title: The antagonism of aldosterone receptor prevents the development of hypertensive heart failure induced by chronic inhibition of nitric oxide synthesis in rats.
abstract: Aldosterone promotes cardiovascular inflammation and remodeling, both of which are characteristic changes in hypertensive and failing hearts. Since chronic inhibition of nitric oxide (NO) synthase with N(omega)-nitro-L-arginine methyl ester (L-NAME) induces systemic hypertension associated with cardiovascular inflammation and remodeling, we examined the potential role of aldosterone in this process using eplerenone, a selective aldosterone receptor antagonist. Ten-week-old male Wistar-Kyoto rats were randomly divided into 3 groups: the control group (no treatment), the L-NAME group (received L-NAME 1 g/L in drinking water), and the L-NAME+Eplerenone group (L-NAME plus eplerenone at 100 mg/kg/day). After 8 weeks of the treatment, the L-NAME group showed significantly higher systolic blood pressure than the control group (198 +/- 7 vs. 141 +/- 3 mmHg, P < 0.05). Eplerenone did not affect the increase in blood pressure caused by L-NAME (189 +/- 12 mmHg). Chronic inhibition of NO synthesis increased the plasma aldosterone concentration and CYP11B2 mRNA in adrenal glands. Cardiac inflammation and fibrosis were detected in the L-NAME group, while both changes were completely prevented by eplerenone. Cardiac hypertrophy was induced in L-NAME group, but was partially prevented by eplerenone. In the L-NAME group, left ventricular fractional shortening (LVFS: 27 +/- 2 vs. 38 +/- 1%) and E/A ratio (1.7 +/- 0.1 vs. 2.1 +/- 0.1) were significantly lower and LV end-diastolic pressure (LVEDP) was higher (4.9 +/- 0.6 vs. 13.9 +/- 0.5 mmHg) without LV enlargement, compared with those in the control group (P < 0.05). Eplerenone completely normalized LVFS (36 +/- 2%), E/A ratio (2.2 +/- 0.1), and LVEDP (6.2 +/- 0.7 mmHg). These results suggest that chronic inhibition of NO synthesis induces cardiac inflammation and dysfunction via an aldosterone receptor-dependent mechanism.
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Tsukamoto
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Minamino
authors.forename: Shoji
authors.initials: S
authors.lastname: Sanada
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Okada
authors.forename: Akio
authors.initials: A
authors.lastname: Hirata
authors.forename: Masashi
authors.initials: M
authors.lastname: Fujita
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Shintani
authors.forename: Liao
authors.initials: L
authors.lastname: Yulin
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Asano
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamasaki
authors.forename: Hitonobu
authors.initials: H
authors.lastname: Tomoike
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
mesh_terms: D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000450:Aldosterone / Q000097:blood; D000818:Animals; D015153:Blotting, Western; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics / Q000378:metabolism; D004359:Drug Therapy, Combination; D000077545:Eplerenone; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D006333:Heart Failure / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006973:Hypertension / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D007150:Immunohistochemistry; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D016328:NF-kappa B / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology / Q000627:therapeutic use; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D010446:Peptide Fragments / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011498:Protein Precursors / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D011921:Rats, Inbred WKY; D018161:Receptors, Mineralocorticoid / Q000502:physiology; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
chemical_list: D000199:Actins; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D000077545:Eplerenone; D000451:Mineralocorticoid Receptor Antagonists; D016328:NF-kappa B; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D010446:Peptide Fragments; D018809:Proliferating Cell Nuclear Antigen; D011498:Protein Precursors; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C508962:Tgfb1 protein, rat; C498862:Acta2 protein, rat