.url?scp=0027400644&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027400644&partnerID=8YFLogxK

M3 - Article

C2 - 7678825

AN - SCOPUS:0027400644

VL - 42

SP - 221

EP - 232

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 2

ER -