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Diabetologia
Published in: Diabetologia 12/2008

01-12-2008 | Article

Enhancement of endothelial nitric oxide synthase production reverses vascular dysfunction and inflammation in the hindlimbs of a rat model of diabetes

Authors: A. Riad, D. Westermann, S. Van Linthout, Z. Mohr, S. Uyulmaz, P. M. Becher, H. Rütten, P. Wohlfart, H. Peters, H.-P. Schultheiss, C. Tschöpe

Published in: Diabetologia | Issue 12/2008

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Abstract

Aims/hypothesis

Reduced bioavailability of nitric oxide (NO) is a hallmark of diabetes mellitus-induced vascular complications. In the present study we investigated whether a pharmacological increase of endothelial NO synthase (eNOS) production can restore the impaired hindlimb flow in a rat model of severe diabetes.

Methods

A model of diabetes mellitus was induced in male Sprague–Dawley rats by a single injection of streptozotozin. Rats were treated chronically with the eNOS transcription enhancer AVE3085 (10 mg [kg body weight]−1 day−1; p.o.) or vehicle for 48 days and compared with controls. Endothelial function and arterial BP were investigated in vivo using an autoperfused hindlimb model and TIP-catheter measurement, respectively. Protein production of eNOS, total and phosphorylated vasodilator-stimulated phosphoprotein (VASP) were assessed in their quadriceps muscle tissue, whereas cyclic GMP (cGMP) concentrations were assessed in blood plasma. RNA levels of intracellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1) were measured by real-time PCR.

Results

Untreated diabetic rats showed significantly reduced quadriceps muscle contents of eNOS (−64%) and phosphorylated VASP (−26%) protein associated with impaired vascular function (maximum vasodilatation: −30%, p < 0.05) and enhanced production of ICAM-1 (+121%) and VCAM-1 (+156%). Chronic treatment with AVE3085 did not alter arterial BP or severe hyperglycaemia, but did lead to significantly increased production of eNOS (+95%), cGMP (+128%) and VASP phosphorylation (+65%) as well as to improved vascular function (+36%) associated with reduced production of ICAM-1 (−36%) and VCAM-1 (−58%).

Conclusions/interpretation

In a rat model of severe diabetes, pharmacological enhancement of impaired eNOS production and NO–cGMP signalling by AVE3085 restores altered hindlimb blood flow and prevents vascular inflammation.
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Metadata
Title
Enhancement of endothelial nitric oxide synthase production reverses vascular dysfunction and inflammation in the hindlimbs of a rat model of diabetes
Authors
A. Riad
D. Westermann
S. Van Linthout
Z. Mohr
S. Uyulmaz
P. M. Becher
H. Rütten
P. Wohlfart
H. Peters
H.-P. Schultheiss
C. Tschöpe
Publication date
01-12-2008
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 12/2008
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-008-1159-9

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