Neutral endopeptidase inhibition, a new approach in the exploration of diabetic vasculopathy in rats

Abstract

Diabetic complications are mostly vascular and involve alteration in blood vessel reactivity and permeability. The contribution of the latter dysfunction to the development of target organ damage has not been thoroughly examined. In this study, we verify the acute effect of three peptidase inhibitors (phosphoramidon: N-(α-rhamnopyranosylhydroxyphosphinyl)-Leu-Trp, thiorphan: 3-mercapto-2-benzyl-propanoylglycine, and SQ 28,603; N-(2-mercaptomethyl)-1-oxo-3-phenylpropyl]-≤ b-alanine; each at a dose of 2 mg/kg), as well as captopril ([2 S]-1-[3-mercapto-2-methyl-propionyl]- l-proline; 10 mg/kg), and an aminopeptidase inhibitor (amastatin: ([(2 S,3 R)-3-amino-2-hydroxy-5-methylhexanoyl]-Val-Val-3 Asp; 2 mg/kg) on capillary extravasation abnormalities in the streptozotocin-induced diabetic rat using the Evans blue method. Untreated diabetic rats exhibited a significant enhancement of Evans blue extravasation in the duodenum, upper bronchus, pancreas and skin (175 ± 19, 94 ± 4, 95 ± 9 and 47 ± 10 μg/g dry tissue respectively compared to 67 ± 9, 44 ± 5, 47 ± 4, and 6 ± 2 μg/g dry tissue). The three endopeptidase inhibitors normalized capillary permeability in all tissues. Also, treatment with captopril was associated with complete correction of capillary dysfunction in the skin and partially in the duodenum, upper bronchus, and pancreas. These findings indicate for the first time that the use of neutral endopeptidase inhibitors may be beneficial in preventing capillary abnormalities in this diabetic rat model.