A brain leptin-renin angiotensin system interaction in the regulation of sympathetic nerve activity

The sympathetic nervous system, leptin, and renin-angiotensin system (RAS) have been implicated in obesity-associated hypertension. There is increasing evidence for the presence of both leptin and angiotensin II receptors in several key brain cardiovascular and metabolic control regions. We tested the hypothesis that the brain RAS plays a facilitatory role in the sympathetic nerve responses to leptin. In rats, intracerebroventricular (ICV) administration of losartan (5 μg) selectively inhibited increases in renal and brown adipose tissue (BAT) sympathetic nerve activity (SNA) produced by leptin (10 μg ICV) but did not reduce the SNA responses to corticotrophin-releasing factor (CRF) or the melanocortin receptor agonist MTII. In mice with deletion of angiotensin II type-1a receptors (AT(1a)R(-/-)), increases in renal and BAT SNA induced by leptin (2 μg ICV) were impaired whereas SNA responses to MTII were preserved. Decreases in food intake and body weight with ICV leptin did not differ in AT(1a)R(-/-) vs. AT(1a)R(+/+) mice. ICV leptin in rats increased AT(1a)R and angiotensin-converting enzyme (ACE) mRNA in the subfornical organ and AT(1a)R mRNA in the arcuate nucleus, suggesting leptin-induced upregulation of the brain RAS in specific brain regions. To evaluate the role of de novo production of brain angiotensin II in SNA responses to leptin, we treated rats with captopril (12.5 μg ICV). Captopril attenuated leptin effects on renal and BAT SNA. In conclusion, these studies provide evidence that the brain RAS selectively facilitates renal and BAT sympathetic nerve responses to leptin while sparing effects on food intake.     

Divergent mechanism regulating fluid intake and metabolism by the brain renin-angiotensin system

The purpose of this review is two-fold. First, I will highlight recent advances in our understanding of the mechanisms regulating angiotensin II (ANG II) synthesis in the brain, focusing on evidence that renin is expressed in the brain and is expressed in two forms: a secreted form, which may catalyze extracellular ANG I generation from glial or neuronal angiotensinogen (AGT), and an intracellular form, which may generate intracellular ANG in neurons that may act as a neurotransmitter. Second, I will discuss recent studies that advance the concept that the renin-angiotensin system (RAS) in the brain not only is a potent regulator of blood pressure and fluid intake but may also regulate metabolism. The efferent pathways regulating the blood pressure/dipsogenic effects and the metabolic effects of elevated central RAS activity appear different, with the former being dependent upon the hypothalamic-pituitary-adrenal axis, and the latter being dependent upon an interaction between the brain and the systemic (or adipose) RAS.     

Effects of alpha1-adrenergic receptor blockade by doxazosin on renin-angiotensin system-regulating aminopeptidase and vasopressin-degrading activities in male and female rat thalamus.

The thalamus has connections with central autonomic centers involved in cardiovascular control and is enervated by noradrenergic fibers. The excitability of thalamic neurons is due to a reduction of ionic currents mediated by alpha(1)-adrenoceptors. The brain renin- angiotensin system (RAS) and the peptide hormone arginine-vasopressin (AVP) are also involved in the central control of blood pressure, and fluid and electrolyte homeostasis. It has been extensively reported that aminopeptidase A (APA), aminopeptidase B (APB), aminopeptidase N (APN), and vasopressin-degrading cystyl aminopeptidase activity (AVP-DA) play an important role in the regulation of the activity of angiotensins and AVP. We have analyzed the effect of alpha(1)-adrenoceptor blockade by doxazosin on RAS-regulating aminopeptidase activities and AVP-DA in soluble and membrane-bound fractions of male and female rat thalamus. Our results show that alpha(1)-adrenoceptors blockade by doxazosin does not modify the RAS through its degrading peptidases at thalamic level either in male or female rats. However, alpha(1)-adrenoceptors blockade shows gender differences in AVP-DA, increasing in males but not in females, supporting an increased capacity of males against females to degrade AVP and, therefore, to regulate cardiovascular homeostasis, under this pharmacological manipulation.     

暖温经历对雌性黑线仓鼠能量代谢、产热和体脂含量的影响

能量代谢的生理调节是小型哺乳动物应对不同环境温度的重要策略之一,为探讨暖温下代谢产热在体重和体脂适应性调节中的作用和机理,本研究将雌性黑线仓鼠(Cricetulus barabensis)暴露于暖温(30°C)1个月、3个月和4个月,测定体重、摄入能、代谢产热、体脂含量、褐色脂肪组织(BAT)细胞色素c氧化酶(COX)活性和解偶联蛋1 (UCP1) mRNA表达等。结果显示,暖温对黑线仓鼠体重无显著影响,但使脂肪含量显著增加。与室温组相比(21°C),暖温组消化率显著升高,但摄入能和消化能显著降低;暖温下非颤抖性产热(NST)显著降低,脑、肝脏和心脏COX活性、BAT COX活性和UCP1 mRNA的表达显著下调。结果表明,暖温下降低代谢产热补偿了能量摄入的减少,机体处于正能量平衡状态,是脂肪含量显著增加的主要原因之一。脑、肝脏、心脏和BAT代谢活性降低是代谢产热降低的主要机制,与脂肪累积有关。     

Mechanisms mediating renal sympathetic activation to leptin in obesity

Leptin plays a critical role in the control of energy homeostasis. The sympathetic cardiovascular actions of leptin have emerged as a potential link between obesity and hypertension. We previously demonstrated that in mice, modest obesity induced by 10 wk of a high-fat diet is associated with preservation of leptin ability to increase renal sympathetic nerve activity (SNA) despite the resistance to the metabolic effects of leptin. Here, we examined whether selective leptin resistance exists in mice with late-stage diet-induced obesity (DIO) produced by 20 wk of a high-fat diet. The decrease in food intake and body weight induced by intraperitoneal or intracerebroventricular injection of leptin was significantly attenuated in the DIO mice. Regional SNA responses to intravenous leptin were also attenuated in DIO mice. In contrast, intracerebroventricularly administered leptin caused contrasting effects on regional SNA in DIO mice. Renal SNA response to intracerebroventricular leptin was preserved, whereas lumbar and brown adipose tissue SNA responses were attenuated. Intact renal SNA response to leptin combined with the increased cerebrospinal fluid leptin levels in DIO mice represents a potential mechanism for the adverse cardiovascular consequences of obesity. Lastly, we examined the role of phosphoinositol-3 kinase (PI3K) and melanocortin receptors (MCR) in mediating the preserved renal SNA response to leptin in obesity. Presence of PI3K inhibitor (LY294002) or MC3/4R antagonist (SHU9119) significantly attenuated the renal SNA response to leptin in DIO and agouti obese mice. Our results demonstrate the importance of PI3K and melanocortin receptors in the transduction of leptin-induced renal sympathetic activation in obesity.     

Intragastric administration of capsiate, a transient receptor potential channel agonist, triggers thermogenic sympathetic responses

The sympathetic thermoregulatory system controls the magnitude of adaptive thermogenesis in correspondence with the environmental temperature or the state of energy intake and plays a key role in determining the resultant energy storage. However, the nature of the trigger initiating this reflex arc remains to be determined. Here, using capsiate, a digestion-vulnerable capsaicin analog, we examined the involvement of specific activation of transient receptor potential (TRP) channels within the gastrointestinal tract in the thermogenic sympathetic system by measuring the efferent activity of the postganglionic sympathetic nerve innervating brown adipose tissue (BAT) in anesthetized rats. Intragastric administration of capsiate resulted in a time- and dose-dependent increase in integrated BAT sympathetic nerve activity (SNA) over 180 min, which was characterized by an emergence of sporadic high-activity phases composed of low-frequency bursts. This increase in BAT SNA was abolished by blockade of TRP channels as well as of sympathetic ganglionic transmission and was inhibited by ablation of the gastrointestinal vagus nerve. The activation of SNA was delimited to BAT and did not occur in the heart or pancreas. These results point to a neural pathway enabling the selective activation of the central network regulating the BAT SNA in response to a specific stimulation of gastrointestinal TRP channels and offer important implications for understanding the dietary-dependent regulation of energy metabolism and control of obesity.     

Agouti-related protein-deficient mice display an age-related lean phenotype

Endogenous modulators of the central melanocortin system, such as the agouti-related protein (AgRP), should hold a pivotal position in the regulation of energy intake and expenditure. Despite this, AgRP-deficient mice were recently reported to exhibit normal food intake, body weight gain, and energy expenditure. Here we demonstrate that 2- to 3-month-old Agrp null mice do in fact exhibit subtle changes in response to feeding challenges (fasting and MCR agonists) but, of more significance and magnitude, exhibit reduced body weight and adiposity after 6 months of age. This age-dependent lean phenotype is correlated with increased metabolic rate, body temperature, and locomotor activity and increased circulating thyroid hormone (T4 and T3) and BAT UCP-1 expression. These results provide further proof of the importance of the AgRP neuronal system in the regulation of energy homeostasis.     

Energy metabolism, testosterone and corticosterone in white-crowned sparrows

The influence of the steroid hormones testosterone and corticosterone on energy metabolism and activity of birds is largely enigmatic. We measured resting metabolic rate during night and day in 12 long-term castrated and 12 intact male white-crowned sparrows (Zonotrichia leucophrys gambelii) under short-day (8:16 SD), long-day (20:4 LD), LD+testosterone implant and LD−testosterone implant conditions. Each male was sequentially measured under all four conditions. Photostimulation increased testosterone, resting metabolic rate, food intake, hopping activity and body mass in castrates and intact males. Surprisingly, testosterone levels and metabolic rates did not differ between intact and castrated males. Testosterone implantation increased activity and food intake, but decreased body mass and resting metabolic rate in both groups. Removing testosterone implants reversed the effects on resting metabolic rate, activity and food intake. Corticosterone levels, measured immediately at the end of metabolism measurements, showed birds were not stressed. Corticosterone had no apparent relationship with resting metabolic rate and there was no interaction between corticosterone and testosterone. Overall, positive changes in testosterone levels resulted in a decrease of resting metabolic rate. We speculate that testosterone increases activity, and birds compensate for increased activity metabolism by reducing resting metabolic rate. Accepted: 18 July 1999     

长期强迫运动对大绒鼠体重、能量代谢和血清瘦素的影响

动物稳定体重的维持需要能量摄入和消耗之间的平衡。运动是影响动物能量平衡的重要因素之一。为了解运动对大绒鼠(Eothenomys miletus)的生理学效应,在室内条件下,测定了强迫运动训练(运用小鼠封闭跑台)8周后大绒鼠的体重、代谢率、摄入能、血清瘦素和身体组成的变化。结果显示,强迫运动训练8周对大绒鼠的体重无显著影响;大绒鼠的代谢率和摄入能均显著增加,训练8周后静止代谢率较对照组增加了29.9%,运动最大代谢率较对照组增加了10.7%;强迫运动训练8周组的身体脂肪重量比对照组降低了28.9%,血清瘦素水平比对照组下降了27.4%,对照组的瘦素与体脂含量具有明显的相关性,但运动组则不具有相关性;运动组的肝重量和消化道重量较对照组均显著增加;而体水重量则显著降低。这些结果表明,在强迫运动训练期间大绒鼠主要通过动员储存的脂肪、增加代谢率和食物摄入的方式来维持自身的体重及能量平衡。瘦素在长期强迫运动过程中对身体脂肪含量的变化具有调节作用。     

Blood pressure lowering effects of niacin-bound chromium(III) (NBC) in sucrose-fed rats: renin-angiotensin system

Excessive intake of sugars significantly elevates systolic blood pressure (SBP) in susceptible rats. Although the exact pathological mechanisms behind sugar-induced hypertension are uncertain and may be multiple, disturbances in the renin-angiotensin system (RAS) manifested by elevated circulating levels of angiotensin-2 may be involved. We attempted to confirm that the RAS was significantly involved in sugar-induced BP elevations and examined whether the ability of niacin-bound chromium (NBC) to ameliorate sugar-induced SBP elevations was due, at least in part, through effects on the RAS. Initially, 40 mature Sprague-Dawley rats (SD), male and female, were involved in the study comparing two methods to estimate rat blood pressure indirectly. Then 13 were selected to examine the effects of NBC on the RAS. All rats eventually ingested a diet heavy in sucrose (30% w/w). In addition to blood pressure readings, the following procedures were implemented: insulin and losartan challenges, evaluation of serum ACE activity, measurement of serum angiotensin-2 levels, blood chemistries, and LNAME challenge. While dietary sucrose raised SBP significantly in control, adding NBC to the treatment group lowered it back toward baseline. The treatment group was more sensitive to exogenous insulin challenge and showed decreased activity of the RAS estimated by less lowering of SBP after losartan challenge, decreased serum ACE (angiotensin-converting enzyme) activity, and lower levels of circulating angiotensin-2. The former two parameters showed statistical significance; and the latter, a trend toward statistical significance. A separate group receiving captopril served as a positive control and showed decreased ACE activity and circulating levels of angiotensin-2 compared to the control group. Our data suggest that the RAS plays a significant role in sugar-induced hypertension and that NBC lowers SBP, at least in part, via actions on the RAS. Other findings suggest that the NO system is important in sucrose-induced BP elevations as well.     

How NaCl raises blood pressure: a new paradigm for the pathogenesis of salt-dependent hypertension

Excess dietary salt is a major cause of hypertension. Nevertheless, the specific mechanisms by which salt increases arterial constriction and peripheral vascular resistance, and thereby raises blood pressure (BP), are poorly understood. Here we summarize recent evidence that defines specific molecular links between Na(+) and the elevated vascular resistance that directly produces high BP. In this new paradigm, high dietary salt raises cerebrospinal fluid [Na(+)]. This leads, via the Na(+)-sensing circumventricular organs of the brain, to increased sympathetic nerve activity (SNA), a major trigger of vasoconstriction. Plasma levels of endogenous ouabain (EO), the Na(+) pump ligand, also become elevated. Remarkably, high cerebrospinal fluid [Na(+)]-evoked, locally secreted (hypothalamic) EO participates in a pathway that mediates the sustained increase in SNA. This hypothalamic signaling chain includes aldosterone, epithelial Na(+) channels, EO, ouabain-sensitive α(2) Na(+) pumps, and angiotensin II (ANG II). The EO increases (e.g.) hypothalamic ANG-II type-1 receptor and NADPH oxidase and decreases neuronal nitric oxide synthase protein expression. The aldosterone-epithelial Na(+) channel-EO-α(2) Na(+) pump-ANG-II pathway modulates the activity of brain cardiovascular control centers that regulate the BP set point and induce sustained changes in SNA. In the periphery, the EO secreted by the adrenal cortex directly enhances vasoconstriction via an EO-α(2) Na(+) pump-Na(+)/Ca(2+) exchanger-Ca(2+) signaling pathway. Circulating EO also activates an EO-α(2) Na(+) pump-Src kinase signaling cascade. This increases the expression of the Na(+)/Ca(2+) exchanger-transient receptor potential cation channel Ca(2+) signaling pathway in arterial smooth muscle but decreases the expression of endothelial vasodilator mechanisms. Additionally, EO is a growth factor and may directly participate in the arterial structural remodeling and lumen narrowing that is frequently observed in established hypertension. These several central and peripheral mechanisms are coordinated, in part by EO, to effect and maintain the salt-induced elevation of BP.     

黑线仓鼠的BMR个体差异及其应对高脂食物的能量学对策

为探讨高脂食物对小型哺乳动物能量代谢的影响及其与基础代谢率(Basal metabolic rate, BMR)的关系,将成年雌性黑线仓鼠(Cricetulus barabensis)分为高、低BMR组,每组再随机分为低脂、高脂食物组,驯化6周后,测定体重、摄入能和代谢率,以及消化酶活力、褐色脂肪组织(Brown adipose tissue, BAT)和主要内脏器官与肌肉的细胞色素c氧化酶(Cytochrome c oxidase, COX)活性、解偶联蛋白(Uncoupling protein, UCP) mRNA表达等。结果显示,高脂食物对高、低BMR组动物体重均无显著影响。与低脂食物组相比,高脂食物组的摄食量、摄入能和消化能显著下降,小肠脂肪酶活力显著增强,消化率明显增加,但高、低BMR组的组间差异不显著。夜间代谢水平显著高于昼间,高脂食物使高BMR组的夜间代谢率显著升高。BAT、肌肉和内脏器官COX活性不受高脂食物的影响,高、低BMR组的组间差异也不显著。高脂食物组仅肝脏UCP2表达显著上调。结果表明,能量摄入和消化系统形态及功能的可塑性调节是黑线仓鼠应对高脂食物的主要策略;黑线仓鼠的代谢率具有显著的昼夜节律,既受高脂食物的影响,也与动物自身的BMR水平有关,但UCP表达具有组织特异性,这可能不是导致BMR个体差异的因素。     

Effects of neuronal norepinephrine uptake blockade on baroreflex neural and peripheral arc transfer characteristics

Neuronal uptake is the most important mechanism by which norepinephrine (NE) is removed from the synaptic clefts at sympathetic nerve terminals. We examined the effects of neuronal NE uptake blockade on the dynamic sympathetic regulation of the arterial baroreflex because dynamic characteristics are important for understanding the system behavior in response to exogenous disturbance. We perturbed intracarotid sinus pressure (CSP) according to a binary white noise sequence in anesthetized rabbits, while recording cardiac sympathetic nerve activity (SNA), arterial pressure (AP), and heart rate (HR). Intravenous administration of desipramine (1 mg/kg) decreased the normalized gain of the neural arc transfer function from CSP to SNA relative to untreated control (1.03 +/- 0.09 vs. 0.60 +/- 0.08 AU/mmHg, mean +/- SE, P < 0.01) but did not affect that of the peripheral arc transfer function from SNA to AP (1.10 +/- 0.05 vs. 1.08 +/- 0.10 mmHg/AU). The normalized gain of the transfer function from SNA to HR was unaffected (1.01 +/- 0.04 vs. 1.09 +/- 0.12 beats.min(-1).AU(-1)). Desipramine decreased the natural frequency of the transfer function from SNA to AP by 28.7 +/- 7.0% (0.046 +/- 0.007 vs. 0.031 +/- 0.002 Hz, P < 0.05) and that of the transfer function from SNA to HR by 64.4 +/- 2.2% (0.071 +/- 0.003 vs. 0.025 +/- 0.002 Hz, P < 0.01). In conclusion, neuronal NE uptake blockade by intravenous desipramine administration reduced the total buffering capacity of the arterial baroreflex mainly through its action on the neural arc. The differential effects of neuronal NE uptake blockade on the dynamic AP and HR responses to SNA may provide clues for understanding the complex pathophysiology of cardiovascular diseases associated with neuronal NE uptake deficiency.     

Effects of adrenalectomy on energy balance, diet-induced thermogenesis and brown adipose tissue in adult cafeteria-fed rats

Feeding adult male rats a palatable cafeteria diet stimulated energy intake and expenditure but also raised body weight and energy gains. Bilateral adrenalectomy (ADX) had little effect on stock-fed animals, but prevented the development of obesity in cafeteria-fed rats by depressing food intake and energetic efficiency. Adrenalectomy also markedly increased the thermogenic activity of brown adipose tissue, and depressed insulin levels, particularly in the cafeteria group.     

Central efferent pathways mediating skin cooling-evoked sympathetic thermogenesis in brown adipose tissue

Control of thermoregulatory effectors by the autonomic nervous system is a critical component of rapid cold-defense responses, which are triggered by thermal information from the skin. However, the central autonomic mechanism driving thermoregulatory effector responses to skin thermal signals remains to be determined. Here, we examined the involvement of several autonomic brain regions in sympathetic thermogenic responses in brown adipose tissue (BAT) to skin cooling in urethane-chloralose-anesthetized rats by monitoring thermogenic [BAT sympathetic nerve activity (SNA) and BAT temperature], metabolic (expired CO(2)), and cardiovascular (arterial pressure and heart rate) parameters. Acute skin cooling, which did not reduce either rectal (core) or brain temperature, evoked increases in BAT SNA, BAT temperature, expired CO(2), and heart rate. Skin cooling-evoked thermogenic, metabolic, and heart rate responses were inhibited by bilateral microinjections of bicuculline (GABA(A) receptor antagonist) into the preoptic area (POA), by bilateral microinjections of muscimol (GABA(A) receptor agonist) into the dorsomedial hypothalamic nucleus (DMH), or by microinjection of muscimol, glycine, 8-OH-DPAT (5-HT(1A) receptor agonist), or kynurenate (nonselective antagonist for ionotropic excitatory amino acid receptors) into the rostral raphe pallidus nucleus (rRPa) but not by bilateral muscimol injections into the lateral/dorsolateral part or ventrolateral part of the caudal periaqueductal gray. These results implicate the POA, DMH, and rRPa in the central efferent pathways for thermogenic, metabolic, and cardiac responses to skin cooling, and suggest that these pathways can be modulated by serotonergic inputs to the medullary raphe.     

ANG II in median preoptic nucleus and pressor responses to CSF sodium and high sodium intake in SHR

Pressor responses to increases in cerebrospinal fluid (CSF) sodium in Wistar rats and to high salt intake in spontaneously hypertensive rats (SHR) involve both brain ouabainlike activity ("ouabain") and the brain renin-angiotensin system (RAS). Because some of the effects of "ouabain" are mediated by the median preoptic nucleus (MnPO) and this nucleus contains all elements of the RAS, the present study assessed possible interactions of "ouabain" and ANG II in this nucleus. In conscious Wistar rats, injection of ANG II into the MnPO significantly increased mean arterial pressure (MAP) and heart rate (HR). This response was not affected by pretreatment with a subpressor dose of ouabain. MAP and HR increases by ouabain in the MnPO were significantly attenuated by MnPO pretreatment with losartan. In Wistar rats, losartan in the MnPO also abolished pressor and HR responses to intracerebroventricular 0.3 M NaCl and attenuated MAP and HR responses to intracerebroventricular ouabain. Five weeks of a high-salt diet in SHRs resulted in exacerbation of hypertension and increased responses to air-jet stress and intracerebroventricular guanabenz. Losartan injected into the MnPO reversed the salt-sensitive component of the hypertension and normalized the depressor response to guanabenz but did not change responses to air-jet stress. We conclude that in the MnPO, ANG II via AT(1) receptors mediates cardiovascular responses to an acute increase in CSF sodium as well as the chronic pressor responses to high sodium intake in SHR.     

Comparison between two rat sympathetic pathways activated in cold defense

In cold defense and fever, activity increases in sympathetic nerves supplying both tail vessels and interscapular brown adipose tissue (iBAT). These mediate cutaneous vasoconstrictor and thermogenic responses, respectively, and both depend upon neurons in the rostral medullary raphé. To examine the commonality of brain circuits driving these two outflows, sympathetic nerve activity (SNA) was recorded simultaneously from sympathetic fibers in the ventral tail artery (tail SNA) and the nerve to iBAT (iBAT SNA) in urethane-anesthetized rats. From a warm baseline, cold-defense responses were evoked by intermittently circulating cold water through a water jacket around the animal's shaved trunk. Repeated episodes of trunk skin cooling decreased core (rectal) temperature. The threshold skin temperature to activate iBAT SNA was 37.3 +/- 0.5 degrees C (n = 7), significantly lower than that to activate tail SNA (40.1 +/- 0.4 degrees C; P < 0.01, n = 7). A fall in core temperature always strongly activated tail SNA (threshold 38.3 +/- 0.2 degrees C, n = 7), but its effect on iBAT SNA was absent (2 of 7 rats) or weak (threshold 36.9 +/- 0.1 degrees C, n = 5). The relative sensitivity to core vs. skin cooling (K-ratio) was significantly greater for tail SNA than for iBAT SNA. Spectral analysis of paired recordings showed significant coherence between tail SNA and iBAT SNA only at 1.0 +/- 0.1 Hz. The coherence was due entirely to the modulation of both signals by the ventilatory cycle because it disappeared when the coherence spectrum was partialized with respect to airway pressure. These findings indicate that independent central pathways drive cutaneous vasoconstrictor and thermogenic sympathetic pathways during cold defense.     

Tonic nicotinic transmission enhances spinal GABAergic presynaptic release and the frequency of spontaneous network activity

Synaptically driven spontaneous network activity (SNA) is observed in virtually all developing networks. Recurrently connected spinal circuits express SNA, which drives fetal movements during a period of development when GABA is depolarizing and excitatory. Blockade of nicotinic acetylcholine receptor (nAChR) activation impairs the expression of SNA and the development of the motor system. It is mechanistically unclear how nicotinic transmission influences SNA, and in this study we tested several mechanisms that could underlie the regulation of SNA by nAChRs. We find evidence that is consistent with our previous work suggesting that cholinergically driven Renshaw cells can initiate episodes of SNA. While Renshaw cells receive strong nicotinic synaptic input, we see very little evidence suggesting other spinal interneurons or motoneurons receive nicotinic input. Rather, we found that nAChR activation tonically enhanced evoked and spontaneous presynaptic release of GABA in the embryonic spinal cord. Enhanced spontaneous and/or evoked release could contribute to increased SNA frequency. Finally, our study suggests that blockade of nAChRs can reduce the frequency of SNA by reducing probability of GABAergic release. This result suggests that the baseline frequency of SNA is maintained through elevated GABA release driven by tonically active nAChRs. Nicotinic receptors regulate GABAergic transmission and SNA, which are critically important for the proper development of the embryonic network. Therefore, our results provide a better mechanistic framework for understanding the motor consequences of fetal nicotine exposure. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 298–312, 2016     

A new look at the renin-angiotensin system--focusing on the vascular system

The renin–angiotensin system (RAS), critically involved in the control of blood pressure and volume homeostasis, is a dual system comprising a circulating component and a local tissue component. The rate limiting enzyme is renin, which in the circulating RAS derives from the kidney to generate Ang II, which in turn regulates cardiovascular function by binding to AT₁ and AT₂ receptors on cardiac, renal and vascular cells. The tissue RAS can operate independently of the circulating RAS and may be activated even when the circulating RAS is suppressed or normal. A functional tissue RAS has been identified in brain, kidney, heart, adipose tissue, hematopoietic tissue, gastrointestinal tract, liver, endocrine system and blood vessels. Whereas angiotensinsinogen, angiotensin converting enzyme (ACE), Ang I and Ang II are synthesized within these tissues, there is still controversy as to whether renin is produced locally or whether it is taken up from the circulation, possibly by the (pro)renin receptor. This is particularly true in the vascular wall, where expression of renin is very low. The exact function of the vascular RAS remains elusive, but may contribute to fine-tuning of vascular tone and arterial structure and may amplify vascular effects of the circulating RAS, particularly in pathological conditions, such as in hypertension, atherosclerosis and diabetes. New concepts relating to the vascular RAS have recently been elucidated including: (1) the presence of functionally active Ang-(1-7)-Mas axis in the vascular system, (2) the importance of the RAS in perivascular adipose tissue and cross talk with vessels, and (3) the contribution to vascular RAS of Ang II derived from immune and inflammatory cells within the vascular wall. The present review highlights recent progress in the RAS field, focusing on the tissue system and particularly on the vascular RAS.     

Central angiotensin II has catabolic action at white and brown adipose tissue

Considerable evidence implicates the renin-angiotensin system (RAS) in the regulation of energy balance. To evaluate the role of the RAS in the central nervous system regulation of energy balance, we used osmotic minipumps to chronically administer angiotensin II (Ang II; icv; 0.7 ng/min for 24 days) to adult male Long-Evans rats, resulting in reduced food intake, body weight gain, and adiposity. The decrease in body weight and adiposity occurred relative to both ad libitum- and pair-fed controls, implying that reduced food intake in and of itself does not underlie all of these effects. Consistent with this, rats administered Ang II had increased whole body heat production and oxygen consumption. Additionally, chronic icv Ang II increased uncoupling protein-1 and β(3)-adrenergic receptor expression in brown adipose tissue and β3-adrenergic receptor expression in white adipose tissue, which is suggestive of enhanced sympathetic activation and thermogenesis. Chronic icv Ang II also increased hypothalamic agouti-related peptide and decreased hypothalamic proopiomelanocortin expression, consistent with a state of energy deficit. Moreover, chronic icv Ang II increased the anorectic corticotrophin- and thyroid-releasing hormones within the hypothalamus. These results suggest that Ang II acts in the brain to promote negative energy balance and that contributing mechanisms include an alteration in the hypothalamic circuits regulating energy balance, a decrease in food intake, an increase in energy expenditure, and an increase in sympathetic activation of brown and white adipose tissue.