Angiotensin II Type 1 Receptor Blockade Improves Hyperglycemia-Induced Endothelial Dysfunction and Reduces Proinflammatory Cytokine Release From Leukocytes

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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-α 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-α 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.