Article

Diabetologia

, Volume 51, Issue 12, pp 2325-2332

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

  • A. RiadAffiliated withDepartment of Cardiology and Pneumology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin
  • , D. WestermannAffiliated withDepartment of Cardiology and Pneumology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin
  • , S. Van LinthoutAffiliated withDepartment of Cardiology and Pneumology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin
  • , Z. MohrAffiliated withDepartment of Cardiology and Pneumology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin
  • , S. UyulmazAffiliated withDepartment of Cardiology and Pneumology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin
  • , P. M. BecherAffiliated withDepartment of Cardiology and Pneumology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin
  • , H. RüttenAffiliated withSanofi-Aventis Pharma
  • , P. WohlfartAffiliated withSanofi-Aventis Pharma
  • , H. PetersAffiliated withDepartment of Nephrology, Charite Universitätsmedizin Berlin
    • , H.-P. SchultheissAffiliated withDepartment of Cardiology and Pneumology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin
    • , C. TschöpeAffiliated withDepartment of Cardiology and Pneumology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin Email author 

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.

Keywords

Diabetes mellitus Endothelial dysfunction Inflammation Nitric oxide