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

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.

• 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
• Journal: Diabetologia (Diabetologia) Vol. 51 Issue 12 Pg. 2325-32 (Dec 2008) ISSN: 1432-0428 [Electronic] Germany
• PMID: 18825362 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Adhesion Molecules
• Intracellular Signaling Peptides and Proteins
• Microfilament Proteins
• Phosphoproteins
• Vascular Cell Adhesion Molecule-1
• vasodilator-stimulated phosphoprotein
• Streptozocin
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Cyclic GMP

Topics

• Animals
• Cell Adhesion Molecules (metabolism)
• Cyclic GMP (blood)
• Diabetes Complications (blood, enzymology, genetics)
• Diabetes Mellitus, Experimental (blood, chemically induced, enzymology, genetics)
• Gene Expression Regulation
• Hindlimb (blood supply, enzymology)
• Humans
• Inflammation (blood, complications, enzymology, genetics)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Lipid Peroxidation
• Male
• Microfilament Proteins (metabolism)
• Muscles (metabolism)
• Nitric Oxide Synthase Type II (metabolism)
• Nitric Oxide Synthase Type III (genetics, metabolism)
• Phosphoproteins (metabolism)
• Rats
• Rats, Sprague-Dawley
• Streptozocin (pharmacology)
• Vascular Cell Adhesion Molecule-1 (metabolism)
• Vascular Diseases (blood, complications, enzymology, genetics)