This study examined the early neurohumoral events in the progression of congestive heart failure (CHF) after myocardial infarction (MI) in rats. Immediately after MI was induced by coronary artery ligation, rats had severely depressed left ventricular systolic function and increased left ventricular end-diastolic volume (LVEDV). Both left ventricular function and the neurohumoral indicators of CHF underwent dynamic changes over the next 6 wk. LVEDV increased continuously over the study interval, whereas left ventricular stroke volume increased but reached a plateau at 4 wk. Plasma renin activity (PRA), arginine vasopressin, and atrial natriuretic factor all increased, but with differing time courses. PRA declined to a lower steady-state level by 4 wk. Six to 8 wk after MI, CHF rats had enhanced renal sympathetic nerve activity and blunted baroreflex regulation. These findings demonstrate that the early course of heart failure is characterized not by a simple "switching on" of neurohumoral drive, but rather by dynamic fluctuations in neurohumoral regulation that are linked to the process of left ventricular remodeling.

The mineralocorticoid (MC) receptor antagonist spironolactone (SL) improves morbidity and mortality in patients with congestive heart failure (CHF). We tested the hypothesis that the central nervous system actions of SL contribute to its beneficial effects. SL (100 ng/h for 28 days) or ethanol vehicle (VEH) was administered intracerebroventricularly or intraperitoneally to rats with CHF induced by coronary artery ligation (CL) and to SHAM-operated controls. The intracerebroventricular SL treatment prevented the increase in sodium appetite and the decreases in sodium and water excretion observed within a week of CL in VEH-treated CHF rats. Intraperitoneal SL also improved volume regulation in the CHF rats, but only after 3 wk of treatment. Four weeks of SL treatment, either intracerebroventricularly or intraperitoneally, ameliorated both the increase in sympathetic drive and the impaired baroreflex function observed in VEH-treated CHF rats. These findings suggest that activation of MC receptors in the central nervous system plays a critical role in the altered volume regulation and augmented sympathetic drive that characterize clinical heart failure.

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.

In pathophysiological conditions, increased blood-borne TNF-alpha induces a broad range of biological effects, including activation of the hypothalamic-pituitary-adrenal axis and sympathetic drive. In urethane-anesthetized adult Sprague-Dawley rats, we examined the mechanisms by which blood-borne TNF-alpha activates neurons in paraventricular nucleus (PVN) of hypothalamus and rostral ventrolateral medulla (RVLM), two critical brain regions regulating sympathetic drive in normal and pathophysiological conditions. TNF-alpha (0.5 microg/kg), administered intravenously or into ipsilateral carotid artery (ICA), activated PVN and RLVM neurons and increased sympathetic nerve activity, arterial pressure, and heart rate. Responses to intravenous TNF-alpha were not affected by vagotomy but were reduced by mid-collicular decerebration. Responses to ICA TNF-alpha were substantially reduced by injection of the cyclooxygenase inhibitor ketorolac (150 microg) into lateral ventricle. Injection of PGE(2) (50 ng) into lateral ventricle or directly into PVN increased PVN or RVLM activity, respectively, and sympathetic drive, with shorter onset latency than blood-borne TNF-alpha. These findings suggest that blood-borne cytokines stimulate cardiovascular and renal sympathetic responses via a prostaglandin-dependent mechanism operating at the hypothalamic level.

The expression of proinflammatory cytokines increases in the hypothalamus of rats with heart failure (HF). The pathophysiological significance of this observation is unknown. We hypothesized that hypothalamic proinflammatory cytokines upregulate the activity of central neural systems that contribute to increased sympathetic nerve activity in HF, specifically, the brain renin-angiotensin system (RAS) and the hypothalamic-pituitary-adrenal (HPA) axis. Rats with HF induced by coronary ligation and sham-operated controls (SHAM) were treated for 4 wk with a continuous intracerebroventricular infusion of the cytokine synthesis inhibitor pentoxifylline (PTX, 10 microg/h) or artificial cerebrospinal fluid (VEH). In VEH-treated HF rats, compared with VEH-treated SHAM rats, the hypothalamic expression of proinflammatory cytokines was increased, along with key components of the brain RAS (renin, angiotensin-converting enzyme, angiotensin type 1 receptor) and corticotropin-releasing hormone, the central indicator of HPA axis activation, in the paraventricular nucleus (PVN) of the hypothalamus. The expression of other inflammatory/excitatory mediators (superoxide, prostaglandin E(2)) was also increased, along with evidence of chronic neuronal excitation in PVN. VEH-treated HF rats had higher plasma levels of norepinephrine, ANG II, interleukin (IL)-1beta, and adrenocorticotropic hormone, increased left ventricular end-diastolic pressure, and increased wet lung-to-body weight ratio. With the exception of plasma IL-1beta, an indicator of peripheral proinflammatory cytokine activity, all measures of neurohumoral excitation were significantly lower in HF rats treated with intracerebroventricular PTX. These findings suggest that the increase in brain proinflammatory cytokines observed in rats with ischemia-induced HF is functionally significant, contributing to neurohumoral excitation by activating brain RAS and the HPA axis.

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The inflammatory milieu of acute myocardial infarction (MI) is theoretically conducive to enhanced cytokine synthesis within the brain. We tested the hypothesis that synthesis of tumor necrosis factor-alpha (TNF-alpha), an indicator of proinflammatory cytokine activity, increases in brain after MI. MI was induced in rats by ligating the left anterior descending coronary artery and confirmed by echocardiography. Plasma and tissue levels of TNF-alpha were measured using ELISA; TNF-alpha mRNA was measured with real-time PCR. Heart, brain, and plasma samples were obtained 0.5, 1, 4, or 24 h or 4 wk after MI. TNF-alpha synthesis increased in the brain, heart, and plasma within minutes to hours after MI and was sustained over the interval tested. Among the brain tissues examined, TNF-alpha increased selectively in hypothalamus. Chronic treatment with pentoxifylline prevented the increases in TNF-alpha in brain, heart, and plasma measured 4 wk after MI. MI-induced cytokine synthesis in the hypothalamus and its prevention by pentoxifylline have important implications in the context of the development of heart failure after MI.

. The renin-angiotensin-aldosterone system excites hypothalamic paraventricular nucleus neurons in heart failure. Am J Physiol Heart Circ Physiol 283: H423-H433, 2002; 10.1152/ajpheart.00685.2001.-The paraventricular nucleus (PVN) of the hypothalamus has critical homeostatic functions, including the regulation of fluid balance and sympathetic drive. It has been suggested that altered activity of this nucleus contributes to the progression of congestive heart failure (HF). We hypothesized that forebrain influences of the renin-angiotensin-aldosterone system augment the activity of PVN neurons in HF. The rate of PVN neurons (n ϭ 68) from rats with ischemia-induced HF was higher than that of PVN neurons (n ϭ 42) from shamoperated controls (8.7 Ϯ 0.8 vs. 2.7 Ϯ 0.3 spikes/s, P Ͻ 0.001, HF vs. SHAM). Forebrain-directed intracarotid artery injections of the angiotensin type 1 receptor antagonist losartan, the angiotensin-converting enzyme inhibitor captopril, and the mineralocorticoid receptor antagonist spironolactone all significantly (P Ͻ 0.05) reduced PVN neuronal activity in HF rats. These findings demonstrate that the renin-angiotensinaldosterone system drives PVN neuronal activity in HF, likely resulting in increased sympathetic drive and volume accumulation. This mechanism of neurohumoral excitation in HF is accessible to manipulation by blood-borne therapeutic agents.angiotensin type 1 receptors; angiotensin-converting enzyme; mineralocorticoid receptors; spironolactone; baroreceptors THE PARAVENTRICULAR NUCLEUS (PVN) of the hypothalamus is a critical forebrain site mediating neurohumoral responses to stress. PVN is also a principal effector site for forebrain mechanisms regulating extracellular fluid volume and sympathetic drive (1,13,19). The activity of PVN neurons can be modulated by signals from circumventricular organs surrounding the third cerebral ventricle that sense the circulating levels of neuropeptides and by signals ascending from brain stem regions that respond to changes in pressure, volume, and chemical conditions within the cardiovascular system.In rats with ischemia-induced congestive heart failure (HF), metabolic activity within the PVN is increased (22). Blockade of forebrain angiotensin type 1 (AT 1 ) receptors (3, 35) or of mineralocorticoid receptors (5) can reduce sympathetic drive and improve baroreflex regulation of renal sympathetic nerve activity in rats with ischemia-induced HF. Thus we hypothesized that activation of forebrain components of the reninangiotensin-aldosterone system (RAAS) increases the discharge rate of PVN neurons in HF, potentially contributing to the volume accumulation and augmented sympathetic drive characteristic of the HF syndrome. To test this hypothesis, we obtained extracellular recordings from single PVN neurons in rats with ischemia-induced HF and examined their responses to the selective blockade of several specific components of the RAAS at the forebrain level. We observed a generalized increase in PVN neuronal discharge in HF versus sham-operated rat...