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

Ronald G. 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

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299 Scopus citations

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
DOIs
StatePublished - Jan 1 1993

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Tilton, R. G., Chang, K., Hasan, K. S., Smith, S. R., Petrash, J. M., Misko, T. P., Moore, W. M., Currie, M. G., Corbett, J. A., McDaniel, M. L., & 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. https://doi.org/10.2337/diab.42.2.221