Plasma norepinephrine and epinephrine levels in essential hypertension

Almost all comparative studies of plasma catecholamines in patients with essential hypertension (EH) and in normotensive controls have reported higher mean norepinephrine (NE) or epinephrine (E) levels in the hypertensive patients, but only about 40% of the studies have been positive, i.e., have reported statistically significant hypertensive-normotensive (H-N) differences. Virtually all studies of NE in young, consistently hypertensive patients were positive, as well as all studies of E in relatively tachycardic patients. Plasma NE increased with age in normotensive control but not EH groups. The likelihood that a study was positive with respect to NE was independent of the likelihood with respect to E. In 189 individuals with EH and 130 normotensive controls, NE increased with age in controls but not in patients with EH, so that the extent of the H-N difference in NE varied inversely with patient age. Among 41 other individuals with EH and 59 other normotensive controls, the distributions of NE and E values were shifted upward in EH. NE and E values were uncorrelated. Plasma NE levels are abnormally high in some patients with EH--especially those who are young and consistently hypertensive--and E levels are independent of age and NE. Increased sympathetic nervous system and/or sympathoadrenomedullary activity characterize a proportion of patients with EH.     

Plasma norepinephrine and dopamine-β-hydroxylase in genetic hypertensive rats

The relationship between blood pressure, plasma norepinephrine (NE), dopamine-β-hydroxylase (DBH) activity and age was investigated in spontaneously hypertensive rat (SHR), a stroke-prone substrain of the SHR and control Wistar-Kyoto rat (WKR). Blood pressure of both SHR strains increased with age and was significantly higher than that of the WKR at all ages tested (3 15 weeks). The blood pressure of stroke-prone SHR was significantly higher than that of the regular SHR after 6 weeks of age. Plasma DBH activity decreased with age in each strain, although the SHR, and especially the stroke-prone SHR, had significantly higher DBH than the controls at an early age. Plasma NE in the WKR did not change with age. Increased plasma NE was observed only in the young SHRs. The highest values were found in the 6 week old stroke-prone SHR. These data suggest that plasma DBH activity is not correlated directly with plasma NE or blood pressure, but that increased sympathetic nerve activity may occur during the development of hypertension in the SHR and the stroke-prone SHR.     

Aging‐associated formaldehyde‐induced norepinephrine deficiency contributes to age‐related memory decline

A norepinephrine (NE) deficiency has been observed in aged rats and in patients with Alzheimer's disease and is thought to cause cognitive disorder. Which endogenous factor induces NE depletion, however, is largely unknown. In this study, we investigated the effects of aging‐associated formaldehyde (FA) on the inactivation of NE in vitro and in vivo, and on memory behaviors in rodents. The results showed that age‐related DNA demethylation led to hippocampal FA accumulation, and when this occurred, the hippocampal NE content was reduced in healthy male rats of different ages. Furthermore, biochemical analysis revealed that FA rapidly inactivated NE in vitro and that an intrahippocampal injection of FA markedly reduced hippocampal NE levels in healthy adult rats. Unexpectedly, an injection of FA (at a pathological level) or 6‐hydroxydopamine (6‐OHDA, a NE depletor) can mimic age‐related NE deficiency, long‐term potentiation (LTP) impairments, and spatial memory deficits in healthy adult rats. Conversely, an injection of NE reversed age‐related deficits in both LTP and memory in aged rats. In agreement with the above results, the senescence‐accelerated prone 8 (SAMP8) mice also exhibited a severe deficit in LTP and memory associated with a more severe NE deficiency and FA accumulation, when compared with the age‐matched, senescence‐resistant 1 (SAMR1) mice. Injection of resveratrol (a natural FA scavenger) or NE into SAMP8 mice reversed FA accumulation and NE deficiency and restored the magnitude of LTP and memory. Collectively, these findings suggest that accumulated FA is a critical endogenous factor for aging‐associated NE depletion and cognitive decline.     

Inverse blood pressure rhythm of transgenic hypertensive TGR(mREN2)27 rats: role of norepinephrine and expression of tyrosine-hydroxylase and reuptake1-transporter

Transgenic hypertensive TGR(mREN2)27 rats (TGR) exhibit an inverse circadian blood pressure profile from the age of 8 to 9 wk. To investigate the role of the sympathetic nervous system in this pathological blood pressure rhythm, we examined postnatal changes in catecholamine concentration, expression of tyrosine-hydroxylase (TH), and norepinephrine (NE) reuptake₁-transporter (NET) in the heart, adrenal glands, and hypothalamus of non-hypertensive TGR at an age of 4 wk and of hypertensive TGR at an age of 10 wk and compared these to normotensive, age-matched Sprague-Dawley rats. Rats were kept under synchronized light:dark (LD) conditions of 12:12 h. Blood pressure and heart rate were monitored by radiotelemetry, catecholamines by high performance liquid chromatography, expression of TH and NET (mRNA) by RT-PCR, and TH protein by Western blots. In normotensive 4 wk-old Sprague-Dawley rats, cardiac NE concentrations were circadian phase-dependent with lower values at ZT12.5, with no differences observed, in 10-wk-old animals. At both ages however, sympathetic tone was higher during the dark phase, as shown by a higher turnover of NE. This observation confirms earlier data, which indicate that the endogenous amine concentration may not mirror its turnover rate. TGR at either age had lower cardiac NE as well as lower TH expression and did not display a circadian phase-dependency. The increased cardiac NE turnover rate in the dark phase in non-hypertensive TGR was lost in hypertensive rats. Both cardiac NE concentrations and TH expression decreased with age in both strains. In adrenal glands, NE and epinephrine (E) were not circadian phase-dependent in both strains but increased with age. NE concentrations in the hypothalamus were neither circadian phase-dependent nor different in both strains and at both ages. However, sympathetic tone of NE in the hypothalamus, as indicated by the turnover rate, was greater during the dark phase in both strains at an age of 10 wk. Expression of TH and NET were greatly reduced in adrenal glands when compared to Sprague-Dawley rats; whereas, expression of TH in the hypothalamus was significantly increased in hypertensive TGR. These data indicate that the transgene in TGR leads to an increased central stimulation of the sympathetic nervous system and to a consecutive down-regulation in the peripheral organs. It is of interest that rhythmicity in the studied parameters was lost in hypertensive TGR, except in the turnover of NE in the hypothalamus. We concluded that the data on key mechanisms of regulation of the sympathetic system in TGR cannot explain the inverse blood pressure rhythm observed in this transgenic rat strain.     

Age-related augmentation of plasma catecholamines during dynamic exercise in healthy males

Although plasma norepinephrine (NE) increases with age in response to a variety of submaximal adrenergic stimuli, the effect of age on plasma catecholamine levels during maximal aerobic effort and during submaximal work at a fixed percent of peak O2 consumption (VO2) is unknown. We therefore measured NE, epinephrine (E), and VO2 at rest and during graded maximal treadmill exercise in 24 healthy male volunteers (ages 22-77 yr) from the Baltimore Longitudinal Study of Aging who were rigorously screened to exclude the presence of cardiovascular disease. At rest neither heart rate (HR) nor VO2 were age related. Resting NE (pg/ml) was not age related, but resting E (pg/ml) was higher in male subjects 68-77 yr old (group III) than in those aged 22-37 (group I) or 44-55 yr (group II), P less than 0.01. Maximal HR (beats/min) showed a strong inverse relationship to age (203.5 - 0.65 age, r = -0.80, P less than 0.001). Peak VO2 in milliliters per kilogram total body weight per minute decreased with age (47.7 - 0.23 age, r = -0.71, P less than 0.001). At maximal effort both NE (P less than 0.01) and E (P less than 0.05) were higher in group III than in either of the younger groups. At submaximal work levels NE and E also increased with age, and when normalized for relative effort at loads between 45 and 80% of peak VO2 both NE and E were higher in the group III male subjects, although statistical significance was reached for NE (P less than 0.01) but not for E (P = 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)     

自发性高血压大鼠中枢去甲肾上腺素与血管紧张...

The norepinephrine (NE) and angiotensin II (A II) contents in the brain regions of SHR and WKY (Wistar Kyoto) rats at different ages were determined by fluorospectrophotometry and radioimmunoassay. The systolic blood pressure (SBP) of the rats was measured indirectly with a tail cuff technique in conscious state. The results were as follows: There was no significant difference in the central A II and NE contents between SHR and WKY rats at 8-week age. Since 12th week age the SBP of SHR has increased gradually, up to 16th to 20th week and then maintained steady level. Whereas there was no significant change of SBP in WKY rats in the same span of age. In the early and late states of hypertension the A II contents in the medulla oblongata, pons, hypothalamus and nucleus caudatus of SHR were markedly higher than those of the age-matched WKY rats. But the change of NE content of SHR in the early stage showed a different picture as compared with that of WKY rats, i.e., NE decreased in medulla oblongata and anterior hypothalamus but increased in pons, posterior hypothalamus and nucleus caudatus. However, in the late stage there was no such significant difference between SHR and WKY rats. Consequently, it is suggested that the central A II and NE participated in the development of hypertension of SHR, and that the maintenance of hypertension is mainly dependent upon the increased A II content. Microinjection of captopril or 6-OHDA in the lateral cerebroventricle of SHR elicited a decrease of BP and reduction of both A II and NE contents in the medulla and hypothalamus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stress of stoicism: Low emotionality and high control lead to increases in allostatic load

The present longitudinal study examined the combined effects of task persistence and negative emotionality (NE) on allostatic load (AL), a physiological indicator of chronic stress. In line with John Henryism theory, we hypothesized that high persistence combined with low NE may be indicative of a high-effort coping style, leading to high arousal of the nervous system and, as a consequence, increased AL. Mothers reported on children’s NE (N = 158, 72 females) at age 9. Persistence was measured at age 9 using a behavioral measure assessing persistence on an impossible task. AL was measured at ages 9 and 17. The AL measure captured hypothalamic pituitary adrenal axis, sympathetic adrenal medullary system, cardiovascular, and metabolic activity. Consistent with previous research, persistence protected against high AL in the context of high NE. However, combined with low NE, high behavioral persistence was associated with higher physiological stress. Our results have implications for both clinical and intervention contexts.     

Vesicular and Ganglionic Norepinephrine in the Rat: Progressive Increase with Age

This study analyzed dopamine (DA) and norepinephrine (NE) in the synaptic vesicles and cytoplasm of brains of rats of 2 months and 14 months. The data revealed a clear NE increase in the synaptic vesicles of the 14-month-old rats, contrasting with NE in the cytoplasmic fraction of the rat brain, which remained unchanged with age. Synaptic vesicles from different regions of rat brain, including those from the striatum, consistently exhibited higher NE than DA concentrations, suggesting that they are predominantly noradrenergic. In the brain, DA concentrations in vesicular and cytoplasmic fractions did not vary with age, whereas in the superior cervical ganglia DA and NE concentrations increased in the older rats. L-3,4-Dihydroxyphenylalanine administration significantly increased DA without affecting NE in the ganglia of rats of all ages. In the brain, such a treatment significantly raised DA only in the synaptic vesicles of the older rats, suggesting an increased facilitation of DA transport into the synaptic vesicles with age, which may account for the higher vesicular NE in the older rats.     

Elevated hypothalamic norepinephrine content in mice with the hereditary obese-hyperglycemic syndrome.

There is evidence that hypothalamic norepinephrine (NE) plays a role in the control of appetite in the rat. Using specific and sensitive radioenzymatic assays, we determined if there was a difference in the tissue (hypothalamus, cerebral cortex and kidney) concentration of NE or of dopamine (DA) in mice with the hereditary obese-hyperglycemic syndrome (ob/ob) and their normal weight littermates, both when they were in the rapid growth phase (2--3 months of age) and when they were mature (6--7 months of age). The concentration of NE was similar in the cerebral cortex of obese and normal mice and in the kidneys of obese and normal mice. The concentration of DA was similar in the hypothalamus of obese and normal mice. The concentration of DA was similar in the hypothalamus of obese and normal mice and in the cerebral cortex of obese and normal mice. These observations support the concept that alterations in hypothalamic NE may play a role in the obesity of ob/ob mice.     

Hyperinsulinemic yellow KK mice and norepinephrine turnover

To clarify whether hyperinsulinemia accelerates sympathetic nervous system (SNS) activity, norepinephrine (NE) turnover, a reliable indicator of SNS activity, was measured in the interscapular brown adipose tissue (IBAT) and heart of hyperinsulinemic yellow KK and normoinsulinemic C57BL control mice at 12 weeks of age. The yellow KK mice were more obese and had higher levels of plasma glucose (about 2.3 times) and of plasma insulin (about 24 times) than did the control mice. In IBAT, the rate of NE turnover following blockade of NE synthesis with alpha-methyl-p-tyrosine (alpha-MPT) was significantly slower in yellow KK mice than in C57BL mice, although in heart, no significant difference between both groups was observed in NE turnover. These results suggest that hyperinsulinemia dose not always increase NE turnover, and furthermore that the reduced NE turnover in IBAT of yellow KK mice may be one of the important factors in the development of obesity of this animal, as it is recognized that brown adipose tissue is a main effector of diet-induced thermogenesis and its defect or absence would predispose to obesity.     

Norepinephrine content of the rat kidney during development: Alterations induced by perinatal methadone

The concentration and the total content of norepinephrine (NE) in the kidney were measured in Sprague-Dawley rats from 3 to 120 days after birth. Renal NE concentration was relatively low until the end of the second week, when it rose abruptly to adult levels; total NE content per kidney increased steadily throughout development. The effects of perinatal methadone treatment on renal NE development were examined by administering the drug either directly to the pups from 1 to 19 days after birth, or to the mother from 10 days of gestation to 20 days after birth. Both treatments resulted in significant deficits of body weight and kidney weight. Maternal methadone caused a significant deficit in renal NE which was most pronounced at two weeks of postnatal age; direct methadone had less effect on renal NE. These results suggest that renal sympathetic neurotransmission may become mature two weeks after birth and indicate further that maternal methadone interfares with this maturation.     

Uptake and metabolism of [3H]norepinephrine in the cerebral hemispheres of chick embryos

Abstract— The uptake and metabolism of [³H]norepinephrine were studied in slices of cerebral hemispheres removed from chick embryos at 10, 15 and 20 days of embryonic age, as well as from 90-day-old hens. Brain tissue from all age groups concentrated [³H]norepinephrine to much greater levels at 37°C than at 0°C. There was a marked increase in the rate of accumulation of [³H]norepinephrine in tissues from 10 to 15 days of embryonic age, with no further increase in the rate observed from 15 to 20 days of embryonic age. Tissue slices were incubated for 20 min with [³H]norepinephrine, and the deaminated metabolites of norepinephrine were separated by paper chromatography. In tissues from all age groups, the neutral metabolites were produced in greater amounts than the acid metabolites. A significant increase in the amounts of deaminated metabolites formed was observed in the period from 10 to 15 days of embryonic age and a significant decrease in the amounts formed was observed in the period from 15 to 20 days of embryonic age. The deamination at 20 days was very similar to that observed in the adult. A significant decrease in the level of the deaminated metabolites was noted in all age groups in response to cocaine (an inhibitor of neuronal uptake mechanisms), an observation suggesting that mechanisms for neuronal uptake of NE are functional by 10 days of embryonic development in the chick. However, a significant increase in the level of deaminated metabolites in response to reserpine (an inhibitor of uptake of NE into storage granules) was observed only in slices taken from 20-day embryos and from the 90-day-old hen. The effect in the hen was more prominent than in the 20-day embryo. These results were interpreted to indicate that mechanisms for the uptake of NE develop at an earlier embryonic age than mechanisms for the storage of NE and that mechanisms for storage continue to develop after hatching.     

Use of plasma norepinephrine for evaluation of sympathetic neuronal function in man

Levels of norepinephrine (NE) in human plasma have been determined by a radioenzymatic technique sufficiently sensitive to measure 0.014 ng NE per ml plasma. Several procedures which raise plasma NE levels have been compared and a standard procedure developed to evaluate sympathetic neuronal function based on the increments in plasma NE produced by postural change and a standard amount of exertion. The mean basal level of NE in plasma of 74 resting, supine, normal subjects ranging in age from 10 to 70 (mean 32.7 years) was 0.292 ± 0.016 (± SEM) ng/ml and ranged from 0.112 to 0.738 ng/ml. There was a significant correlation between age and basal levels of NE (L.R. = 0.33, p < 0.01). In 44 subjects who stood for 5 minutes after the basal sample of blood was obtained, the mean plasma level of NE increased to 0.538 ± 0.044 ng/ml and further increased to 0.778 ± 0.080 ng/ml after a subsequent isometric hand grip for 5 minutes.     

Norepinephrine concentration in kidneys of normotensive Wistar-Kyoto and spontaneously hypertensive rats.

Renal norepinephrine (NE) concentration was measured in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) at 7, 9, 11, and 13 weeks of age. Although the weight of kidneys was similar in the two strains of rats, renal NE concentration was significantly lower in SHR at all ages (147 +/- 9 to 175 +/- 13 ng/g for SHR, and 216 +/- 8 to 262 +/- 17 ng/g for WKY rats). The difference in renal NE concentration during this time of rapidly increasing arterial pressure in the SHR suggests that renal NE may in some way be related to the development of hypertension.     

Abnormal Neural Responses to Emotional Stimuli but Not Go/NoGo and Stroop Tasks in Adults with a History of Childhood Nocturnal Enuresis

Background

Nocturnal enuresis (NE) is a common disorder in school-aged children. Previous studies have reported that children with NE exhibit structural, functional and neurochemical abnormalities in the brain, suggesting that children with NE may have cognitive problems. Additionally, children with NE have been shown to process emotions differently from control children. In fact, most cases of NE resolve with age. However, adults who had experienced NE during childhood may still have potential cognitive or emotion problems, and this possibility has not been thoroughly investigated.

Methodology/Principal Findings

In this work, we used functional magnetic resonance imaging (fMRI) to evaluate brain functional changes in adults with a history of NE. Two groups, consisting of 21 adults with NE and 21 healthy controls, were scanned using fMRI. We did not observe a significant abnormality in activation during the Go/NoGo and Stroop tasks in adults with a history of NE compared with the control group. However, compared to healthy subjects, young adults with a history of NE mainly showed increased activation in the bilateral temporoparietal junctions, bilateral dorsolateral prefrontal cortex, and bilateral anterior cingulate cortex while looking at negative vs. neutral pictures.

Conclusions/Significance

Our results demonstrate that adults with a history of childhood NE have no obvious deficit in response inhibition or cognitive control but showed abnormal neural responses to emotional stimuli.     

Reduced norepinephrine turnover in brown adipose tissue of pre-obese mice treated with monosodium-L-glutamate

Norepinephrine (NE) turnover, an index of sympathetic nervous system (SNS) activity, was measured in interscapular brown adipose tissue (IBAT), heart and pancreas of 3-weeks-old pre-obese monosodium-L-glutamate (MSG) mice and at 6-weeks-old mildly obese MSG mice. In IBAT, rates of NE turnover were slower not only in 3-weeks-old MSG mice but also in older obese MSG mice than in their saline controls. In heart, rates of NE turnover were slower in 6-weeks-old mildly obese MSG mice, but not in pre-obese MSG mice. No significant difference in NE turnover in pancreas was observed at either age. The low NE turnover in IBAT of MSG-treated mice prior to the onset of gross obesity suggests that low SNS activity may be an initial contributor to their high energy efficiency and resultant obesity.     

Prediction of the net energy value of broiler diets

Thirty pelleted diets were given to broiler chickens (eight birds per diet; 21 to 35 days of age) for individual in vivo measurements of dietary net energy (NE) value, using three trials with 10 diets/trial. Amino acid formulation of diets was done on the basis of ratios to CP. NE was measured according to the body analysis method. The basal metabolism component of NE values was calculated on the basis of mean metabolic weight using a coefficient obtained in a previous experiment. Information about apparent metabolisable energy (AME) value of diets, AME corrected to zero nitrogen retention (AMEn) and digestibilities of proteins, lipids, starch and sugars was available from a previous publication. In each trial, mean NE/AME ratios of diets varied by about 6%. From the multiple regressions (n=30) expressing NE and AMEn values as functions of digestible component contents, it was deduced that the NE/AMEn ratios assigned to dietary components were 0.760, 0.862, 0.806, 0.690 and 0.602 for CP, lipids, starch, (sucrose+glucose) and fermentable sugars (α-galacto-oligosaccharides and lactose), respectively. The NE/AME ratio of CP was 0.680. Regression calculations showed that the NE values assigned to individual birds (n=240) could also be predicted with diet AMEn values (NE=0.80 AMEn; R²=0.770) or with an equation combining AMEn value and CP/AMEn ratio (R²=0.773). The latter ratio was found to be the only additional parameter that was significant when added in the NE regression scheme based on AMEn.     

The effects of race on norepinephrine clearance

Eighteen normotensive and 19 unmedicated hypertensive black and white male subjects were studied twice, during a 10 meq sodium diet for 5 days and a 200 meq sodium diet for 4 days. The subjects received an infusion of 3H-norepinephrine (3H-NE) during both low and high sodium diets to measure NE clearance. Dietary sodium and blood pressure classification had no effect on 3H-NE clearance. Infusion of pressor doses of NE also failed to alter 3H-NE clearance. Both normotensive and hypertensive blacks had increased 3H-NE clearance rates (p less than .001). The increased rate of 3H-NE clearance among blacks was not affected by alterations in dietary sodium or by pressor doses of NE. Increased NE clearance by blacks may help explain observations that white hypertensives in the age range we studied (25-46 years) have elevated plasma NE levels, while blacks have normal NE levels.     

Neutrophil elastase induces mucus cell metaplasia in mouse lung

Goblet cell hyperplasia in the superficial airway epithelia is a signature pathological feature of chronic bronchitis and cystic fibrosis. In these chronic inflammatory airway diseases, neutrophil elastase (NE) is found in high concentrations in the epithelial lining fluid. NE has been reported to trigger mucin secretion and increase mucin gene expression in vitro. We hypothesized that chronic NE exposure to murine airways in vivo would induce goblet cell metaplasia. Human NE (50 microg) or PBS saline was aspirated intratracheally by male Balb/c (6 wk of age) mice on days 1, 4, and 7. On days 8, 11, and 14, lung tissues for histology and bronchoalveolar lavage (BAL) samples for cell counts and cytokine levels were obtained. NE induced Muc5ac mRNA and protein expression and goblet cell metaplasia on days 8, 11, and 14. These cellular changes were the result of proteolytic activity, since the addition of an elastase inhibitor, methoxysuccinyl Ala-Ala-Pro-Val chloromethylketone (AAPV-CMK), blocked NE-induced Muc5ac expression and goblet cell metaplasia. NE significantly increased keratinocyte-derived chemokine and IL-5 in BAL and increased lung tissue inflammation and BAL leukocyte counts. The addition of AAPV-CMK reduced these measures of inflammation to control levels. These experiments suggest that NE proteolytic activity initiates an inflammatory process leading to goblet cell metaplasia.     

Plasma free and conjugated catecholamines in clinical disorders

Plasma free and sulfoconjugated norepinephrine (NE), epinephrine (E) and dopamine (DA) concentrations measured in patients with thrombocytopenia or thrombocytosis, in newborns and pregnant women were not statistically different from values determined in 41 healthy volunteers. The percentage free to total NE, E and DA was 30 +/- 10%, 35 +/- 11% and 1.5 +/- 1.1% (mean +/- SE) in the controls, resp; not different from the previously described patients or from patients with liver failure who showed significantly higher free and conjugated NE and E levels when compared with controls (p less than 0.01, resp.). Conjugated catecholamine (CA) levels from the femoral artery and from multiple sites in the venous system sampled in patients undergoing intracardiac measurements were identical. The data suggest that sulfation of CA may not be simply ascribed to platelets, to the liver, to vascular beds, or to organs along the vena cava including the adrenal glands. The parallel increase of free and conjugated NE with age in healthy controls, as well as the unchanged degree of conjugation in patients with increased spillover of NE and E caused by a pheochromocytoma or by a heart attack, suggest that there is a balance between free and sulfated CA. A normal ratio of free to conjugated NE and E observed in patients receiving high dosage DA infusion further indicates that there is an adequate sulfate supply and no apparent substrate inhibition of the conjugation process. Because the percentage free of total NE, E and DA were significantly lower in patients in the hypothyroid state when compared with controls (p less than 0.01, resp.), hypothyroidism may affect the balance of free to conjugated CA in a yet unknown way.