The role of aldosterone in mediating the dependence of angiotensin hypertension on IL-6.
Knockout (KO) of IL-6 has been shown to attenuate ANG II hypertension, and mineralocorticoid receptors (MR) have been reported to contribute to the increase in IL-6 during acute ANG II infusion. This study determined whether that MR action is sustained with chronic ANG II infusion and whether it plays a role in mediating ANG II hypertension. ANG II infusion (90 ng/min) increased plasma IL-6 from 1.6 +/- 0.6 to 22.7 +/- 2.2 and 19.9 +/- 3.2 pg/ml on days 7 and 14, respectively, and chronic MR blockade with spironolactone attenuated that only at day 7 (7.2 +/- 2.2 pg/ml). ANG II increased MAP (19 h/day with telemetry) approximately 40 mmHg, but in ANG II+spironolactone mice (25 or 50 mg*kg(-1)*day(-1)), mean arterial pressure (MAP) was not significantly different despite a tendency for lower pressure the first 6 days. To isolate further the mineralocorticoid link to IL-6 and blood pressure, DOCA-salt hypertension was induced in IL-6 KO and wild-type (WT) mice. Plasma IL-6 increased from 4.1 +/- 1.7 to 34.5 +/- 7.0 pg/ml by day 7 of DOCA treatment in the WT mice but was back to control levels by day 14. An IL-6 bioassay using the murine B9, B-cell hybridoma cell line demonstrated that plasma IL-6 measurements reflected actual IL-6 bioactivity. The hypertension was not different and virtually superimposable in WT vs. IL-6 KO mice, averaging 145 +/- 2 and 144 +/- 3 mmHg, respectively. Both experiments confirm chronic stimulation of IL-6 by mineralocorticoids but show that it is transient. In addition, IL-6 was not required for mineralocorticoid hypertension. This suggests that aldosterone contributes to the increase in plasma IL-6 in the early stage of ANG II hypertension but that the blood pressure actions of IL-6 in that model are linked most likely to ANG II rather than aldosterone.
Sturgis
LaShon C
LC
Department of Physiology, Medical College of Georgia, Augusta, Georgia 30912-3000, USA.
Cannon
Joseph G
JG
Schreihofer
Derek A
DA
Brands
Michael W
MW
D000450:Aldosterone / Q000378:metabolism*; D000809:Angiotensins / Q000008:administration & dosage; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003900:Desoxycorticosterone; D004195:Disease Models, Animal; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D015918:Infusion Pumps, Implantable; D055104:Infusions, Subcutaneous; D015850:Interleukin-6 / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D013148:Spironolactone / Q000494:pharmacology; D013997:Time Factors
D000809:Angiotensins; D000959:Antihypertensive Agents; D015850:Interleukin-6; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D003900:Desoxycorticosterone; D000450:Aldosterone