Novel Effect of Mineralocorticoid Receptor Antagonism to Reduce Proinflammatory Cytokines and Hypothalamic Activation in Rats With Ischemia-Induced Heart Failure

Abstract

Abstract-Blocking brain mineralocorticoid receptors (MRs) reduces the high circulating levels of tumor necrosis factor (TNF)-␣ in heart failure (HF) rats. TNF-␣ 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-␣, interleukin (IL)-1␤ 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-␣, IL-1␤, 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 HFϩvehicle versus shamϩvehicle rats; these increases were attenuated (26% and 25%, respectively) in HFϩeplerenone 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.

Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation

“…2003; Kang et al. 2006), however, a specific role for EC‐MR could not be determined from those studies. The lack of TNF α induction in the LV of EC‐MR −/− in response to TAC could potentially explain the preserved systolic function as TNF α can directly contribute to cardiac dysfunction (Bozkurt et al.…”

TNF-.ALPHA. in Hypothalamic Paraventricular Nucleus Contributes to Sympathoexcitation in Heart Failure by Modulating AT1 Receptor and Neurotransmitters

“…Rats underwent sterile surgery under anesthesia (ketamine + xylazine, ip) for induction of HF by ligation of the left anterior descending coronary artery, or the same surgery without vessel ligation (SHAM), as previously described (Kang et al 2006(Kang et al , 2008a(Kang et al , 2008b(Kang et al , 2009aGuggilam et al 2008).…”

“…Echocardiography was performed under ketamine sedation to assess left ventricular (LV) function as previously described (Kang et al 2006(Kang et al , 2008a(Kang et al , 2008b. Ischemic zone (IZ) was estimated by planimetry of the region of the LV endocardial silhouette which demonstrated akinesis or dyskinesis, and expressed as a percentage of the whole (%IZ).…”

Delayed expression of cytokines after reperfused myocardial infarction: possible trigger for cardiac dysfunction and ventricular remodeling

“…The role of cytokines in heart failure has been investigated either during the very early time period following infarction (first 48 h) (9,16) or in the advanced phase of the development of congestive heart failure (1,12,15), but very few data are available concerning the phenomena that occur in the myocardium within the first week after MI. From the literature it appears that after an initial raise in the infarcted region of the myocardium, the cytokine level decreases to return to basal values after 24 -48 h (9).…”