gms | German Medical Science

In diabetes mellitus (DM), nitric oxide synthases (NOS) are sources of enhanced oxidative stress, which in turn leads to cardiovascular dysfunction. We determined effects of treatment with an angiotensin type-1 receptor antagonist (AT1A) and a beta blocker (BB). Experiments were performed in streptozotocin (STZ)-induced diabetic Sprague Dawley (SD) rats treated with the AT1A candesartan (Can) (1.5mg/kg/d), or the BB metoprolol (Met) (30mg/kg/d) or vehicle and in age matched controls (n=9/group). Endothelial NOS (eNOS) mRNA (real-time PCR) and protein expression and inducible NOS (iNOS) protein expression (immunohistochemistry) were quantified in rat quadriceps musculature. Function of the inherent vascular bed was measured in vivo in the autoperfused hindlimb by injection of Krebs-Henseleit solution (200µl/kg) and of sodium nitroprusside (SNP, 40µg/kg). Increased expression of eNOS (mRNA: 0.43+/-0.18 vs. 23.1+/-13.4; protein: 0.54+/-0.09 vs. 2.81+/-0.37; p<0.05) and iNOS (protein: 1.27+/-0.17 vs. 5.24+/-0.13; p<0.05) displayed increased levels of oxidative stress in diabetic rats when compared with non-diabetic controls. In addition, DM was associated with severe impairment of endothelium-dependent and -independent vascular function. Both alterations in eNOS (mRNA: 0.04+/-0.02 vs. 23.1+/-13.4; protein: 0.93+/-0.19 vs. 2.81+/-0.37 and iNOS (1.45+/-0.45 vs. 5.24+/-0.13; p<0.05) expression and endothelial function (pressure amplitude: 38.9+/-3.1 vs. 22.9+/-1.9 mmHg; integral: 1844+/-160 vs. 1093+/-83 mmHg*s; p<0.05) were nearly reversed by AT1A as compared to vehicle-treated STZ-diabetic rats. BB whether altered eNOS or iNOS expression nor improved vascular function under diabetic conditions. Our findings indicate that AT1 receptor activation is crucial for the maintenance of pathologic vascular alterations during DM, and that their blockade is of therapeutic advantage.