Premium
Telmisartan treatment upregulates GTP‐cyclohydrolase I and prevents eNOS uncoupling in streptozotocin‐induced diabetes
Author(s) -
Daiber Andreas,
Oelze Matthias,
Wenzel Philip,
Müller Johanna,
Alhamdani Mohamed S.S.,
Reifenberg Kurt,
Münzel Thomas
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.466.5
Subject(s) - telmisartan , streptozotocin , medicine , nadph oxidase , endocrinology , enos , diabetes mellitus , xanthine oxidase , downregulation and upregulation , angiotensin ii receptor type 1 , oxidative stress , chemistry , angiotensin ii , receptor , nitric oxide synthase , enzyme , nitric oxide , biochemistry , blood pressure , gene
Cardiovascular complications in patients with diabetes mellitus are associated with increased oxidative stress in vascular tissue. A key event for NO synthase (NOS) uncoupling involves downregulation of BH4 synthesizing enzyme GTP‐cyclohydrolase I (GCH‐I). We here investigated the effects of AT1‐receptor blockade with chronic telmisartan therapy on GCH‐I expression, NOS uncoupling and endothelial function in streptozotocin (STZ)‐induced diabetes mellitus (type I). Diabetes was induced by single i.v. injection of STZ (60mg/kg, 7 weeks) in male Wistar rats (250g). Telmisartan (25mg/kg/d) therapy did not improve blood glucose and body weight. Aorta from diabetic animals had vascular dysfunction as revealed by isometric tension studies. ROS produced by NADPH oxidase, mitochondria and xanthine oxidase were increased in the diabetic group. NADPH oxidase subunits mRNA and protein expression was increased in response to STZ. Importantly, the expression of the GCH‐I and eNOS activating Ser1177 phosphorylation was decreased by STZ. Therapy with telmisartan normalized all these parameters almost completely. The results of the present studies demonstrate for the first time that AT1 receptor treatment of diabetic animals with telmisartan is able to prevent downregulation of the important BH4 synthesizing enzyme GCH‐I, which prevents eNOS uncoupling and an activation of cardiovascular superoxide sources.