title: ADMA and oxidative stress may relate to the progression of renal disease: rationale and design of the VIVALDI study.
abstract: The renin angiotensin system has been shown to be involved in the pathogenesis of vascular and renal sequelae of diabetes mellitus. In type 2 diabetes mellitus, angiotensin receptor blockers have been shown to exert clinical benefit by reducing the progression of diabetic nephropathy. They also improve endothelium-mediated vascular function. The latter effect is partly due to the reduction of angiotensin II-associated oxidative stress. Moreover, small clinical studies have shown that treatment with angiotensin receptor blockers also reduces the circulating levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase. In the VIVALDI trial, the ability of the angiotensin receptor blocker telmisartan to reduce the progression of diabetic nephropathy (associated with proteinuria) in comparison with valsartan in more than 800 patients with type 2 diabetes during 1 year of treatment is being studied. In order to gain more detailed insight into the potential pathomechanisms associated with this effect, further end-points have been defined. Among these are the circulating levels of ADMA and the urinary excretion rate of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha). The former is an endogenous inhibitor of NO-mediated vascular function(s) and a prospectively determined marker of major cardiovascular events and mortality; the latter is a lipid peroxidation product resulting from the nonenzymatic peroxidation of arachidonic acid, which exerts detrimental vascular effects similar to those of thromboxane A2. Urinary 8-iso-PGF2alpha has been shown in clinical studies to be an independent marker of cardiovascular disease. Highlighting the effects of telmisartan on ADMA and 8-iso-PGF levels in such a large cohort of diabetic patients will enhance our understanding of the roles of dysfunctional NO metabolism and redox mechanisms in the pathogenesis of end-organ damage and its prevention by pharmacotherapy with angiotensin receptor blockers.
authors.affiliation: Institute of Experimental and Clinical Pharmacology, University Hospital Hamburg-Eppendorf, Germany. boeger@uke.uni-hamburg.de
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Böger
authors.forename: Edzard
authors.initials: E
authors.lastname: Schwedhelm
authors.forename: Renke
authors.initials: R
authors.lastname: Maas
authors.forename: Sabine
authors.initials: S
authors.lastname: Quispe-Bravo
authors.forename: Cord
authors.initials: C
authors.lastname: Skamira
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D001562:Benzimidazoles / Q000627:therapeutic use; D001565:Benzoates / Q000627:therapeutic use; D002985:Clinical Protocols; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology / Q000652:urine; D003928:Diabetic Nephropathies / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology / Q000652:urine; D015237:Dinoprost / Q000031:analogs & derivatives / Q000652:urine; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology / Q000652:urine; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D018384:Oxidative Stress / Q000187:drug effects; D016032:Randomized Controlled Trials as Topic; D051437:Renal Insufficiency / Q000517:prevention & control; D000077333:Telmisartan; D013777:Tetrazoles / Q000627:therapeutic use; D014633:Valine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000068756:Valsartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D013777:Tetrazoles; C075750:8-epi-prostaglandin F2alpha; C018524:N,N-dimethylarginine; D000068756:Valsartan; D001120:Arginine; D015237:Dinoprost; D014633:Valine; D000077333:Telmisartan