eplerenone and Vasculitis

The optimal medical management to delay the progression of aortic aneurysms has not been fully clarified, and the only standard treatment at present is antihypertensive therapy. Previous studies have shown beneficial effects of selective mineralocorticoid receptor (MR) antagonists on cardiovascular remodeling. The aim of the present study was to investigate the effect of a selective MR antagonist on aortic aneurysm progression.. Seven-week-old C57BL/6J male mice were administered with angiotensin II and β-aminopropionitrile for 4 weeks. The mice received either vehicle or eplerenone, a selective MR antagonist (100 mg/kg daily) every day by gavage, starting at 7 weeks of age. The production of inflammatory cytokines in cultures of high mobility group box-1-stimulated macrophages with or without a MR antagonist was also analyzed using an enzyme-linked immunosorbent assay.. Although no differences were found in the peak systolic blood pressure between the experimental groups, the mice in the eplerenone group showed a significant reduction in aneurysm development. On histologic analysis, coarse and stretched elastic fibers were markedly improved in the aortic wall in the eplerenone group. Real-time polymerase chain reaction of both aortic wall and perivascular adipose tissue demonstrated the expression of tumor necrosis factor-α, interleukin-6, and matrix metalloproteinase-2 was significantly decreased in eplerenone group, and that of monocyte chemoattractant protein-1 in the aortic wall was also significantly decreased. Macrophage infiltration in the aortic wall and perivascular adipose tissue in the eplerenone group was also significantly decreased. The production of tumor necrosis factor-α and interleukin-6 in macrophage culture, which was stimulated by high mobility group box-1 and CpG oligodeoxynucleotides, was also significantly decreased in the eplerenone group.. Eprelenone suppressed aortic aneurysm progression through an anti-inflammatory effect. Thus, selective MR antagonists might be effective in preventing the progression of aortic aneurysms.

Topics: Animals; Aortic Aneurysm; Blood Pressure; Chemokine CCL2; Disease Models, Animal; Disease Progression; Eplerenone; Gene Expression; Interleukin-6; Macrophages; Male; Mice; Mice, Inbred C57BL; Mineralocorticoid Receptor Antagonists; Spironolactone; Tumor Necrosis Factor-alpha; Vasculitis

Mineralocorticoid receptor (MR) antagonism reverses established inflammation, oxidative stress, and cardiac fibrosis in the mineralocorticoid/salt-treated rat, whereas withdrawal of the mineralocorticoid deoxycorticosterone (DOC) alone does not. Glucocorticoid receptors (GRs) play a central role in regulating inflammatory responses but are also involved in cardiovascular homeostasis. Physiological glucocorticoids bind MR with high affinity, equivalent to that for aldosterone, but are normally prevented from activating MR by pre-receptor metabolism by 11beta-hydroxysteroid dehydrogenase 2. We have previously shown a continuing fibrotic and hypertrophic effect after DOC withdrawal, putatively mediated by activation of glucocorticoid/MR complexes; the present study investigates whether this effect is moderated by antiinflammatory effects mediated via GR. Uninephrectomized rats, drinking 0.9% saline solution, were treated as follows: control; DOC (20 mg/wk) for 4 wk; DOC for 4 wk and no steroid wk 5-8; DOC for 4 wk plus the MR antagonist eplerenone (50 mg/kg.d) wk 5-8; DOC for 4 wk plus the GR antagonist RU486 (2 mg/d) wk 5-8; and DOC for 4 wk plus RU486 and eplerenone for wk 5-8. After steroid withdrawal, mineralocorticoid/salt-induced cardiac hypertrophy is sustained, but not hypertension. Inflammation and fibrosis persist after DOC withdrawal, and GR blockade with RU486 has no effect on these responses. Rats receiving RU486 for wk 5-8 after DOC withdrawal showed marginal blood pressure elevation, whereas eplerenone alone or coadministered with RU486 reversed all DOC/salt-induced circulatory and cardiac pathology. Thus, sustained responses after mineralocorticoid withdrawal appear to be independent of GR signaling, in that blockade of endogenous antiinflammatory effects via GR does not lead to an increase in the severity of responses in the mineralocorticoid/salt-treated rat after steroid withdrawal.

Topics: Animals; Biomarkers; Blood Pressure; Cardiomegaly; Cardiomyopathies; Coronary Vessels; Desoxycorticosterone; Drug Administration Schedule; Eplerenone; Fibrosis; Hormone Antagonists; Male; Mifepristone; Myocardium; Organ Size; Oxidative Stress; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid; Signal Transduction; Sodium Chloride; Spironolactone; Vasculitis

Chronic elevation of plasma aldosterone contributes to heart failure. Mineralocorticoid receptor (MR) antagonism is cardioprotective in such a setting, but whether such protection occurs in the presence of low-aldosterone concentrations remains unclear. We investigated whether MR blockade attenuates cardiac hypertrophy and failure in rats with salt-sensitive hypertension. Dahl salt-sensitive (DS) rats fed a high-salt diet from 7 weeks develop concentric left ventricular (LV) hypertrophy secondary to hypertension at 12 weeks followed by heart failure at 19 weeks (DS-CHF). DS rats on such a diet were treated with a non-antihypertensive dose of the selective MR antagonist eplerenone from 12 to 19 weeks. Renin activity and aldosterone concentration in plasma were decreased in DS-CHF rats compared with controls. LV hypertrophy and fibrosis, as well as macrophage infiltration around coronary vessels, were apparent in DS-CHF rats. The amounts of mRNAs for 11beta-hydroxysteroid dehydrogenase type 1, MR, monocyte chemoattractant protein 1, and osteopontin were increased in these hearts. Treatment of DS-CHF rats with eplerenone inhibited these changes in gene expression, as well as coronary vascular inflammation and heart failure. Eplerenone attenuated both the decrease in the ratio of reduced to oxidized glutathione and the increase in NADPH oxidase activity apparent in DS-CHF rat hearts. MR blockade with eplerenone thus resulted in attenuation of LV hypertrophy and failure, without an antihypertensive effect, in rats with low-aldosterone hypertension. The beneficial cardiac effects of eplerenone are likely attributable, at least in part, to attenuation of myocardial oxidative stress and coronary vascular inflammation induced by glucocorticoid-activated MRs.

Topics: Aldosterone; Animals; Cardiac Output, Low; Cardiomegaly; Cardiotonic Agents; Coronary Vessels; Corticosterone; Echocardiography; Eplerenone; Hypertension; Male; Mineralocorticoid Receptor Antagonists; Myocardium; Osmolar Concentration; Oxidative Stress; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Dahl; Receptor, Angiotensin, Type 1; Receptors, Mineralocorticoid; Renin; RNA, Messenger; Spironolactone; Vasculitis; Ventricular Function; Ventricular Remodeling

To investigate the participation of aldosterone in the vascular inflammatory process associated with hypertension, as well as the possible involvement of the NFkappaB/IkappaB system.. Male spontaneously hypertensive rats (SHR; 20-22 weeks old) untreated or treated with either the aldosterone receptor antagonist, eplerenone (100 mg/kg per day) or triple antihypertensive therapy (HHR: hydralazine + hydrochlorothiazide + reserpine; 20 + 7 + 0.15 mg/kg per day) were used in the study. Wistar-Kyoto rats (WKY) were used as a normotensive reference group. Aortic mRNA expression and plasma levels of interleukin (IL)-1beta, IL-6 and tumour necrosis factor alpha (TNFalpha) were measured. Likewise, the aortic expression of the nuclear factor kappaB (NFkappaB) p50 subunit precursor, p105, and its inhibitor (IkappaB) were measured.. SHR showed higher aortic expression of IL-1beta, IL-6 and TNFalpha than WKY (P < 0.05) and higher plasma levels of IL-1beta and IL-6 than WKY (P < 0.05). Moreover, SHR also presented increased aortic expression of nuclear transcription factor NFkappaB p50 subunit precursor (p105), and a reduction of its inhibitor IkappaB. Both eplerenone and HHR decreased blood pressure to a comparable extent (P < 0.05). This effect was accompanied by a reduction in plasma levels of IL-1beta and IL-6 and aortic mRNA expression of IL-1beta, IL-6 and TNFalpha. However, the effect of eplerenone was more marked, since eplerenone-treated rats showed significantly lower inflammatory parameters than SHR receiving HHR. In addition, both antihypertensive treatments increased IkappaB mRNA expression in a similar manner, but only eplerenone reduced NFkappaB mRNA expression.. Aldosterone, as well as an increase in haemodynamic forces produced by hypertension, participate in the vascular inflammatory process associated with hypertension in SHR. This effect seems to be mediated by enhanced vascular expression of cytokines through a modification of the NFkappaB/IkappaB system.

Topics: Aldosterone; Animals; Antihypertensive Agents; Drug Therapy, Combination; Eplerenone; Hypertension; I-kappa B Proteins; Interleukin-1; Interleukin-6; Male; Mineralocorticoid Receptor Antagonists; NF-kappa B; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Spironolactone; Tumor Necrosis Factor-alpha; Vasculitis

Aldosterone has been thought to act primarily on epithelia to regulate fluid and electrolyte homeostasis. Mineralocorticoid receptors (MR), however, are also expressed in nonepithelial tissues, such as the heart and vascular smooth muscle. Recently, pathophysiological effects of nonepithelial MR activation by aldosterone have been demonstrated in the context of inappropriate mineralocorticoid levels for salt status, including coronary vascular inflammation and cardiac fibrosis. These effects are mostly prevented by the concomitant administration of MR antagonists, but to date, no equivalent studies have determined whether MR blockade can reverse established inflammation and fibrosis. Uninephrectomized rats maintained on 0.9% NaCl solution to drink were treated as follows: group 1 served as controls; group 2 received deoxycorticosterone (DOC; 20 mg/wk) for 4 wk until death, and group 3 received DOC for 8 wk. Group 4 received DOC for 4 wk and no steroid from wk 5-8; group 5 received DOC for 8 wk and eplerenone in their chow during wk 5-8. DOC progressively raised cardiac collagen accumulation at 4 and 8 wk. Rats given DOC for 4 wk and killed at 8 wk showed levels of fibrosis identical to those in animals killed at 4 wk, i.e. persistently elevated above control values. Rats given DOC for 8 wk and eplerenone for the second half of the period showed cardiac collagen levels indistinguishable from control values. Values for inflammatory marker and NAD(P)H oxidase subunit expression in coronary vessels showed a similar pattern of response, with minor variation. Thus, MR antagonists do not only prevent cardiac fibrosis, but also reverse cardiac fibrosis once it is established. In addition, the continuing vascular inflammatory response and fibrosis after DOC withdrawal (group 4) support a role for activation of vascular MR by endogenous glucocorticoids in the context of tissue damage and generation of reactive oxygen species.

Topics: Animals; Biomarkers; Coronary Vessels; Desoxycorticosterone; Eplerenone; Fibrosis; Male; Mineralocorticoid Receptor Antagonists; Myocardium; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Sodium Chloride, Dietary; Spironolactone; Vasculitis

In epithelial tissues such as kidney, mineralocorticoid receptors (MR) are protected against glucocorticoid occupancy by the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) type 2. If the enzyme is congenitally inactive, or blocked by carbenoxolone, physiologic glucocorticoids act as MR agonists in such tissues. In most nonepithelial tissues, including cardiomyocytes, 11 beta HSD2 is expressed at minimal levels; in these tissues physiologic glucocorticoids act as MR antagonists, with the basis for this tissue selectivity currently unknown. Vascular smooth muscle cells (VSMC) express MR and 11 beta HSD1/2, with 11 beta HSD1 reported to show uncharacteristic oxidase activity, so that VSMC thus constitute a potential physiologic aldosterone target tissue. Because mineralocorticoid/salt administration triggers marked inflammatory responses in coronary vasculature, we reasoned that VSMC (like epithelial) MR may be activated by glucocorticoids if the protective enzyme is blocked. We thus gave uninephrectomized rats 0.9% NaCl solution to drink, and deoxycorticosterone (DOC, as a single 20 mg sc dose) or carbenoxolone (CBX, 2.5 mg/d in the drinking solution). Both DOC and CBX increased systolic blood pressure, heart, and kidney weight, and expression of cyclooxygenase 2, ED-1-positive macrophages, and osteopontin, with effects of both DOC and CBX blocked by the selective MR antagonist eplerenone. These findings suggest that local glucocorticoid excess, reflecting lower VSMC 11 beta HSD1/2 activity may mimic systemic mineralocorticoid excess, and play a direct etiologic role in coronary vascular inflammatory responses under circumstances of a high salt intake.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; Animals; Blood Pressure; Carbenoxolone; Cardiomegaly; Coronary Disease; Desoxycorticosterone; Enzyme Inhibitors; Eplerenone; Fibrosis; Heart; Hydroxysteroid Dehydrogenases; Kidney; Male; Mineralocorticoid Receptor Antagonists; Muscle, Smooth, Vascular; Myocardium; Nephrectomy; Organ Size; Rats; Rats, Sprague-Dawley; Sodium Chloride; Solutions; Spironolactone; Vasculitis

Vascular inflammation was examined as a potential mechanism of aldosterone-mediated myocardial injury in uninephrectomized rats receiving 1% NaCl-0.3% KCl to drink for 1, 2, or 4 wk and 1) vehicle, 2) aldosterone infusion (0.75 microg/h), or 3) aldosterone infusion (0.75 microg/h) plus the selective aldosterone blocker eplerenone (100 mg. kg(-1). day(-1)). Aldosterone induced severe hypertension at 4 wk [systolic blood pressure (SBP), 210 +/- 3 mmHg vs. vehicle, 131 +/- 2 mmHg, P < 0.001], which was partially attenuated by eplerenone (SBP, 180 +/- 7 mmHg; P < 0.001 vs. aldosterone alone and vehicle). No significant increases in myocardial interstitial collagen fraction or hydroxyproline concentration were detected throughout the study. However, histopathological analysis of the heart revealed severe coronary inflammatory lesions, which were characterized by monocyte/macrophage infiltration and resulted in focal ischemic and necrotic changes. The histological evidence of coronary lesions was preceded by and associated with the elevation of cyclooxygenase-2 (up to approximately 4-fold), macrophage chemoattractant protein-1 (up to approximately 4-fold), and osteopontin (up to approximately 13-fold) mRNA expression. Eplerenone attenuated proinflammatory molecule expression in the rat heart and subsequent vascular and myocardial damage. Thus aldosterone and salt treatment in uninephrectomized rats led to severe hypertension and the development of a vascular inflammatory phenotype in the heart, which may represent one mechanism by which aldosterone contributes to myocardial disease.

Topics: Aldosterone; Animals; Blood Pressure; Chemokine CCL2; Coronary Vessels; Cyclooxygenase 2; Endomyocardial Fibrosis; Eplerenone; Gene Expression; Hypertension; Immunohistochemistry; In Situ Hybridization; Intercellular Adhesion Molecule-1; Isoenzymes; Male; Myocardium; Osteopontin; Phenotype; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Sialoglycoproteins; Spironolactone; Vascular Cell Adhesion Molecule-1; Vasculitis

We studied the role of aldosterone (aldo) in myocardial injury in a model of angiotensin (Ang) II-hypertension. Wistar rats were given 1% NaCl (salt) to drink and randomized into one of the following groups (n = 10; treatment, 21 d): 1) vehicle control (VEH); 2) Ang II infusion (25 ng/min, sc); 3) Ang II infusion plus the selective aldo blocker, eplerenone (epl, 100 mg/kg.d, orally); 4) Ang II infusion in adrenalectomized (ADX) rats; and 5) Ang II infusion in ADX rats with aldo treatment (20 micro g/kg.d, sc). ADX rats received also dexamethasone (12 micro g/kg.d, sc). Systolic blood pressure increased with time in all treatment groups except the VEH group (VEH, 136 +/- 6; Ang II/NaCl, 203 +/- 12; Ang II/NaCl/epl, 196 +/- 10; Ang II/NaCl/ADX, 181 +/- 7; Ang II/NaCl/ADX/aldo, 236 +/- 8 mm Hg). Despite similar levels of hypertension, epl and ADX attenuated the increase in heart weight/body weight induced by Ang II. Histological examination of the hearts evidenced myocardial and vascular injury in the Ang II/salt (7 of 10 hearts with damage, P < 0.05 vs. VEH) and Ang II/salt/ADX/aldo groups (10 of 10 hearts with damage, P < 0.05). Injury included arterial fibrinoid necrosis, perivascular inflammation (primarily macrophages), and focal infarctions. Vascular lesions were associated with expression of the inflammatory mediators cyclooxygenase 2 (COX-2) and osteopontin in the media of coronary arteries. Myocardial injury, COX-2, and osteopontin expression were markedly attenuated by epl treatment (1 of 10 hearts with damage, P < 0.05 vs. Ang II/salt) and adrenalectomy (2 of 10 hearts with damage, P < 0.05 vs. Ang II/salt). Our data indicate that aldo plays a major role in Ang II-induced vascular inflammation in the heart and implicate COX-2 and osteopontin as potential mediators of the damage.

Topics: Adrenalectomy; Aldosterone; Angiotensin II; Animals; Body Weight; Coronary Disease; Coronary Vessels; Corticosterone; Cyclooxygenase 2; Diuresis; Drinking; Eating; Eplerenone; Heart; Hypertension; Isoenzymes; Macrophages; Male; Mineralocorticoid Receptor Antagonists; Myocardium; Necrosis; Organ Size; Osteopontin; Potassium; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Renin; Sialoglycoproteins; Sodium; Sodium Chloride; Spironolactone; Vasculitis