title: Angiotensin II induces interleukin-6 in humans through a mineralocorticoid receptor-dependent mechanism.
abstract: 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 mug/kg per hour for 10 hours followed by 0.9 mug/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/m(2); 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 F(2)-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 F(2)-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 F(2)-isoprostanes, is mineralocorticoid receptor independent and may be pressor dependent.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-6602, USA. james.luther@vanderbilt.edu
authors.forename: James M
authors.initials: JM
authors.lastname: Luther
authors.forename: James V
authors.initials: JV
authors.lastname: Gainer
authors.forename: Laine J
authors.initials: LJ
authors.lastname: Murphey
authors.forename: Chang
authors.initials: C
authors.lastname: Yu
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Vaughan
authors.forename: Jason D
authors.initials: JD
authors.lastname: Morrow
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Brown
mesh_terms: D000328:Adult; D000450:Aldosterone / Q000008:administration & dosage; D000804:Angiotensin II / Q000378:metabolism*; D018592:Cross-Over Studies; D004039:Diet, Sodium-Restricted; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006889:Hydroxycorticosteroids / Q000008:administration & dosage; D007262:Infusions, Intravenous; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D013148:Spironolactone / Q000494:pharmacology
chemical_list: D006889:Hydroxycorticosteroids; D015850:Interleukin-6; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D000804:Angiotensin II; D013148:Spironolactone; D000450:Aldosterone