title: Angiotensin II type 1 receptor blockade improves hyperglycemia-induced endothelial dysfunction and reduces proinflammatory cytokine release from leukocytes.
abstract: Angiotensin II and glucose share components of their intracellular redox signaling pathways in endothelial and inflammatory cells. We hypothesized that valsartan, an angiotensin II blocker, attenuates hyperglycemia-induced endothelial dysfunction and downregulates release of proinflammatory cytokines from leukocytes. A sustained hyperglycemic clamp (12 mmol/L) to induce endothelial dysfunction was performed in healthy volunteers before and after 4 weeks of treatment with 160 mg of valsartan. Brachial artery flow-mediated vasodilation (FMD), lipopolysaccharide-induced release of interleukin-6 and TNF-alpha from peripheral blood leukocytes ex vivo, and circulating proinflammatory cytokines were determined before and during the clamp. The hyperglycemic clamp induced a decrease in FMD from 9.2 +/- 0.8 (t = 0 hr) to 4.4+/- 0.5 (t = 2 hr), 3.8 +/- 0.5 (t = 4 hr), and 4.8 +/- 0.5% (t = 22 hr) during the clamp. Valsartan attenuated endothelial dysfunction [FMD 7.0 +/- 0.7 (t = 2 hr), 6.1 +/- 0.7 (t = 4 hr), 6.2 +/- 0.6% (t = 22 hr); P < 0.005] and decreased the release of interleukin-6 and TNF-alpha from leukocytes both before and during the clamp (P < 0.05). Valsartan improves hyperglycemia-induced endothelial dysfunction and reduces the cytokine response to an inflammatory stimulus. A pathophysiological link between the effects of hyperglycemia and the renin-angiotensin system on endothelium and peripheral blood leukocytes may underlie the beneficial effects of inhibitors of the renin-angiotensin system on cardiovascular outcome in patients with diabetes mellitus.
authors.affiliation: Department of Nephrology, Academic Medical Center, Amsterdam, The Netherlands. J.M.Willemsen@amc.uva.nl
authors.forename: Judith M
authors.initials: JM
authors.lastname: Willemsen
authors.forename: Jan W
authors.initials: JW
authors.lastname: Westerink
authors.forename: Geesje M
authors.initials: GM
authors.lastname: Dallinga-Thie
authors.forename: Anton-Jan
authors.initials: AJ
authors.lastname: van Zonneveld
authors.forename: Carlo A
authors.initials: CA
authors.lastname: Gaillard
authors.forename: Ton J
authors.initials: TJ
authors.lastname: Rabelink
authors.forename: Eelco J P
authors.initials: EJ
authors.lastname: de Koning
mesh_terms: D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism*; D004727:Endothelium / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D016207:Cytokines; D018836:Inflammation Mediators; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000068756:Valsartan; D014633:Valine