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Short sleep duration and poor sleep quality are associated with cardiovascular risk, and sympathetic nervous system (SNS) dysfunction appears to be a key contributor. The present review will characterize sympathetic function across several sleep disorders and insufficiencies in humans, including sleep deprivation, insomnia, narcolepsy, and obstructive sleep apnea (OSA). We will focus on direct assessments of sympathetic activation, e.g., plasma norepinephrine and muscle sympathetic nerve activity, but include heart rate variability (HRV) when direct assessments are lacking. The review also highlights sex as a key biological variable. Experimental models of total sleep deprivation and sleep restriction are converging to support several epidemiological studies reporting an association between short sleep duration and hypertension, especially in women. A systemic increase of SNS activity via plasma norepinephrine is present with insomnia and has also been confirmed with direct, regionally specific evidence from microneurographic studies. Narcolepsy is characterized by autonomic dysfunction via both HRV and microneurographic studies but with opposing conclusions regarding SNS activation. Robust sympathoexcitation is well documented in OSA and is related to baroreflex and chemoreflex dysfunction. Treatment of OSA with continuous positive airway pressure results in sympathoinhibition. In summary, sleep disorders and insufficiencies are often characterized by sympathoexcitation and/or sympathetic/baroreflex dysfunction, with several studies suggesting women may be at heightened risk.

Restraint stress stimulates sympathetic nerve activity and can affect adiposity and metabolism. However, the effects of restraint stress on cardiovascular and metabolic disorders in metabolic syndrome (MetS) have remained unclear. We investigated the effects of chronic restraint stress and β-adrenergic receptor (β-AR) blockade on cardiac and adipose tissue pathology and metabolic disorders in a rat model of MetS. DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats. Rats were exposed to restraint stress (restraint cage, 2 h/day) for 4 wk from 9 wk of age with or without daily subcutaneous administration of the β-AR blocker propranolol (2 mg/kg). Age-matched homozygous lean littermates of DS/obese rats (DahlS.Z-Lepr(+)/Lepr(+) rats) served as control animals. Chronic restraint stress exacerbated hypertension as well as left ventricular hypertrophy, fibrosis, diastolic dysfunction, and oxidative stress in a manner sensitive to propranolol treatment. Restraint stress attenuated body weight gain in DS/obese rats, and this effect tended to be reversed by propranolol (P = 0.0682). Restraint stress or propranolol did not affect visceral or subcutaneous fat mass. However, restraint stress potentiated cardiac and visceral adipose tissue inflammation in DS/obese rats, and these effects were ameliorated by propranolol. Restraint stress also exacerbated glucose intolerance, insulin resistance, and abnormal lipid metabolism in a manner sensitive to propranolol. In addition, restraint stress increased urinary norepinephrine excretion, and propranolol attenuated this effect. Our results thus implicate β-ARs in the exacerbation of cardiac and adipose tissue pathology and abnormal glucose and lipid metabolism induced by restraint stress in this model of MetS., (Copyright © 2015 the American Physiological Society.)

The cardiac sympathetic afferent (CSA), which plays an important role in heart-brain communication for sympathoexcitation, is stimulated in heart failure. Additionally, high salt intake leads to further sympathoexcitation due to activation of hypothalamic epithelial Na(+) channels (ENaCs) in heart failure. In the present study, we stimulated the CSA in adult male mice by epicardial application of capsaicin and using ethanol as a control to determine whether CSA stimulation led to activation of hypothalamic ENaCs, resulting in salt-induced sympathoexcitation. Three days after capsaicin treatment, an upregulation of hypothalamic α-ENaCs, without activation of mineralocorticoid receptors, was observed. We also examined expression levels of the known ENaC activator TNF-α. Hypothalamic TNF-α increased in capsaicin-treated mice, whereas intracerebroventricular infusion of the TNF-α blocker etanercept prevented capsaicin-induced upregulation of α-ENaCs. To examine brain arterial pressure (AP) sensitivity toward Na(+), we performed an intracerebroventricular infusion of high Na(+)-containing (0.2 M) artificial cerebrospinal fluid. AP and heart rate were significantly increased in capsaicin-treated mice compared with control mice. CSA stimulation also caused excitatory responses with high salt intake. Compared with a regular salt diet, the high-salt diet augmented AP, heart rate, and 24-h urinary norepinephrine excretion, which is an indirect marker of sympathetic activity with mineralocorticoid receptor activation, in capsaicin-treated mice but not in ethanol-treated mice. Treatment with etanercept or the ENaC blocker benzamil prevented these salt-induced excitatory responses. In summary, we show that CSA stimulation leads to an upregulation of hypothalamic α-ENaCs mediated via an increase in TNF-α and results in increased salt sensitivity., (Copyright © 2015 the American Physiological Society.)

Enhanced central sympathetic outflow worsens left ventricular (LV) remodeling and prognosis in heart failure after myocardial infarction (MI). Previous studies suggested that activation of brain angiotensin II type 1 receptors (AT₁R) in the brain stem leads to sympathoexcitation due to neuronal AT₁R upregulation. Recent studies, however, revealed the importance of astrocytes for modulating neuronal activity, but whether changes in astrocytes influence central sympathetic outflow in heart failure is unknown. In the normal state, AT₁R are only weakly expressed in astrocytes. We hypothesized that AT₁R in astrocytes are upregulated in heart failure and modulate the activity of adjacent neurons, leading to enhanced sympathetic outflow. In the present study, by targeting deletion of astrocyte-specific AT₁R, we investigated whether AT₁R in astrocytes have a key role in enhancing central sympathetic outflow, and thereby influencing LV remodeling process and the prognosis of MI-induced heart failure. Using the Cre-LoxP system, we generated glial fibrillary acidic protein (GFAP)-specific AT₁R knockout (GFAP/AT₁RKO) mice. Urinary norepinephrine excretion for 24 h, as an indicator of sympathoexcitation, was significantly lower in GFAP/AT₁RKO-MI mice than in control-MI mice. LV size and heart weight after MI were significantly smaller in GFAP/AT₁RKO mice than in control mice. Prognosis was significantly improved in GFAP/AT₁RKO-MI mice compared with control-MI mice. Our findings indicated that AT₁R expression was upregulated in brain stem astrocytes in MI-induced heart failure, which worsened LV remodeling and prognosis via sympathoexcitation. Thus, in addition to neuronal AT₁R, AT₁R in astrocytes appear to have a key role in enhancing central sympathetic outflow in heart failure., (Copyright © 2014 the American Physiological Society.)

The rostral ventrolateral medulla (RVLM) plays a key role in cardiovascular regulation. It has been reported that tonically active glutamatergic input to the RVLM is increased in hypertensive rats, whereas angiotensin-converting enzyme 2 (ACE2) in the brain has been suggested to be beneficial to hypertension. This study was designed to determine the effect of ACE2 gene transfer into the RVLM on tonically active glutamatergic input in spontaneously hypertensive rats (SHRs). Lentiviral particles containing enhanced green fluorescent protein (lenti-GFP) or ACE2 (lenti-ACE2) were injected bilaterally into the RVLM. Both protein expression and activity of ACE2 in the RVLM were increased in SHRs after overexpression of ACE2. A significant reduction in blood pressure and heart rate in SHRs was observed 6 wk after lenti-ACE2 injected into the RVLM. The concentration of glutamate in microdialysis fluid from the RVLM was significantly reduced by an average of 61% in SHRs with lenti-ACE2 compared with lenti-GFP. ACE2 overexpression significantly attenuated the decrease in blood pressure and renal sympathetic nerve activity evoked by bilateral injection of the glutamate receptor antagonist kynurenic acid (2.7 nmol in 100 nl) into the RVLM in SHRs. Therefore, we suggest that ACE2 overexpression in the RVLM attenuates the enhanced tonically active glutamatergic input in SHRs, which may be an important mechanism underlying the beneficial effect of central ACE2 to hypertension., (Copyright © 2014 the American Physiological Society.)

Phenylethanolamine N-methyltransferase (PNMT) catalyzes the synthesis of epinephrine from norepinephrine. We previously identified and functionally characterized common sequence variation in the PNMT gene. In the present study, we set out to determine whether common PNMT genetic polymorphisms might be associated with individual variation in circulating epinephrine levels during exercise in 74 Caucasian American subjects. Circulating epinephrine levels were measured in each subject at baseline and during two different levels of exercise, approximately 40% and approximately 75% of peak workload. The PNMT gene was resequenced with DNA from each study subject. Eight novel PNMT polymorphisms were identified, including a C319T (Arg107Cys) nonsynonymous single nucleotide polymorphism (SNP) and I1G(280)A, a SNP located in the first intron of the gene. The I1G(280)A SNP was significantly associated with decreased exercise-induced circulating epinephrine levels and with a decreased epinephrine-to-norepinephrine ratio. The Cys107 recombinant allozyme displayed significantly lower levels of both PNMT activity and immunoreactive protein than the wild-type allozyme after transfection into COS-1 cells, but it did not appear to be associated with level of epinephrine in these subjects. Electrophoretic mobility shift and reporter gene assays performed with the I1G(280)A SNP indicated that this polymorphism could bind nuclear proteins and might modulate gene transcription. Our studies suggest that functionally significant variant sequence in the human PNMT gene might contribute to individual variation in levels of circulating epinephrine during exercise.

Obstructive sleep apnea (OSA) is characterized by noradrenergic activation. Nasal continuous positive airway pressure (CPAP) is the treatment of choice and has been shown to effectively reduce elevated norepinephrine (NE) levels. This study examined whether the reduction in NE after CPAP is due to an increase in NE clearance and/or a decrease of NE release rate. Fifty CPAP-naive OSA patients with an apnea-hypopnea index >15 were studied. NE clearance and release rates, circulating NE levels, urinary NE excretion, and blood pressure and heart rate were determined before and after 14 days of CPAP, placebo CPAP (CPAP administered at ineffective pressure), or oxygen supplementation. CPAP led to a significant increase in NE clearance (P < or = 0.01), as well as decreases in plasma NE levels (P < or = 0.018) and daytime (P < 0.001) and nighttime (P < 0.05) NE excretion. NE release rate was unchanged with treatment. Systolic (P < or = 0.013) and diastolic (P < or = 0.026) blood pressure and heart rate (P < or = 0.014) were decreased in response to CPAP but not in response to oxygen or placebo CPAP treatment. Posttreatment systolic blood pressure was best predicted by pretreatment systolic blood pressure and posttreatment NE clearance and release rate (P < 0.01). The findings indicate that one of the mechanisms through which CPAP reduces NE levels is through an increase in the clearance of NE from the circulation.

Reduced nitric oxide (NO) in the brain might contribute to enhanced sympathetic drive in heart failure (HF). The aim of this study was to determine whether increased NO production induced by local overexpression of endothelial NO synthase (eNOS) in the nucleus tractus solitarius (NTS) of the brain stem reduces the enhanced sympathetic drive in mice with HF. Myocardial infarction (MI) was induced in mice by ligating the left coronary artery. MI mice exhibited left ventricular dilatation and a reduced left ventricular ejection fraction. Urinary norepinephrine excretion in MI mice was greater than that in sham-operated mice, indicating that sympathetic drive was enhanced in this model. Thus this model has features that are typical of HF. Western blot analysis and immunohistochemical staining for neuronal NOS (nNOS) indicated that nNOS protein expression was significantly reduced in the brain stem of MI mice. MI mice had a significantly smaller increase in blood pressure evoked by intracisternal injection of N(G)-monomethyl-L-arginine than sham-operated mice. Adenoviral vectors encoding either eNOS (AdeNOS) or beta-galactosidase (Adbeta gal) were transfected into the NTS to examine the effect of increased NO production in the NTS on the enhanced sympathetic drive in HF. After the gene transfer, urinary norepinephrine excretion was reduced in AdeNOS-transfected MI mice but not in Adbeta gal-transfected MI mice. These results indicate that nNOS expression in the brain stem, especially in the NTS, is reduced in the MI mouse model of HF, and increased NO production induced by overexpression of eNOS in the NTS attenuates the enhanced sympathetic drive in this model.

Regulator of G protein signaling (RGS2) deletion in mice prolongs signaling by G protein-coupled vasoconstrictor receptors and increases blood pressure. However, the exact mechanism of the increase in blood pressure is unknown. To address this question we tested autonomic nervous system function and blood pressure regulation in RGS2-deficient mice (RGS2-/-). We measured arterial blood pressure and heart rate (HR) with telemetry, computed time and frequency-domain measures for blood pressure and HR variability (HRV) as well as baroreflex sensitivity [BRS-low frequency (LF)], and assessed environmental stress sensitivity. Mean arterial blood pressure (MAP) was approximately 10 mmHg higher in RGS2-/-compared with RGS2+/+mice, while HR was not different between the groups, indicating a resetting of the baroreceptor reflex. Atropine increased MAP more in RGS2-/-than in RGS2+/+mice while HR responses were not different. Urinary norepinephrine excretion was higher in RGS2-/-than in RGS2+/+mice. The blood pressure decrease following prazosin was more pronounced in RGS2-/-mice than in RGS2+/+mice. The LF and high-frequency (HF) power of HRV were reduced in RGS2-/-compared with controls while BRS-LF and SBP-LF were not different. Atropine and atropine+metoprolol markedly reduced the HRV parameters in the time (RMSSD) and frequency domain (LF, HF, LF/HF) in both strains. Environmental stress sensitivity was increased in RGS2-/-mice compared with controls. We conclude that the increase in blood pressure in RGS2-/-mice is not solely explained by peripheral vascular mechanisms. A central nervous system mechanism might be implicated by an increased sympathetic tone. This state of affairs could lead to a baroreceptor-HR reflex resetting, while BRS remains unimpaired.

Gender and ethnic disparities in cardiovascular disease and mortality have spurred interest in the epidemiology of stress hormone production. Greater disease burden among men and blacks raises the possibility of gender and ethnic differences in stress hormone production. The purpose of this study was to determine whether urinary stress hormones were higher among men and blacks in a population-based sample. Urinary hormone analysis permits a time-integrated assessment of the stress response system. However, differences in collection and standardization strategies have led to inconsistent findings. Subjects were an ethnically diverse population-based sample of 229 men and women aged 50-67 yr who provided an overnight urine specimen. Urine concentration was standardized using a traditional creatinine-based approach as well as a new method that accounts for muscle mass. With the use of creatinine standardization, no gender or ethnic differences were noted in epinephrine or cortisol production. Norepinephrine levels were higher among women compared with men (P = 0.001), however. After accounting for muscle mass, we found that both epinephrine (P = 0.018) and norepinephrine (P = 0.033) levels were higher among men compared with women. No significant differences in cortisol production were found by gender or ethnicity. The consistency of these results with previous studies of 24-h urine samples suggests muscle mass should be accounted for when comparing overnight urinary hormone values across gender and ethnicity.

Unlabelled: Compared with men, women appear to have a decreased sympathetic nervous system (SNS) response to stress. The two manifestations where the sexual dimorphism has been the most pronounced involve the response of the SNS to fluid shifts and fuel metabolism during exercise. The objectives of this study were to investigate whether a similar sexual dimorphism was found in the response to spaceflight. To do so, we compared catecholamine excretion by male and female astronauts from two similar shuttle missions, Spacelab Life Sciences 1 (SLS1, 1991) and 2 (SLS2, 1993) for evidence of sexual dimorphism. To evaluate the variability of the catecholamine response in men, we compared catecholamine excretion from the two SLS missions against the 1996 Life and Microgravity Sciences Mission (LMS) and the 1973 Skylab missions., Results: No gender- or mission-dependent changes were found with epinephrine. Separating out the SLS1/2 data by gender shows that norepinephrine excretion was essentially unchanged with spaceflight in women (98 +/- 10%; n = 3) and substantially decreased with the men (41 +/- 9%; n = 4, P < 0.05). Data are a percentage of mean preflight value +/- SE. Comparisons among males demonstrated significant mission effects on norepinephrine excretion. After flight, there was a transient increase in norepinephrine but no evidence of any gender-specific effects. We conclude that norepinephrine excretion during spaceflight is both mission and gender dependent. Men show the greater response, with at least three factors being involved, a response to microgravity, energy balance, and the ratio of carbohydrate to fat in the diet.

We have previously documented the importance of the sympathetic nervous system in acclimatizing to high altitude in men. The purpose of this investigation was to determine the extent to which alpha-adrenergic blockade affects the sympathoadrenal responses to exercise during acute high-altitude exposure in women. Twelve eumenorrheic women (24.7 +/- 1.3 yr, 70.6 +/- 2.6 kg) were studied at sea level and on day 2 of high-altitude exposure (4,300-m hypobaric chamber) in either their follicular or luteal phase. Subjects performed two graded-exercise tests at sea level (on separate days) on a bicycle ergometer after 3 days of taking either a placebo or an alpha-blocker (3 mg/day prazosin). Subjects also performed two similar exercise tests while at altitude. Effectiveness of blockade was determined by phenylephrine challenge. At sea level, plasma norepinephrine levels during exercise were 48% greater when subjects were alpha-blocked compared with their placebo trial. This difference was only 25% when subjects were studied at altitude. Plasma norepinephrine values were significantly elevated at altitude compared with sea level but to a greater extent for the placebo ( upward arrow 59%) vs. blocked ( upward arrow 35%) trial. A more dramatic effect of both altitude ( upward arrow 104% placebo vs. 95% blocked) and blockade ( upward arrow 50% sea level vs. 44% altitude) was observed for plasma epinephrine levels during exercise. No phase differences were observed across any condition studied. It was concluded that alpha-adrenergic blockade 1) resulted in a compensatory sympathoadrenal response during exercise at sea level and altitude, and 2) this effect was more pronounced for plasma epinephrine.

Chronic administration of sibutramine lowers body weight, presumably by altering brain monoamine metabolism. Here the effect of sibutramine on sympathoadrenal function (24-h urine norepinephrine and epinephrine levels) and arcuate nucleus (ARC) neuropeptide Y (NPY) and proopiomelanocortin (POMC) expression was assessed in diet-induced obese rats fed a low-fat diet. Chronic (10 wk) sibutramine [5 mg. kg(-1). day(-1) ip; rats fed ad libitum and injected with sibutramine (AS)] lowered body weight by 15% but only transiently (3-4 wk) reduced intake compared with vehicle-treated controls [rats fed chow ad libitum and injected with vehicle daily (AV)]. Other rats food restricted (RS) to 90% of the weight of AS rats and then given sibutramine restored their body weights to the level of AS rats when allowed libitum food intake. After reequilibration, RS rats were again energy restricted to reduce their weight to 90% of AS rats, and additional vehicle-treated rats (RV) were restricted to keep their body weights at the level of AS rats for 3 wk more. Terminally, total adipose depot weights and leptin levels paralleled body weights (AV > AS = RV > RS), although AS rats had heavier abdominal and lighter peripheral depots than RV rats of comparable body weights. Sibutramine treatment increased sympathetic activity, attenuated the increased ARC NPY, and decreased POMC mRNA levels induced by energy restriction in RV rats. Thus sibutramine lowered the defended body weight in association with compensatory changes in those central pathways involved in energy homeostasis.

This study assessed the role of adrenergic receptors on the regulation of the uptake of L-dopa and the production of dopamine by renal tubular cells. Scatchard analysis showed two L-dopa uptake sites with different affinities (K(m) 0.316 vs 1.53 microM). L-Dopa uptake was decreased by the nonselective adrenergic agonists epinephrine or norepinephrine (40%), by the beta-selective agonist isoproterenol or the beta(2)-selective agonist terbutaline (60%), but not by alpha-selective agonists (all 1 microM). The effect of norepinephrine, isoproterenol, or terbutaline was unaffected by addition of the beta(1)-antagonist atenolol, abolished by ICI-118, 551, a beta(2)-antagonist (both 0.1 microM), and mimicked by the addition of dibutyryl-cAMP (1 microM). Preincubation with terbutaline decreased the number of high-affinity uptake sites (V(max) = 1.10 +/- 0.3 vs. 0.5 +/- 0.1 pmol. mg protein(-1). min(-1)) without changing their affinity. Norepinephrine or terbutaline decreased dopamine production by isolated cells, and this effect was abolished by ICI-118,551 (0.1 microM). In vivo administration of ICI-118,551 reduced the urinary excretion of L-dopa and increased the excretion of 3,4-dihydroxyphenylacetic acid without significant changes in plasma L-dopa concentrations. These results demonstrate that stimulation of beta(2)-adrenergic receptors decreases the number of high-affinity L-dopa uptake sites in isolated tubular cells resulting in a reduction of the uptake of L-dopa and the production of dopamine and provide evidence for the presence of this mechanism in the intact animal.

Half of Sprague-Dawley rats develop and defend diet-induced obesity (DIO) or diet resistance (DR) when fed a high-energy (HE) diet. Here, adult male rats were made DIO or DR after 10 wk on HE diet. Then half of each group was food restricted for 8 wk on chow to maintain their body weights at 90% of their respective baselines. Rate and magnitude of weight loss were comparable, but maintenance energy intake and the degree of sympathetic activity (24-h urine norepinephrine) inhibition were 17 and 29% lower, respectively, in restricted DR than DIO rats. Restricted DIO rats reduced adipose depot weights, plasma leptin, and insulin levels by 35%. Restricted DR rats reduced none of these. When fed ad libitum, both DR and DIO rats returned to the body weights of their respective chow-fed phenotype controls within 2 wk. This was associated with increased adipose mass and leptin and insulin levels only in DIO rats. Thus DR rats appear to alter primarily their lean body mass, whereas DIO rats primarily alter their adipose mass during chronic caloric restriction and refeeding.

Changes in the renin-angiotensin system (RAS) mRNAs in the brain and the kidney of rats after administration of DOCA and/or sodium chloride were assessed by use of a competitive PCR method. Benzamil, a blocker of amiloride-sensitive sodium channels, was infused intracerebroventricularly or intravenously for 7 days in DOCA-salt or renal hypertensive rats, and the effects of benzamil on the brain RAS mRNAs were determined. Renin and ANG I-converting enzyme (ACE) mRNAs were not downregulated in the brain of rats administered DOCA and/or salt; however, these mRNAs were decreased in the kidney. Intracerebroventricular infusion of benzamil decreased renin, ACE, and ANG II type 1 receptor mRNAs in the brain of DOCA-salt hypertensive rats but not in the brain of renal hypertensive rats. The gene expression of the brain RAS, particularly renin and ACE, is regulated differently between the brain and the kidney in DOCA-salt hypertensive rats, and benzamil-blockable brain sodium channels may participate in the regulation of the brain RAS mRNAs.

In outbred Sprague-Dawley rats, about one-half develop diet-induced obesity (DIO) on a diet relatively high in fat and energy (HE diet). The rest are diet resistant (DR), gaining weight and fat at the same rate as chow-fed controls. Here we selectively bred for high (DIO) and low (DR) weight gainers after 2 wk on HE diet. By the F5 generation, both male and female inbred DIO rats gained > 90% more weight than inbred DR rats on HE diets. Even on low-fat chow diet, DIO males were 31% and females were 22% heavier than their respective DR rats. Full metabolic characterization in male rats showed that weight-matched, chow-fed DIO-prone rats had similar energy intakes and feed efficiency [body weight (kg0.75)/energy intake (kcal)] but 44% more carcass fat than comparable DR-prone rats. Their basal plasma insulin and glucose levels in the fed state were 70 and 14% higher, respectively. But, when fasted, DIO-prone oral glucose tolerance results were comparable to DR-prone rats. Chow-fed DIO-prone males also had 42% greater 24-h urine norepinephrine levels than DR-prone males. During 2 wk on HE diet, DIO rats ate 25% more, gained 115% more weight, had 36% more carcass fat, and were 42% more feed efficient than comparable DR rats. Fasted HE diet-fed DIO rats developed frank glucose intolerance during a glucose tolerance test with 55 and 158% greater insulin and glucose areas under the curve, respectively. Thus the DIO and DR traits in the outbred Sprague-Dawley population appear to be due to a polygenic pattern of inheritance.

Although an improvement of insulin sensitivity has been shown to be a new therapeutic approach for treating diabetes mellitus, details of effects of this treatment on the cardiovascular system and possible renal complications remain unknown. In the present study, we investigated the effects of a thiazolidine derivative, pioglitazone, and examined the insulin-sensitizing action on blood pressure, nephropathy, and vascular changes in genetically obese diabetic Wistar fatty (WF) rats. Pioglitazone (3 mg.kg-1.day-1) was orally administered for 13 wk starting at the age of 5 wk, and the results were compared with those of vehicle-treated WF rats. At the age of 18 wk, vehicle-treated WF rats were associated with mild hypertension, nephropathy with proteinuria histological glomerular injury, and renal arteriolosclerosis in addition to hyperglycemia, hyperinsulinemia, and hyperlipidemia. Treatment with pioglitazone significantly improved glucose and lipid metabolism. In addition, it lowered blood pressure, decreased proteinuria, and prevented glomerular injury, renal arteriolosclerosis, and aortic medial wall thickening, whereas body weight, food intake, sodium balance, and urinary norepinephrine excretion were significantly increased. These results suggest that the insulin-sensitizing agent pioglitazone is effective in correcting not only glucose and lipid metabolism but also cardiovascular and renal complications in non-insulin-dependent diabetes mellitus.

Neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC) produce metabolic and physiological effects that promote the development and maintenance of obesity. In turn, NPY metabolism in these neurons is inhibited by dopamine release. In this study, ARC prepro-NPY mRNA and ARC/median eminence (ME) dopamine turnover were assessed in chow-fed male Sprague-Dawley rats prone to develop diet-induced obesity (DIO) or to be diet resistant (DR) when fed a high-energy (HE) diet. By in situ hybridization, DIO-prone rats had 39% more ARC NPY mRNA expression than DR-prone rats under chow-fed conditions. DIO-prone rat ARC/ME dopamine levels were 14% higher, but dopamine half-life was 176% longer and turnover was 59% less than DR-prone rats. Neither a 48-h fast nor 50% energy intake restriction for 5 days affected the already increased ARC NPY mRNA levels in DIO-prone rats. Both manipulations increased NPY expression to the level of DIO-prone rats in DR-prone rats by 23 and 35%, respectively. Finally, when fed HE diet for 2 wk, neither DIO- nor DR-prone rats altered their ARC NPY expression despite the development of obesity and hyperinsulinemia in DIO rats. Thus DIO-prone rats overexpress and fail to regulate ARC NPY mRNA to energy restriction or hyperinsulinemia. This dysregulation is possibly secondary to reduced inhibition because of defective ARC/ME dopamine turnover. Both may be important predisposing factors in the development of DIO.

One-half of the adult male Sprague-Dawley rats fed a diet relatively high in fat, sucrose, and energy content (HE diet) develop diet-induced obesity (DIO). The rest are diet resistant (DR). The role of peripheral and central norepinephrine (NE) activity in predisposing them to these weight gain patterns was assessed before HE diet exposure. Chow-fed male 3-mo-old Sprague-Dawley rats were separated as being prone to become DIO or DR by their high (3.06 +/- 0.14 micrograms) vs. low (1.17 +/- 0.10 micrograms; P = 0.001) 24-h urine NE output, respectively. Turnover of NE, an index of sympathetic activity, was assessed by synthesis inhibition with alpha-methyl-p-tyrosine. DIO-prone rats had significant 53 and 18% reductions in heart and pancreas NE turnover, with interscapular brown adipose tissue turnover comparable to that of DR-prone rats. Hypothalamic NE turnover was significantly decreased by 85 and 60% in the ventromedial nucleus and lateral area vs. DR-prone rats. Although present in DR-prone rats, no turnover was found in the dorsomedial nucleus of DIO-prone rats. Endogenous NE was reduced by 28% in the paraventricular nucleus, whereas arcuate/median eminence turnover was increased by 100% in DIO-prone rats. Amygdalar NE turnover was similar between phenotypes. These intrinsic differences in NE metabolism may play an important role in the development of DIO on HE diets.

To study the effect of aging on human sympathetic nervous function, we applied kinetic methods for measuring the fluxes to plasma of neurochemicals relevant to sympathetic neurotransmission in younger (aged 20-30 yr) and older (aged 60-75 yr) healthy men. Mean plasma norepinephrine concentration was 66% higher in older men, attributable to 22% lower norepinephrine plasma clearance (P < 0.05) and 29% higher norepinephrine spillover to plasma (difference not statistically significant). Regional venous sampling disclosed that sympathetic outflow to all organs was not activated by aging. Renal norepinephrine spillover was normal in older men. Although spillover of norepinephrine from the heart was increased in older men, 21.1 +/- 11.4 ng/min compared with 11.4 +/- 8.6 ng/min (P < 0.05), diminished norepinephrine reuptake rather than increased cardiac sympathetic nerve firing was the most likely cause, although somewhat reduced intracardiac methylation of norepinephrine with aging also possibly contributed. The extraction of tritiated norepinephrine from plasma during transit through the heart was reduced, suggesting neuronal norepinephrine reuptake was lowered and overflow of the norepinephrine precursor dihydroxyphenylalanine and metabolites dihydroxyphenylglycol and 3-methoxy-4-hydroxy phenylglycol was normal, indicating that norepinephrine synthesis and release were not increased.

The adaptive responses of the cardiovascular system to altitude appear to be dominated by increased sympathetic neural activity. We investigated the combined roles of the sympathetic and parasympathetic nervous systems (SNS and PNS, respectively) in the early (days 4-5) and subsequent (days 11-12) phases of acclimatization on Pike's Peak, CO (4,300 m), by spectral analysis of heart rate variability. Male subjects were randomly assigned to groups receiving oral propranolol (240 mg/day; n = 6) or a matched placebo (n = 3). On ascent to altitude, the high-frequency, fractal, and total spectral powers were reduced in the placebo group during days 4-5 and 11-12. At altitude during days 4-5, all three placebo group subjects increased SNS and decreased PNS activities compared with at sea level, and during days 11-12 SNS decreased and PNS increased compared with days 4-5. Relative to the placebo group, propranolol caused lengthening of the R-R interval; increases in high-frequency power, total spectral power, and the PNS indicator; and a decrease in the SNS indicator. Total spectral power tended to decrease at altitude, but there were no effects of altitude on PNS and SNS indicators in the propranolol group. The data from the placebo and propranolol groups suggest that both the PNS and SNS are involved in the elevated heart rate during the early phase of altitude acclimatization. Changes in heart rate variability during days 11-12 at altitude must be considered in light of the possible reductions in sympathetic receptor number noted in previous studies.

Residence at high altitude has been associated with elevation in systemic arterial blood pressure, but the time course has been little studied and the mechanism is unknown. Because plasma epinephrine (E) and norepinephrine (NE) also increase at altitude, we hypothesized that heightened sympathoadrenal activity may cause increased arterial pressure. We measured ambulatory blood pressure by cuff monitor in relation to 24-h urinary excretion of E and NE at sea level and during 3 wk of residence at 4,300 m (Pikes Peak, CO) in 11 healthy men. In five subjects taking placebo, arterial pressure progressively increased at 4,300 m from 82 +/- 1 (SE) mmHg at sea level to 88 +/- 3 on day 2, 91 +/- 3 on day 8, and 97 +/- 6 on day 17. In six subjects, propranolol (240 mg/day) decreased pressure from 85 +/- 4 to 77 +/- 1 mmHg at sea level but did not prevent sustained increase in pressure at 4,300 m (84 +/- 1, 81 +/- 1, and 85 +/- 3 mmHg on days 2, 8, and 17, respectively). Compared with the placebo group, blood pressure did not increase further over the initial elevation observed on day 2 in the propranolol group. There was interindividual variability in the blood pressure responses in both groups, with some subjects demonstrating a more marked increase in blood pressure. Urinary excretion of NE increased concomitantly with pressure at altitude in both groups, with a greater rise in the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of glucose, acetylcholine, and norepinephrine on insulin secretion from pancreatic islets of 8- to 9-wk-old female genetically obese (ob/ob) and lean mice were determined. The ob/ob islets were 60% larger in diameter than lean mouse islets, secreted fourfold more insulin in response to glucose, and secreted insulin at lower glucose concentrations than lean islets. In the presence of 15 mM glucose, ob/ob islets showed an 8-fold greater absolute increase in insulin secretion in response to acetylcholine and a 12-fold greater absolute decrease in insulin secretion in response to norepinephrine inhibition compared with lean islets. In the presence of 5 mM glucose, acetylcholine increased insulin secretion by threefold from ob/ob islets with no effect on lean islets. When both ob/ob and lean islets were stimulated by glucose to equivalent levels of insulin secretion, acetylcholine potentiated glucose-induced insulin secretion equally in ob/ob and lean islets. Enhanced glucose-induced responsiveness of ob/ob islets thus can explain the greater acetylcholine potentiation of insulin secretion and probably the greater norepinephrine inhibition of insulin secretion in ob/ob islets compared with lean islets. These data are consistent with the hypotheses that the major alteration in ob/ob mouse islets is in glucose sensitivity and responsiveness, which subsequently increases ob/ob islet susceptibility to neural regulation of insulin secretion.

The impact of sympathetic nervous system (SNS) activity on energy expenditure (EE) was evaluated in nondiabetic Caucasian and Pima Indian men while on a weight-maintenance diet using two approaches as follows. 1) The relationship between 24-h EE, measured in a respiratory chamber, and 24-h urinary norepinephrine was studied in 36 Caucasians [32 +/- 8 (SD) yr, 95 +/- 41 kg, 22 +/- 13% fat] and 33 Pimas (29 +/- 6 yr, 103 +/- 28 kg, 30 +/- 9% fat). There was no difference between the two groups in 24-h EE (2,422 vs. 2,523 kcal/24 h) and in urinary norepinephrine (28 vs. 31 micrograms/24 h), even after adjusting for body size and composition. Twenty-four-hour EE correlated significantly with 24-h urinary norepinephrine in Caucasians (r = 0.78, P less than 0.001) but not in Pimas (r = 0.03), independent of fat-free mass (FFM), fat mass, and age. 2) The effect of beta-adrenoceptor blockade with propranolol (120 micrograms/kg FFM bolus and 1.2 micrograms.kg FFM-1.min-1 for 45 min) on the resting metabolic rate (RMR) was evaluated in 36 Caucasians (30 +/- 6 yr, 103 +/- 36 kg, 25 +/- 11% fat) and 32 Pimas (28 +/- 6 yr, 100 +/- 34 kg, 27 +/- 10% fat). The RMR was similar in the two groups (2,052 vs. 1,973 kcal/24 h) even after adjustment for FFM, fat mass, and age and dropped significantly after propranolol infusion in Caucasians (-3.9%, P less than 0.001) but not in Pimas (-0.8%, P = 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)

In spontaneously hypertensive (SHR) and normotensive (WKY) rats fed different diets, blood pressure (BP) increased significantly in both strains when the carbohydrate (CHO) source was from refined rather than from natural ingredients. This BP increase was observed whether sucrose, glucose, or starch was the principal CHO. Urinary excretion of norepinephrine, dopamine, and, to some extent, epinephrine also increased, while myocardial concentrations were unaffected. Despite a comparable elevation of catecholamine excretion in both SHR and WKY rats fed high amounts of refined CHO, the BP increases were greater in the former. The strain differences were explained by the known dissimilar response of their blood vessels to catecholamines. The results suggest that BP elevation after high CHO ingestion is mediated via increased catecholamine production and/or release, thus implying a neurogenic mechanism.

This study examined the hormonal and thermal responses of two groups of subjects during 16 days in the Arctic (mean temperature -26.8 degrees C). One group (NPA) received no prior cold exposure, whereas the second group (PA) was subjected to nine daily immersions (20-40 min) in cold water (15 degrees C) 20 days before the Arctic exposure. Nude cold tolerance tests (cold air at 10 degrees C) were administered to both groups before and after the Arctic exposure. The NPA group showed an increase in metabolism and rectal temperature, whereas the PA group showed no elevation in metabolism and a decrease in rectal temperature. In the Arctic significant daily increases over the control period of urine volume (+86%), urinary norepinephrine (+48%), epinephrine (+84%), and 17-hydroxycorticosteroids (+34%) occurred in the NPA group. Only epinephrine (+65%) increased in the PA group. The hormonal and thermal responses of the NPA group in the Arctic were characteristic of metabolic adaption, whereas those in the PA group were suggestive of a hypothermic type of adaptation or habituation with no evidence of sympathetic or adrenocortical stimulation. The hormonal and thermal responses observed in this study indicate that a degree of cold resistance can be induced rapidly in humans by short intermittent exposures to an intense cold stress, which persists for a significant period of time after the last exposure.

Fasting decreases and cold exposure increases sympathetic nervous system activity. The present studies examine the effect of fasting and cold together on sympathoadrenal function. At 4 degrees C animals fasted for 2 days excreted 29% less norepinephrine (NE) than fed animals, averaging 458 +/- 32ng NE/mg creatinine and 646 +/- 68, respectively (P less than 0.005), but 122% more epinephrine (E) 77.9 +/- 11.7 ng E/mg creatinine and 35.1 +/- 6.7, respectively (P less than .01). Fasting for 2 days reduced cardiac NE turnover, a direct measure of sympathetic neuronal activity, 33% in animals at 22 degrees C from 28.2 +/- 3.6 ng NE . heart-1 . h-1 to 18.9 +/- 4.8 (95% confidence intervals) and 25% in animals acutely exposed to 4 degrees C from 60.7 +/- 8.0 to 45.6 +/- 9.5. Similar reductions in urinary NE excretion and cardiac NE turnover were observed in adrenal-demedullated rats. Thus fasting at 4 degrees C lowers sympathetic activity and enhances adrenal medullary secretion. This pattern of decreased sympathetic and increased adrenal medullary activity, previously seen with fasting hypoglycemia, suggests an important role for the adrenal medulla in internal homeostasis at times when the sympathetic nervous system is suppressed.

The urinary excretion of dihydroxyphenylalanine (DOPA), catecholamines (CA) [dopamine (DA), norepinephrine (NE), and epinephrine (e)], their 3-O-methylated derivatives [3-O-methyldopamine (3-MT), normetanephrine (NMN), and metanephrine (MN)], and their deaminated metabolites [dihydroxyphenylacetic acid (DOPAC) and vanilmandelic acid (VMA)] was studied in six healthy men, at rest during short-term (15 min) or exhaustive submaximal exercise, and in the 2-h postexercise recovery period. During short-term exercise only NE and VMA excretions increased, whereas in postexercise period only DA output was enhanced. Exhaustive muscular work induced a rise in NE and E excretion during the test, and an increase in DA, NE, and NMN urinary levels during postexercise recovery, while the output of deaminated metabolites was unaltered. It is concluded that both release and synthesis of CA are stimulated by submaximal exercise, which induces, in addition to NE, a specific release of DA. A possible role of NE in lipid mobilization during recovery from exhaustive muscular work is evoked. The origin and role of released DA are also discussed.

Iron-deficient anemic rats had a significant elevation in urinary norepinephrine (NE) after 7 days at 30 and 24 degrees C, but not at 10 degrees C, compared with control animals. NE turnover studies were performed to examine sympathetic nervous system activity in a tissue-specific fashion. NE content in myocardium decreased by nearly 50% in hypertrophied iron-deficient hearts at all three temperatures, whereas fractional turnover rates were compensatorily increased. In contrast, interscapular brown adipose tissue NE turnover was significantly reduced to 30% of normal in iron-deficient animals at both 30 and 10 degrees C. Serum triiodothyronine concentrations were similar to controls at 30 degrees C but were decreased at lower temperatures. Serum tetraiodothyronine concentrations were lower in iron-deficient animals at all three environmental temperatures. We conclude that increased sympathetic nervous system activity compensatory to temperatures below thermoneutrality is less well controlled in iron-deficient animals than in controls, and at a low environmental temperature this may possibly explain the poor thermoregulatory capacity of iron-deficient animals. A generalized hypernoradrenergic state is not supported by our NE turnover study and does not explain the elevated urine NE concentrations.

Basal metabolic rate (BMR), thermic effect of food (TEF), and total daily energy expenditure (TDEE) were measured in six nonobese and seven obese adolescents during periods of weight maintenance and 2 wk of carbohydrate overfeeding. BMR and TEF were measured by indirect calorimetry and TDEE by the doubly labeled water method. Fasting blood levels of insulin, thyroid, and norepinephrine (NE) and urinary excretion of NE and 4-hydroxy-3-methoxymandelic acid (VMA) were measured before and after overfeeding. Energy intake was 1.61 X BMR during maintenance and 2.45 X BMR during overfeeding. BMR increased comparably in both groups during overfeeding (obese, 7.9 +/- 1.2%, nonobese, 8.6 +/- 1.9%). TEF was similar and did not change significantly during overfeeding (maintenance: obese, 9.4 +/- 0.6%; nonobese, 9.8 +/- 0.4% vs. overfeeding: obese, 8.6 +/- 0.3%; nonobese, 9.2 +/- 0.7%). TDEE did not differ significantly between obese and nonobese. Increases in insulin and 3,5,3'-triiodothyronine levels were significant but did not differ between the two groups. Plasma NE and urinary excretion of VMA and NE did not increase during overfeeding. The thermogenic response to food or to overfeeding does not appear reduced in obese adolescents, nor does facultative thermogenesis appear to be a significant factor in weight maintenance in adolescents.

Urinary levels of 2,3-dinorthromboxane B2 (Tx-M) and 2,3-dinor-6-ketoprostaglandin F1 alpha (PGI-M), measured by gas chromatography-negative ion-chemical ionization mass spectrometry, accurately reflect in vivo biosynthesis of thromboxane A2 (TxA2) and prostacyclin (PGI2), respectively. Although the basal excretion of Tx-M and PGI-M is adequately documented, no systemic data on the excretion during controlled exercise have been presented. We studied the effect of maximal tolerated exercise (2 h of bicycle ergometry) on the excretion of Tx-M and PGI-M in healthy humans. In addition, their urinary levels of epinephrine (E) and norepinephrine (NE) were analyzed. To address the impact of locally formed adenosine, all subjects were reinvestigated after administration of theophylline. Exercise did not affect the excretion of Tx-M (47 +/- 21 vs. 34 +/- 9 pg/mg creatinine) but increased the excretion of PGI-M (74 +/- 14 vs. 267 +/- 70 pg/mg creatinine; P less than 0.02). Theophylline augmented urinary NE and E but did not significantly change the PGI-M response to exercise. We suggest that the normal cardiovascular eicosanoid response to exercise is a platelet-independent increase in vascular PGI2 formation.

Bolus intracerebroventricular delivery of corticotropin-releasing factor (CRF) elicits acute responses of both the pituitary-adrenal axis and the sympathetic nervous system. We examined whether these stresslike responses could be maintained over a period of days by central delivery of CRF in nonstressed rats, as would be predicted if this peptide participates in the central nervous system regulation of chronic stress. CRF (4.3 or 21.5 micrograms/day) was continuously delivered into the cerebral ventricle via Alzet minipumps. In contrast to saline-infused controls, rats receiving CRF exhibited elevated excretions of corticosterone, norepinephrine, and urea nitrogen for several days. Thereafter, an attenuation of CRF responsiveness occurred when corticosterone excretion returned to basal levels despite continued central CRF infusion. However, CRF delivered intravenously during attenuation stimulated adrenocorticotropic hormone and corticosterone secretion, implicating a hypothalamic rather than pituitary locus for central CRF resistance. The present data do not permit a conclusion on whether the attenuation of the CRF response with time is the result of an ultrashort-loop negative-feedback mechanism or CRF receptor desensitization.

The influence of chronic exercise was investigated with male rats assigned to normal (N) and sympathectomized (IS) groups. Animals in the latter group were injected daily for 5 days with the antiserum to the nerve growth factor beginning 24 h after birth. Training was introduced when the animals were 35--45 days old and lasted for 12 wk. The exercise program used by both groups was progressive in nature and modified in accordance with the performance capability of the IS animals. When IS and N rats performed a standardized treadmill test, the IS rats had significantly higher rectal temperatures than normal animals. Significant training differences were observed in resting heart rate and in mean blood pressures, but only in the N animals. However, both trained groups exhibited significantly less vasoconstricting ability to conditions of lower body negative pressure than their nontrained controls. Varied doses of epinephrine and norepinephrine were injected into both groups and training per se had no significant influence on the responses recorded. However, both IS group had changes which indicated that a supersensitivity to catecholamines had occurred. Although selective training adaptations can occur without sympathetic nerves, it was concluded that an intact nervous system was essential for maximal training effects to occur.