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The heart is the main organ of the circulatory system and requires fatty acids to maintain its activity. Stress is a contributor to aggravating cardiovascular diseases and even death, and exacerbates the abnormal lipid metabolism. The cardiac metabolism may be disturbed by stress. Cholecystokinin (CCK), which is a classical peptide hormone, and its receptor (CCKR) are expressed in myocardial cells and affect cardiovascular function. Nevertheless, under stress, the exact role of CCKR on cardiac function and cardiac metabolism is unknown and the mechanism is worth exploring. After unpredictable stress, a common stress-inducing model that induces the development of mood disorders such as anxiety and reduces motivated behavior, we found that the abnormal contraction and diastole of the heart, myocardial injury, oxidative stress and inflammation of mice were aggravated. Cholecystokinin A receptor and cholecystokinin B receptor knockout (CCK1R2R-/-) significantly reversed these changes. Mechanistically, fatty acid metabolism was found to be altered in CCK1R2R-/- mice. Differential metabolites, especially L-tryptophan, L-aspartic acid, cholesterol, taurocholic acid, ADP, oxoglutaric acid, arachidonic acid and 17-Hydroxyprogesterone, influenced cardiac function after CCK1R2R knockout and unpredictable stress. We conclude that CCK1R2R-/- ameliorated myocardial damage caused by unpredictable stress via altering fatty acid metabolism. [ABSTRACT FROM AUTHOR]

Shrub encroachment has been a worldwide phenomenon, but the interactions between the surface hydrological cycle and the shrub‐encroached landscape at different hillslope positions remain poorly investigated. The present study was undertaken to explore the interactions between the water infiltration patterns affected by shrub encroachment. At four slope positions of a hillslope encroached by Caragana microphylla Lam, soil water content and temperature were continuously measured at 10‐min intervals at four or five depths in both the presence (shrub patches) and absence (grass matrix) of shrubs. Then, the infiltration of rainfall and meltwater was estimated based on analyses of the above data. The rainfall infiltration ratios (IRs) of grass matrix were as high as 0.78 ± 0.08, except at the lower site, which had a value of only 0.47. The IRs of shrub patches increased from 0.38 at the top site to 0.77 at the lower site. In snowy years, snow and ice were blown upward by wind and accumulated in the shrub patches and their leeward areas, which resulted in higher water input for the shrub patches than for the grass matrix. Shrub encroachment changed the microtopography and soil properties of the hillslope and further affected the surface hydrological processes. The feedbacks between shrub encroachment and water infiltration varied among sites of the hillslope, which may in turn have affected the development of shrub patches. [ABSTRACT FROM AUTHOR]

ANG II type 1 receptors ([AT.sub.1]R) mediate most of the central effects of ANG II on cardiovascular function, fluid homeostasis, and sympathetic drive. The mechanisms regulating [AT.sub.1]R expression in the brain are unknown. In some tissues, the [AT.sub.1]R can be upregulated by prolonged exposure to ANG II. We examined the hypothesis that ANG II upregulates the [AT.sub.1]R in the brain by stimulating the intracellular mitogen-activated protein kinase (MAPK) signaling pathway. Using molecular and immunochemical approaches, we examined expression of the [AT.sub.1]R and phosphorylated MAPK in the paraventricular nucleus of the hypothalamus (PVN) and the subfornical organ (SFO) of rats receiving a chronic (4-wk) subcutaneous infusion of ANG II (0.6 [micro]g/h) or saline (vehicle control), with or without concomitant (4-wk) intracerebroventricular (ICV) infusions of MAPK inhibitors or the [AT.sub.1]R blocker losartan. Subcutaneous infusion of ANG II markedly increased phosphorylation of MAPK and expression of [AT.sub.1]R mRNA and protein and [AT.sub.1]R-like immunoreactivity in the PVN and SFO. ANG II-induced [AT.sub.1]R expression was blocked by ICV infusion of the p44142 MAPK inhibitor PD-98059 (0.025 [micro]g/h) and the JNK inhibitor SP-600125 (0.125 [micro]g/h), but not by the p38 MAPK inhibitor SB203580 (0.125 [micro]g/h). Upregulation of the [AT.sub.1]R in the PVN and SFO by peripheral ANG II was abolished by ICV losartan (10 [micro]g/h). The data indicate that blood-borne ANG II upregulates brain [AT.sub.1]R by activating intracellular p44/42 MAPK and JNK signaling pathways. paraventricular nucleus; subfornical organ; angiotensin II type 1 receptor; autonomic regulation

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 I-IF 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 [micro]g/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.sub.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)-1[beta], and adrenocorticotropic hormone, increased left ventricular end-diastolic pressure, and increased wet lung-to-body weight ratio. With the exception of plasma IL-1[beta], an indicator of peripheral pro-inflammatory cytokine activity, all measures of neurohumoral excitation were significantly lower in HF rats treated with intracerebro-ventricular 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. paraventricular nucleus of hypothalamus; inflammation; sympathetic nervous system; brain renin-angiotensin system; hypothalamic-pituitary-adrenal axis

Aldosterone acts upon mineralocorticoid receptors in the brain to increase blood pressure and sympathetic nerve activity, but the mechanisms are still poorly understood. We hypothesized that aldosterone increases sympathetic nerve activity by upregulating the renin-angiotensin system (RAS) and oxidative stress in the brain, as it does in peripheral tissues. In Sprague-Dawley rats, aldosterone (Aldo) or vehicle (Veh) was infused for 1 wk via an intracerebroventricular (ICV) cannula, while RU28318 (selective mineralocorticoid receptor antagonist), Tempol (superoxide dismutase mimetic), losartan [angiotensin II type 1 receptor (A[T.sub.1]R) antagonist], or Veh was infused simultaneously via a second ICV cannula. After 1 wk of ICV Aldo, plasma norepinephrine was increased and mean arterial pressure was slightly elevated, but heart rate was unchanged. These effects were ameliorated by ICV infusion of RU-28318, Tempol or losartan. Aldo increased expression of A[T.sub.1]R and angiotensin-converting enzyme (ACE) mRNA in hypothalamic tissue. RU-28318 minimized and Tempol prevented the increase in A[T.sub.1]R mRNA; RU-28318 prevented the increase in ACE mRNA. Losartan had no effect on A[T.sub.1]R or ACE mRNA. Immunohistochemistry revealed Aldo-induced increases in dihydroethidium staining (indicating oxidative stress) and Fra-like activity (indicating neuronal excitation) in neurons of the hypothalamic paraventricular nucleus (PVN). RU-28318 prevented the increases in superoxide and Fra-like activity in PVN; Tempol and losartan minimized these effects. Acute ICV infusions of sarthran (A[T.sub.1]R antagonist) or Tempol produced greater sympathoinhibition in Aldo-treated than in Veh-treated rats. Thus aldosterone upregulates key elements of brain RAS and induces oxidative stress in the hypothalamus. Aldosterone may increase sympathetic nerve activity by these mechanisms. mineralocorticoid receptor; central nervous system; angiotensin-converting enzyme; angiotensin II type 1 receptor; sympathetic nerve activity

Within minutes of acute myocardial infarction (MI), proinflammatory cytokines increase in the brain, heart, and plasma. We hypothesized that cardiac afferent nerves stimulated by myocardial injury signal the brain to increase central cytokines. Urethane-anesthetized male Sprague-Dawley rats underwent ligation of the left anterior descending coronary artery (LAD) or sham LAD ligation after bilateral cervical vagotomy, sham vagotomy, or application of a 10% phenol solution to the epicardial surface of the myocardium at risk. MI caused a significant increase in tumor necrosis factor (TNF)-[alpha] and interleukin (IL)-1[beta] in the plasma and heart, which was blunted by vagotomy. MI also caused a significant increase in hypothalamic TNF-[alpha] and IL-1[beta], which was not affected by vagotomy. In contrast, epicardial phenol blocked MI-induced increases in hypothalamic TNF-[alpha] and IL-1[beta] without affecting increases in the plasma and heart. These findings demonstrate that the appearance of proinflammatory cytokines in the brain after MI is independent of blood-borne cytokines and suggest that cardiac sympathetic afferent nerves activated by myocardial ischemia signal the brain to increase cytokine production. In addition, an intact vagus nerve is required for the full expression of proinflammatory cytokines in the injured myocardium and in the circulation. We conclude that the sympathetic and parasympathetic innervation of the heart both contribute to the acute proinflammatory response to MI. cardiac sympathetic afferents; cardiac vagal afferents; tumor necrosis factor-[alpha]; interleukin-1[beta]; hypothalamus

The central pathways and mediators involved in sympathoexcitatory responses to circulating leptin are not well understood, although the arcuate-paraventricular nucleus (ARC-PVN) pathway likely plays a critical role. In urethane-anesthetized rats, ipsilateral intracarotid artery (ICA) injection of murine leptin (100 [micro]g/kg) activated most PVN neurons tested. These responses were reduced by intracerebroventricular injection of the melanocortin subtype 3 and 4 receptor (MC3/4-R) antagonist SHU-9119 (0.6 nmol). The MC3/4-R agonist MTII (0.6 nmol icv) activated PVN neurons. Some PVN neurons that were excited by ICA leptin were inhibited by local application of neuropeptide Y (NPY, 2.5 ng). ICA leptin (100 [micro]g/kg) excited presympathetic rostral ventrolateral medulla neurons and renal sympathetic nerve activity without significant change in blood pressure or heart rate; these effects were mimicked by intracerebroventricular injection of MTII (0.6 nmol). These data provide in vivo electrophysiological evidence to support the hypothesis that circulating leptin activates the sympathetic nervous system by stimulating the release of [alpha]-melanocyte-stimulating hormone in the vicinity of PVN neurons that are inhibited by the orexogenic peptide NPY. obesity; sympathetic nerve activity; extracellular recording; neuropeptide Y; [alpha]-melanocyte stimulating hormone

In pathophysiological conditions, increased bloodborne 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 [micro]g/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 [micro]g) into lateral ventricle. Injection of PG[E.sub.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. cytokines; paraventricular nucleus of hypothalamus; rostral ventrolateral medulla; renal sympathetic nerve activity; prostaglandin [E.sub.2]

Despite recent therapeutic advances, the prognosis for patients with heart failure remains dismal. Unchecked neurohumoral excitation is a critical element in the progressive clinical deterioration associated with the heart failure syndrome, and its peripheral manifestations have become the principal targets for intervention. The link between peripheral systems activated in heart failure and the central nervous system as a source of neurohumoral drive has therefore come under close scrutiny. In this context, the forebrain and particularly the paraventricular nucleus of the hypothalamus have emerged as sites that sense humoral signals generated peripherally in response to the stresses of heart failure and contribute to the altered volume regulation and augmented sympathetic drive that characterize the heart failure syndrome. This brief review summarizes recent studies from our laboratory supporting the concept that the forebrain plays a critical role in the pathogenesis of ischemia-induced heart failure and suggesting that the forebrain contribution must be considered in designing therapeutic strategies. Forebrain signaling by neuroactive products of the renin-angiotensin system and the immune system are emphasized. angiotensin; aldosterone; cytokines; tumor necrosis factor; immune system; renin; vasopressin; sympathetic; extracellular fluid volume; baroreflex

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 = 68) from rats with ischemia-induced HF was higher than that of PVN neurons (n = 42) from shamoperated controls (8.7 [+ or -] vs. 2.7 [+ or -] 0.3 spikes/s, P < 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 < 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