AT1-receptor blockade by telmisartan upregulates GTP-cyclohydrolase I and protects eNOS in diabetic rats.
Several enzymatic sources of reactive oxygen species (ROS) were described as potential reasons of eNOS uncoupling in diabetes mellitus. In the present study, we investigated the effects of AT1-receptor blockade with chronic telmisartan (25 mg/kg/day, 6.5 weeks) therapy on expression of the BH4-synthesizing enzyme GTP-cyclohydrolase I (GCH-I), eNOS uncoupling, and endothelial dysfunction in streptozotocin (STZ, 60 mg/kg iv, 7 weeks)-induced diabetes mellitus (type I). Telmisartan therapy did not modify blood glucose and body weight. Aortas from diabetic animals had vascular dysfunction as revealed by isometric tension studies (acetylcholine and nitroglycerin potency). Vascular and cardiac ROS produced by NADPH oxidase, mitochondria, eNOS, and xanthine oxidase were increased in the diabetic group as was the expression of NADPH oxidase subunits at the protein level. The expression of GCH-I and the phosphorylation of eNOS at Ser1177 was decreased by STZ treatment. Therapy with telmisartan normalized these parameters. The present study demonstrates for the first time that AT1-receptor blockade by telmisartan prevents downregulation of the BH4 synthase GCH-I and thereby eNOS uncoupling in experimental diabetes. In addition, telmisartan inhibits activation of superoxide sources like NADPH oxidase, mitochondria, and xanthine oxidase. These effects may explain the beneficial effects of telmisartan on endothelial dysfunction in diabetes.
2nd Medical Clinic, Department of Cardiology, Johannes Gutenberg University, Mainz, Germany.
Philip
P
Wenzel
Eberhard
E
Schulz
Matthias
M
Oelze
Johanna
J
Müller
Swenja
S
Schuhmacher
Mohamed S S
MS
Alhamdani
Johannes
J
Debrezion
Marcus
M
Hortmann
Kurt
K
Reifenberg
Ingrid
I
Fleming
Thomas
T
Münzel
Andreas
A
Daiber
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003920:Diabetes Mellitus / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D006136:GTP Cyclohydrolase / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D000077333:Telmisartan; D015854:Up-Regulation / Q000187:drug effects*
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D001786:Blood Glucose; D044140:Receptor, Angiotensin, Type 1; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D006136:GTP Cyclohydrolase; D000077333:Telmisartan