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(Hypertension. 2006;48:1050.)
© 2006 American Heart Association, Inc.

Original Articles

Angiotensin II Induces Interleukin-6 in Humans Through a Mineralocorticoid Receptor–Dependent Mechanism

James M. Luther; James V. Gainer; Laine J. Murphey; Chang Yu; Douglas E. Vaughan; Jason D. Morrow; Nancy J. Brown

From the Divisions of Clinical Pharmacology (J.M.L., J.V.G., L.J.M., J.D.M., N.J.B.), Nephrology and Hypertension (J.M.L.), and Cardiovascular Medicine (D.E.V.), the Departments of Medicine and Pharmacology, and the Department of Biostatistics (C.Y.), Vanderbilt University Medical Center; Nashville, Tenn; and the Veterans Affairs Medical Center (D.E.V.), Nashville, Tenn.

Correspondence to James M. Luther, 560 RRB, Vanderbilt University Medical Center, Nashville, TN 37232-6602. E-mail james.luther{at}vanderbilt.edu

This study tested the hypothesis that angiotensin promotes oxidative stress and inflammation in humans via aldosterone and the mineralocorticoid receptor. We measured the effect of intravenous aldosterone (0.7 µg/kg per hour for 10 hours followed by 0.9 µg/kg per hour for 4 hours) and vehicle in a randomized, double-blind crossover study in 11 sodium-restricted normotensive subjects. Aldosterone increased interleukin (IL)-6 (from 4.7±4.9 to 9.4±7.1 pg/mL; F=4.94; P=0.04) but did not affect blood pressure, serum potassium, or high-sensitivity C-reactive protein. We next conducted a randomized, double-blind, placebo-controlled, crossover study to measure the effect of 3-hour infusion of angiotensin II (2 ng/kg per minute) and norepinephrine (30 ng/kg per minute) on separate days after 2 weeks of placebo or spironolactone (50 mg per day) in 14 salt-replete normotensive subjects. Angiotensin II increased blood pressure (increase in systolic pressure: 13.7±7.5 and 15.2±9.4 mm Hg during placebo and spironolactone, respectively; P<0.001 for angiotensin II) and decreased renal plasma flow (–202±73 and –167±112 mL/min/1.73 kg/m²; P<0.001 for angiotensin II effect) similarly during placebo and spironolactone. Spironolactone enhanced the aldosterone response to angiotensin II (increase of 17.0±10.6 versus 9.0±5.7 ng/dL; P=0.002). Angiotensin II transiently increased free plasma F₂-isoprostanes similarly during placebo and spironolactone. Angiotensin II increased serum IL-6 concentrations during placebo (from 1.8±1.1 to 2.4±1.4 pg/mL; F=4.5; P=0.04) but spironolactone prevented this effect (F=6.4; P=0.03 for spironolactone effect). Norepinephrine increased blood pressure and F₂-isoprostanes but not aldosterone or IL-6. Aldosterone increases IL-6 in humans. These data suggest that angiotensin II induces IL-6 through a mineralocorticoid receptor–dependent mechanism in humans. In contrast, angiotensin II–induced oxidative stress, as measured by F₂-isoprostanes, is mineralocorticoid receptor independent and may be pressor dependent.

Key Words: angiotensin II • aldosterone • spironolactone • mineralocorticoid receptor • inflammation • stress • oxidative • IL-6 • F₂-isoprostanes

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