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

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 48; no. 6; pp. 1050 - 1057
• Main Authors: Luther, James M., Gainer, James V., Murphey, Laine J., Yu, Chang, Vaughan, Douglas E., Morrow, Jason D., Brown, Nancy J.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.12.2006; Hagerstown, MD Lippincott
• Subjects: Adult; Aldosterone - administration & dosage; Angiotensin II - metabolism; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Cross-Over Studies; Diet, Sodium-Restricted; Double-Blind Method; Endocrine kidney. Renin-angiotensin-aldosterone system; Female; Fundamental and applied biological sciences. Psychology; Humans; Hydroxycorticosteroids - administration & dosage; Infusions, Intravenous; Interleukin-6 - metabolism; Male; Medical sciences; Mineralocorticoid Receptor Antagonists - pharmacology; Oxidative Stress - drug effects; Receptors, Mineralocorticoid - metabolism; Spironolactone - pharmacology; Vertebrates: endocrinology; Systolic pressure; Oxidative stress; Potassium sparing diuretic; Intravenous administration; Mineralocorticoid; Peptide hormone; Cardiovascular disease; Aldosterone; Inorganic element; Interleukin 6; Octapeptide; Spironolactone; oxidative; Arterial pressure; Blood pressure; Angiotensin II; C reactive protein; Human; Hypertension; stress; F2-isoprostanes; Steroid hormone; Inflammation; mineralocorticoid receptor; Catecholamine; IL-6; Aldosterone antagonist; Sodium; Adrenal hormone; Neurotransmitter; Double blind study; Norepinephrine; Potassium; Comparative study
• ISSN: 0194-911X; 1524-4563; 1524-4563
• DOI: 10.1161/01.HYP.0000248135.97380.76

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 pressure13.7±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/m; 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.