The antagonism of aldosterone receptor prevents the development of hypertensive heart failure induced by chronic inhibition of nitric oxide synthesis in rats.
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.
Tsukamoto
Osamu
O
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.
Minamino
Tetsuo
T
Sanada
Shoji
S
Okada
Ken-ichiro
K
Hirata
Akio
A
Fujita
Masashi
M
Shintani
Yasunori
Y
Yulin
Liao
L
Asano
Yoshihiro
Y
Takashima
Seiji
S
Yamasaki
Satoru
S
Tomoike
Hitonobu
H
Hori
Masatsugu
M
Kitakaze
Masafumi
M
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
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