期刊
CIRCULATION RESEARCH
卷 99, 期 7, 页码 758-766出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000244092.95152.86
关键词
congestive heart failure; aldosterone; cytokines; cyclooxygenase-2; nervous system
资金
- NHLBI NIH HHS [R01-HL-073986, R01-HL-063915] Funding Source: Medline
Blocking brain mineralocorticoid receptors (MRs) reduces the high circulating levels of tumor necrosis factor (TNF)-alpha in heart failure (HF) rats. TNF-alpha and other proinflammatory cytokines activate neurons in the paraventricular nucleus (PVN) of hypothalamus, including corticotropin-releasing hormone (CRH) neurons, by inducing cyclooxygenase (COX)-2 activity and synthesis of prostaglandin E-2 by perivascular cells of the cerebral vasculature. We tested the hypothesis that systemic treatment with a MR antagonist would reduce hypothalamic COX-2 expression and PVN neuronal activation in HF rats. Rats underwent coronary ligation to induce HF, confirmed by echocardiography, or sham surgery, followed by 6 weeks treatment with eplerenone (30 mg/kg per day, orally) or vehicle ( drinking water). Eplerenone-treated HF rats had lower plasma TNF-alpha, interleukin (IL)-1 beta and IL-6, less COX-2 staining of small blood vessels penetrating PVN, fewer PVN neurons expressing Fra-like activity ( indicating chronic neuronal activation), and fewer PVN neurons staining for TNF-alpha, IL-1 beta, and CRH than vehicle-treated HF rats. COX-2 and CRH protein expression in hypothalamus were 1.7- and 1.9-fold higher, respectively, in HF+ vehicle versus sham + vehicle rats; these increases were attenuated (26% and 25%, respectively) in HF + eplerenone rats. Eplerenone-treated HF rats had less prostaglandin E-2 in cerebrospinal fluid, lower plasma norepinephrine levels, lower left ventricular end-diastolic pressure, and lower right ventricle/body weight and lung/body weight ratios, but no improvement in left ventricular function. Treatment of HF rats with anticytokine agents, etanercept or pentoxifylline, produced very similar results. This study reveals a previously unrecognized effect of MR antagonism to minimize cytokine-induced central neural excitation in rats with HF.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据