Lower Plasma Norepinephrine Research Articles

Transforming Growth Factor-α Acts in Hypothalamic Paraventricular Nucleus to Upregulate ERK1/2 Signaling and Expression of Sympathoexcitatory Mediators in Heart Failure Rats

Activation of epidermal growth factor receptor (EGFR) tyrosine kinase is associated with increased extracellular signal-regulated kinase (ERK) 1/2 signaling in the hypothalamic paraventricular nucleus (PVN), which contributes to the sympathetic excitation in heart failure (HF). Transforming growth factor (TGF)-α is a major endogenous ligand for EGFR. The present study sought to determine whether TGF-α increases in the PVN in HF and promotes the activation of EGFR to increase ERK1/2 activity. Male rats received bilateral PVN microinjections of an EGFR siRNA or a scrambled siRNA followed by an intracerebroventricular (ICV) injection of TGF-α or vehicle one week later. In rats pretreated with the scrambled siRNA, ICV TGF-α increased phosphorylated (p-) EGFR and upregulated the expression of p-ERK1/2 and mRNA levels of proinflammatory cytokines (PICs) and renin-angiotensin system (RAS) components in the PVN, when compared with the untreated age-matched control rats. These responses to ICV TGF-α were significantly attenuated in rats pretreated with the EGFR siRNA. Furthermore, bilateral PVN microinjection of a TGF-α siRNA in HF rats significantly decreased the elevated levels of TGF-α, p-EGFR, p-ERK1/2 and the mRNA expression of PICs and RAS components in the PVN, compared with the HF rats treated with a scrambled siRNA. The TGF-α siRNA-treated HF rats also exhibited lower plasma norepinephrine levels and improved peripheral manifestations of HF. These data suggest that TGF-α expression is upregulated in the PVN in HF and induces the activation of EGFR-mediated ERK1/2 signaling to augment the inflammation and RAS activity that drives sympathetic excitation in HF.

Pharmacologic treatment of orthostatic hypotension.

Neurogenic orthostatic hypotension (OH) is a disabling disorder caused by impairment of the normal autonomic compensatory mechanisms that maintain upright blood pressure. Nonpharmacologic treatment is always the first step in the management of this condition, but a considerable number of patients will require pharmacologic therapies. Denervation hypersensitivity and impairment of baroreflex buffering makes these patients sensitive to small doses of pressor agents. Understanding the underlying pathophysiology can help in selecting between treatment options. In general, patients with low "sympathetic reserve", i.e., those with peripheral noradrenergic degeneration (pure autonomic failure, Parkinson's disease) and low plasma norepinephrine, tend to respond better to "norepinephrine replacers" (midodrine and droxidopa). On the other hand, patients with relatively preserved "sympathetic reserve", i.e., those with impaired central autonomic pathways but spared peripheral noradrenergic fibers (multiple system atrophy) and normal or slightly reduced plasma norepinephrine, tend to respond better to "norepinephrine enhancers" (pyridostigmine, atomoxetine, and yohimbine). There is, however, a spectrum of responses within these extremes, and treatment should be individualized. Other nonspecific treatments include fludrocortisone and octreotide. The presence of associated clinical conditions, such as supine hypertension, heart failure, postprandial hypotension, PD, MSA, and diabetes need to be considered in the pharmacologic management of these patients.

Does sympathetic dysfunction occur before denervation in pure autonomic failure?

Pure autonomic failure (PAF) is a rare sporadic disorder characterized by autonomic failure in the absence of a movement disorder or dementia and is associated with very low plasma norepinephrine (NE) levels-suggesting widespread sympathetic denervation, however due to its rarity the pathology remains poorly elucidated. We sought to correlate clinical and neurochemical findings with sympathetic nerve protein abundances, accessed by way of a forearm vein biopsy, in patients with PAF and in healthy controls and patients with multiple systems atrophy (MSA) in whom sympathetic nerves are considered intact. The abundance of sympathetic nerve proteins, extracted from forearm vein biopsy specimens, in 11 patients with PAF, 8 patients with MSA and 9 age-matched healthy control participants was performed following a clinical evaluation and detailed evaluation of sympathetic nervous system function, which included head-up tilt (HUT) testing with measurement of plasma catecholamines and muscle sympathetic nerve activity (MSNA) in addition to haemodynamic assessment to confirm the clinical phenotype. PAF participants were found to have normal abundance of the NE transporter (NET) protein, together with very low levels of tyrosine hydroxylase (TH) (P<0.0001) and reduced vesicular monoamine transporter 2 (VMAT2) (P<0.05) protein expression compared with control and MSA participants. These findings were associated with a significantly higher ratio of plasma 3,4-dihydroxyphenylglycol (DHPG):NE in PAF participants when compared with controls (P<0.05). The finding of normal NET abundance in PAF suggests intact sympathetic nerves but with reduced NE synthesis. The finding of elevated plasma ratio of DHPG:NE and reduced VMAT2 in PAF indicates a shift towards intraneuronal NE metabolism over sequestration in sympathetic nerves and suggests that sympathetic dysfunction may occur ahead of denervation.

Natural history of pure autonomic failure: A United States prospective cohort.

To define the clinical features and biomarkers that predict which patients with pure autonomic failure will develop Parkinson disease, dementia with Lewy bodies, or multiple system atrophy. One hundred patients who presented with pure autonomic failure were recruited at 5 medical centers in the United States. Seventy-four patients agreed to be followed prospectively. Patients underwent clinical evaluations including neurological rating scales, sleep questionnaires, smell test, and sympathetic and parasympathetic cardiovascular autonomic function tests. At enrollment, patients were 68 ± 12 years old (median ± interquartile range) and had had autonomic failure for 5 ± 7 years. Within 4 years of follow-up, 25 of 74 subjects (34%) developed dementia with Lewy bodies (n = 13), Parkinson disease (n = 6), or multiple system atrophy (n = 6). The presence of probable rapid eye movement (REM) sleep behavior disorder was strongly associated with the development of a manifest central nervous system (CNS) synucleinopathy (odds ratio = 7.1). Patients who phenoconverted to multiple system atrophy had younger age at onset of autonomic failure, severe bladder/bowel dysfunction, preserved olfaction, and a cardiac chronotropic response upon tilt > 10 beats per minute. Those who phenoconverted to Parkinson disease or dementia with Lewy bodies had decreased olfaction, a lesser chronotropic response to tilt, and a longer duration of illness. The small group of patients retaining the pure autonomic failure phenotype had very low plasma norepinephrine levels, slow resting heart rate, no REM sleep behavior disorder, and preserved smell. Patients presenting with pure autonomic failure are at high risk of phenoconverting to a manifest CNS synucleinopathy. Specific clinical features predict future diagnosis. Ann Neurol 2017;81:287-297.

ERK1/2 MAPK signaling in hypothalamic paraventricular nucleus contributes to sympathetic excitation in rats with heart failure after myocardial infarction.

Brain MAPK signaling pathways are activated in heart failure (HF) induced by myocardial infarction and contribute to augmented sympathetic nerve activity. We tested whether decreasing ERK1/2 (also known as p44/42 MAPK) signaling in the hypothalamic paraventricular nucleus (PVN), a forebrain source of presympathetic neurons, would reduce the upregulation of sympathoexcitatory mediators in the PVN and augmented sympathetic nerve activity in rats with HF. Sprague-Dawley rats underwent left anterior descending coronary artery ligation to induce HF, with left ventricular dysfunction confirmed by echocardiography. One week after coronary artery ligation or sham operation, small interfering (si)RNAs targeting ERK1/2 or a nontargeting control siRNA was microinjected bilaterally into the PVN. Experiments were conducted 5-7 days later. Confocal images revealed reduced phosphorylated ERK1/2 immunofluorescence in the PVN of HF rats treated with ERK1/2 siRNAs compared with HF rats treated with control siRNA. Western blot analysis confirmed significant reductions in both total and phosphorylated ERK1/2 in the PVN of HF rats treated with ERK1/2 siRNAs along with reduced expression of renin-angiotensin system components and inflammatory mediators. HF rats treated with ERK1/2 siRNAs also had reduced PVN neuronal excitation (fewer Fos-related antigen-like-immunoreactive neurons), lower plasma norepinephrine levels, and improved peripheral manifestations of HF compared with HF rats treated with control siRNAs. These results demonstrate that ERK1/2 signaling in the PVN plays a pivotal role in mediating sympathetic drive in HF induced by myocardial infarction and may be a novel target for therapeutic intervention.

Effects of low-dose clonidine on cardiovascular and autonomic variables in adolescents with chronic fatigue: a randomized controlled trial.

BackgroundChronic Fatigue Syndrome (CFS) is a common and disabling condition in adolescence with few treatment options. A central feature of CFS is orthostatic intolerance and abnormal autonomic cardiovascular control characterized by sympathetic predominance. We hypothesized that symptoms as well as the underlying pathophysiology might improve by treatment with the alpha2A–adrenoceptor agonist clonidine.MethodsA total of 176 adolescent CFS patients (12–18 years) were assessed for eligibility at a single referral center recruiting nation-wide. Patients were randomized 1:1 by a computer system and started treatment with clonidine capsules (25 μg or 50 μg twice daily, respectively, for body weight below/above 35 kg) or placebo capsules for 9 weeks. Double-blinding was provided. Data were collected from March 2010 until October 2012 as part of The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL). Effect of clonidine intervention was assessed by general linear models in intention-to-treat analyses, including baseline values as covariates in the model.ResultsA total of 120 patients (clonidine group n = 60, placebo group n = 60) were enrolled and started treatment. There were 14 drop-outs (5 in the clonidine group, 9 in the placebo group) during the intervention period. At 8 weeks, the clonidine group had lower plasma norepinephrine (difference = 205 pmol/L, p = 0.05) and urine norepinephrine/creatinine ratio (difference = 3.9 nmol/mmol, p = 0.002). During supine rest, the clonidine group had higher heart rate variability in the low-frequency range (LF-HRV, absolute units) (ratio = 1.4, p = 0.007) as well as higher standard deviation of all RR-intervals (SDNN) (difference = 12.0 ms, p = 0.05); during 20° head-up tilt there were no statistical differences in any cardiovascular variable. Symptoms of orthostatic intolerance did not change during the intervention period.ConclusionsLow-dose clonidine reduces catecholamine levels in adolescent CFS, but the effects on autonomic cardiovascular control are sparse. Clonidine does not improve symptoms of orthostatic intolerance.Trial registrationClinical Trials ID: NCT01040429, date of registration 12/28/2009.

Relationship Between Blood- and Cerebrospinal Fluid–Bound Neurotransmitter Concentrations and Conditioned Pain Modulation in Pain-Free and Chronic Pain Subjects

Descending pain inhibition is an endogenous pain control system thought to depend partially on the activation of bulbospinal monoaminergic pathways. Deficits in descending pain inhibition have been reported in numerous human chronic pain conditions, but there is currently no consensus regarding the neurochemical correlates responsible for this deficit. The aims of this study were to 1) assess the efficacy of descending pain inhibition in pain-free and chronic pain subjects, 2) screen for changes in centrally (ie, cerebrospinal fluid) and peripherally (ie, plasma) acting monoamine concentrations, and 3) explore the relationship between descending pain inhibition and monoamine neurotransmitter concentrations. Our results clearly show a deficit in pain inhibition, along with lower plasma norepinephrine and metanephrine concentrations in chronic pain subjects, compared to pain-free subjects. No differences were found in cerebrospinal fluid neurotransmitter concentrations. Finally, our results revealed a positive relationship between blood-bound norepinephrine and metanephrine concentrations and the efficacy of descending pain inhibition. Thus, basal monoamine levels in blood were related to descending pain inhibition. This finding supports the emerging idea that individual differences in descending pain inhibition may be linked to individual differences in peripheral processes, such as monoamines release in blood, which are possibly related to cardiovascular control. PerspectivesThis article presents psychophysical and neurochemical findings that indicate that the latent potential of descending pain inhibitory responses is associated with differential activity in peripheral processes governed by monoamine neurotransmitter release, bringing insights into the relationship between descending pain inhibition and cardiovascular control in humans.

Disease Mechanisms and Clonidine Treatment in Adolescent Chronic Fatigue Syndrome

Chronic fatigue syndrome (CFS) is a disabling condition with unknown disease mechanisms and few treatment options. To explore the pathophysiology of CFS and assess clonidine hydrochloride pharmacotherapy in adolescents with CFS by using a hypothesis that patients with CFS have enhanced sympathetic activity and that sympatho-inhibition by clonidine would improve symptoms and function. Participants were enrolled from a single referral center recruiting nationwide in Norway. A referred sample of 176 adolescents with CFS was assessed for eligibility; 120 were included (34 males and 86 females; mean age, 15.4 years). A volunteer sample of 68 healthy adolescents serving as controls was included (22 males and 46 females; mean age, 15.1 years). The CSF patients and healthy controls were assessed cross-sectionally at baseline. Thereafter, patients with CFS were randomized 1:1 to treatment with low-dose clonidine or placebo for 9 weeks and monitored for 30 weeks; double-blinding was provided. Data were collected from March 2010 until October 2012 as part of the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial. Clonidine hydrochloride capsules (25 µg or 50 µg twice daily for body weight <35 kg or >35 kg, respectively) vs placebo capsules for 9 weeks. Number of steps per day. At baseline, patients with CFS had a lower number of steps per day (P < .001), digit span backward score (P = .002), and urinary cortisol to creatinine ratio (P = .001), and a higher fatigue score (P < .001), heart rate responsiveness (P = .02), plasma norepinephrine level (P < .001), and serum C-reactive protein concentration (P = .04) compared with healthy controls. There were no significant differences regarding blood microbiology evaluation. During intervention, the clonidine group had a lower number of steps per day (mean difference, -637 steps; P = .07), lower plasma norepinephrine level (mean difference, -42 pg/mL; P = .01), and lower serum C-reactive protein concentration (mean ratio, 0.69; P = .02) compared with the CFS placebo group. Adolescent CFS is associated with enhanced sympathetic nervous activity, low-grade systemic inflammation, attenuated hypothalamus-pituitary-adrenal axis function, cognitive impairment, and large activity reduction, but not with common microorganisms. Low-dose clonidine attenuates sympathetic outflow and systemic inflammation in CFS but has a concomitant negative effect on physical activity; thus, sympathetic and inflammatory enhancement may be compensatory mechanisms. Low-dose clonidine is not clinically useful in CFS. clinicaltrials.gov Identifier: NCT01040429.

Effect of Insular Injury on Autonomic Functions in Patients With Ruptured Middle Cerebral Artery Aneurysms

Insular injuries are known to cause autonomic derangements. Patients with ruptured middle cerebral artery aneurysms frequently develop temporal hematomas (THs) in addition to subarachnoid hemorrhages, and those with TH may sustain autonomic derangements more frequently than those without TH. Hemispheric lateralization in autonomic derangements has been reported in patients with insular ischemic stroke, and this study was conducted to clarify whether such lateralization was also observed in patients with TH resulting from middle cerebral artery aneurysm rupture. A retrospective analysis on the medical records of 79 patients with ruptured middle cerebral artery aneurysms was performed on the basis of lateralization and presence of TH. They were quadrichotomized as left TH+ (LTH+; n=17), right TH+ (n=25), left TH- (n=15), and right TH- (n=22). Comparisons, mainly between LTH+ and right TH+, were made on demographic variables, autonomic/cardiac parameters, plasma catecholamine and glucose levels, and outcomes. There were no significant differences in demographic or cardiac parameters between the 2 groups. Systolic blood pressures were lower in LTH+ (139±34 versus 174±47 mm Hg; P=0.05). The LTH+ group also tended to be more bradycardiac (80±19 versus 101±22 bpm; P=0.13). The LTH+ group exhibited significantly lower plasma norepinephrine (1008±975 versus 2549±2133 pg/mL; P=0.03) and glucose levels (9.3±1.8 versus 12.2±4.5 mmol/L; P=0.04). However, in-hospital mortality did not differ significantly (41% versus 44%; P=1.00). Lateralization of autonomic derangements observed might not have had a significant effect on the outcomes. Nevertheless, autonomic derangements associated with insular injury should be considered in the management of subarachnoid hemorrhage patients with TH.

Neuroadrenergic Dysfunction Along the Diabetes Continuum

Neuroadrenergic function in type 2 diabetic (T2D) patients without neuropathy is poorly characterized. We therefore compared sympathetic nervous system activity at rest and during an oral glucose tolerance test in obese metabolic syndrome (MetS) subjects classified as glucose intolerant (impaired glucose tolerance [IGT]; n = 17) or treatment-naive T2D (n = 17). Untreated subjects, matched for age (mean 59 ± 1 year), sex, BMI (32.4 ± 0.6 kg/m2), and family history of diabetes were studied. We measured resting muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine kinetics by isotope dilution, insulin sensitivity by euglycemic-hyperinsulinemic clamp (steady-state glucose utilization adjusted for fat-free mass and steady-state insulin concentration [M/I]), and MetS components. T2D subjects had higher resting MSNA burst incidence (67 ± 4 versus 55 ± 3 bursts per 100 heartbeats; P = 0.05) and arterial norepinephrine levels (264 ± 33 versus 167 ± 16 pg/mL; P = 0.02), lower plasma norepinephrine clearance (by 17%; P = 0.03), and reduced neuronal reuptake compared with IGT subjects (by 46%; P = 0.04). Moreover, norepinephrine spillover responses to glucose ingestion were blunted in T2D subjects. The M/I value independently predicted whole-body norepinephrine spillover (r = −0.47; P = 0.008), whereas fasting insulin level related to neuronal norepinephrine reuptake (r = −0.35, P = 0.047). These findings demonstrate that progression to T2D is associated with increased central sympathetic drive, blunted sympathetic responsiveness, and altered norepinephrine disposition.

Central Sympathetic Inhibition by Mineralocorticoid Receptor But Not Angiotensin II Type 1 Receptor Blockade

See related article, pp 319–325 Chronic sympathetic hyperactivity, characteristic of the majority of patients with hypertension or heart failure, can contribute to cardiovascular morbidity and mortality via a number of actions. Pharmacological strategies to prevent these adverse effects have had variable success. β-Blockers clearly benefit patients with heart failure but have less definitive effects in patients with hypertension, whereas α1-blockers or centrally acting agents have shown mixed results, and all of these classes can cause bothersome adverse effects. Device-based approaches, such as baroreflex activation therapy and renal denervation, have been shown to lower sympathetic activity in patients with hypertension, but beneficial actions on cardiovascular outcomes have yet to be demonstrated. So, where do the central nervous system (CNS) actions of angiotensin II (Ang II), aldosterone, and, hence, Ang II type 1 (AT1) receptor and mineralocorticoid receptor (MR) blockers fit in? Experimental studies have demonstrated that both circulating Ang II and aldosterone act within the CNS to cause sympatho-excitation and raise blood pressure.1,2 Ang II stimulates AT1 receptors in nuclei of the lamina terminalis and thereby activates mainly angiotensinergic pathways to the paraventricular nucleus (PVN) and rostral ventrolateral medulla. Circulating Ang II, in addition, activates an MR-endogenous ouabain pathway. This slowly acting, neuromodulatory pathway appears responsible for most of the persistent neuronal activation in, for example, the PVN, and the progressive hypertension induced by circulating Ang II. Studies using central infusions of an aldosterone synthase inhibitor suggest that the CNS MR activation by Ang II largely depends on locally produced aldosterone rather than circulation-derived aldosterone.1 However, the progressive hypertension caused by a chronic increase in circulating aldosterone can also be prevented by specific CNS blockade of either MR or AT1 receptors,2 suggesting that both circulating aldosterone and Ang II may activate …

Plasma oxytocin is related to lower cardiovascular and sympathetic reactivity to stress

In addition to known reproductive and social affiliation functions, oxytocin (OT) has been identified as a cardiovascular hormone. OT synthesis and receptors are found in cardiac and vascular tissue. Animal studies suggest that OT activates an ‘anti-stress’ response that reduces cardiovascular and neuroendocrine stress reactivity. We tested 28 early postpartum mothers, obtaining multiple blood samples for OT, the sympathetic marker, norepinephrine (NE), and the lactation hormone, prolactin, while monitoring their cardiovascular responses to two stressors: public speaking and forehead cold pressor. Although plasma OT did not increase reliably from pre-stress levels during stressors, greater overall OT level was related to greater vasodilation and cardiac stroke volume responses to both tasks, to reduction in heart rate to the cold pressor, as well as to lower plasma NE and higher prolactin levels. In contrast, higher NE was linked to increases in heart rate and decreases in stroke volume. These data support a cardioprotective role for OT, which may influence the magnitude and hemodynamic determinants of cardiovascular stress responses.

A cross-sectional study contrasting olfactory function in autonomic disorders

To compare odor identification function in patients with peripheral or central autonomic neurodegeneration and in patients with intact autonomic neurons but undetectable norepinephrine. Olfactory function was evaluated with the University of Pennsylvania Smell Identification Test (UPSIT) in 12 patients with pure autonomic failure, 10 patients with multiple system atrophy, and 4 patients with dopamine β-hydroxylase deficiency. Blood pressure and catecholamine data were also compared. Odor identification was significantly impaired in patients with pure autonomic failure relative to patients with multiple system atrophy or dopamine β-hydroxylase deficiency. Out of 40 odors, the patients correctly identified mean (95% confidence interval) 19.2 (14.1 to 24.2), 34.4 (32.2 to 36.6), and 31.7 (29.4 to 34.1) (p < 0.001). The difference between patients with pure autonomic failure and those with multiple system atrophy or dopamine β-hydroxylase deficiency persisted after adjustment for age (p = 0.001). Patients with pure autonomic failure also had a greater orthostatic fall in blood pressure and lower plasma norepinephrine levels than patients with multiple system atrophy. Olfactory function was relatively intact in patients with dopamine β-hydroxylase deficiency, who have intact noradrenergic neurons but lack norepinephrine. Odor identification was impaired in pure autonomic failure but not in multiple system atrophy, suggesting that 1) peripheral noradrenergic innervation is important for olfactory identification but norepinephrine is not essential and 2) UPSIT may be useful in the differential diagnosis between these disorders.

Excessive Nitric Oxide Function and Blood Pressure Regulation in Patients With Autonomic Failure

Approximately 50% of patients with autonomic failure (AF) suffer from supine hypertension, even those with very low plasma norepinephrine and renin. Because NO is arguably the most potent metabolic modulator of blood pressure, we hypothesized that impaired NO function contributes to supine hypertension in AF. However, we found that AF patients (n=14) were more sensitive to the pressor effects of the NO synthase inhibitor N(G)-monomethyl-l-arginine, suggesting increased NO function rather than deficiency; a lower dose of N(G)-monomethyl-l-arginine was needed to produce a similar increase in blood pressure in AF patients, as in healthy control subjects in whom AF was induced with the ganglionic blocker trimethaphan (171+/-37 mg versus 512+/-81 mg, respectively; P=0.001). Furthermore, potentiation of the actions of endogenous NO with the phosphodiesterase inhibitor sildenafil (25 mg PO) decreased nighttime supine systolic blood pressure from 182+/-11 to 138+/-4 mm Hg in 8 AF patients with supine hypertension (P=0.012 compared with placebo). Finally, AF patients tolerated a greater degree of upright tilt during infusion of N(G)-monomethyl-l-arginine (56+/-6 degrees versus 41+/-4 degrees with placebo; n=7; P=0.014), an improvement in orthostatic tolerance similar to that obtained with equipressor doses of phenylephrine. In conclusion, AF patients do not have NO deficiency contributing to supine hypertension. Instead, they have increased NO function contributing to their orthostatic hypotension. Potentiation of NO could be used in the treatment of supine hypertension, and its inhibition offers a novel approach to improve orthostatic hypotension.

Does Aldosterone Upregulate the Brain Renin-Angiotensin System in Rats With Heart Failure?

The brain renin-angiotensin system (RAS) contributes to increased sympathetic drive in heart failure (HF). The factors upregulating the brain RAS in HF remain unknown. We hypothesized that aldosterone (ALDO), a downstream product of the systemic RAS that crosses the blood-brain barrier, signals the brain to increase RAS activity in HF. We examined the relationship between circulating and brain ALDO in normal intact rats, in adrenalectomized rats receiving subcutaneous infusions of ALDO, and in rats with ischemia-induced HF and sham-operated controls. Brain ALDO levels were proportional to plasma ALDO levels across the spectrum of rats studied. Compared with sham-operated controls rats, HF rats had higher plasma and hypothalamic tissue levels of ALDO. HF rats also had higher expression of mRNA and protein for angiotensin-converting enzyme and angiotensin type 1 receptors in the hypothalamus, increased reduced nicotinamide-adenine dinucleotide phosphate oxidase activity and superoxide generation in the paraventricular nucleus of the hypothalamus, increased excitation of paraventricular nucleus neurons, and increased plasma norepinephrine. HF rats treated for 4 weeks with intracerebroventricular RU28318 (1 microg/h), a selective mineralocorticoid receptor antagonist, had less hypothalamic angiotensin-converting enzyme and angiotensin type 1 receptor mRNA and protein, less reduced nicotinamide-adenine dinucleotide phosphate-induced superoxide in the paraventricular nucleus, fewer excited paraventricular nucleus neurons, and lower plasma norepinephrine. RU28318 had no effect on plasma ALDO or on angiotensin-converting enzyme or angiotensin type 1 receptor expression in brain cortex. The data demonstrate that ALDO of adrenal origin enters the hypothalamus in direct proportion to plasma levels and suggest that ALDO contributes to the upregulation of hypothalamic RAS activity and sympathetic drive in heart failure.

Persistent alterations in biological profiles in women with abuse histories: Influence of premenstrual dysphoric disorder.

To examine dysregulation in biological measures associated with histories of abuse in women and whether women with premenstrual dysphoric disorder (PMDD) differ in their dysregulation. Twenty-five women meeting prospective criteria for PMDD and 42 non-PMDD controls underwent structured interview to determine abuse histories and lifetime Axis I diagnoses, excluding those with current Axis I disorders or using medications. Plasma cortisol and norepinephrine (NE), heart rate (HR), blood pressure (BP), and vascular resistance index (VRI) were assessed at rest and in response to mental stress. A greater proportion of PMDD women had prior abuse compared with non-PMDD women. Regardless of PMDD status, all abused women had lower plasma NE and higher HRs and tended to have lower plasma cortisol at rest and during stress. Abused women also reported more severe daily emotional and physical symptoms. Greater VRI and BP at rest and during stress were seen only in PMDD women with abuse. There is persistent dysregulation in stress-responsive systems in all abused women that cannot be accounted for by current psychiatric illness or medications, and PMDD women may be differentially more vulnerable to the impact of abuse on measures reflecting alpha-adrenergic receptor function.

Novel Effect of Mineralocorticoid Receptor Antagonism to Reduce Proinflammatory Cytokines and Hypothalamic Activation in Rats With Ischemia-Induced Heart Failure

Blocking brain mineralocorticoid receptors (MRs) reduces the high circulating levels of tumor necrosis factor (TNF)-alpha in heart failure (HF) rats. TNF-alpha and other proinflammatory cytokines activate neurons in the paraventricular nucleus (PVN) of hypothalamus, including corticotropin-releasing hormone (CRH) neurons, by inducing cyclooxygenase (COX)-2 activity and synthesis of prostaglandin E2 by perivascular cells of the cerebral vasculature. We tested the hypothesis that systemic treatment with a MR antagonist would reduce hypothalamic COX-2 expression and PVN neuronal activation in HF rats. Rats underwent coronary ligation to induce HF, confirmed by echocardiography, or sham surgery, followed by 6 weeks treatment with eplerenone (30 mg/kg per day, orally) or vehicle (drinking water). Eplerenone-treated HF rats had lower plasma TNF-alpha, interleukin (IL)-1beta and IL-6, less COX-2 staining of small blood vessels penetrating PVN, fewer PVN neurons expressing Fra-like activity (indicating chronic neuronal activation), and fewer PVN neurons staining for TNF-alpha, IL-1beta, and CRH than vehicle-treated HF rats. COX-2 and CRH protein expression in hypothalamus were 1.7- and 1.9-fold higher, respectively, in HF+vehicle versus sham+vehicle rats; these increases were attenuated (26% and 25%, respectively) in HF+eplerenone rats. Eplerenone-treated HF rats had less prostaglandin E2 in cerebrospinal fluid, lower plasma norepinephrine levels, lower left ventricular end-diastolic pressure, and lower right ventricle/body weight and lung/body weight ratios, but no improvement in left ventricular function. Treatment of HF rats with anticytokine agents, etanercept or pentoxifylline, produced very similar results. This study reveals a previously unrecognized effect of MR antagonism to minimize cytokine-induced central neural excitation in rats with HF.

Effect of ω-3 fatty acid-containing phospholipids on blood catecholamine concentrations in healthy volunteers: a randomized, placebo-controlled, double-blind trial

Objective We previously reported that administration of fish oil rich in docosahexaenoic acid (DHA) increased the plasma ratio of epinephrine to norepinephrine (NE) at rest in young adults who were under chronic stress and that this effect was achieved mainly through depression of NE. However, not many reports have documented the effects of eicosapentaenoic acid (EPA) and DHA on blood catecholamine levels in healthy humans. Therefore, we performed another intervention study to test their effect on catecholamines with healthy subjects under no chronic stress. Methods Twenty-one healthy young adults (15 men and 6 women) were randomly assigned to an ω-3 group ( n = 9) or a control group ( n = 12) in a double-blind manner. Twenty capsules of shellfish-derived lipids containing 762 mg of EPA plus DHA per day were administered to the ω-3 group for 2 mo. The controls took the same amount of placebo capsules. Fasting blood samples after a 30-min rest with a catheter in a forearm vein were obtained at the start and the end of the study for catecholamine measurements. Results EPA but not DHA concentrations in red blood cells significantly increased in the ω-3 group compared with the control group ( P < 0.001). Plasma NE concentrations were significantly decreased in the ω-3 group (from 1.49 ± 0.39 nmol/L to 1.05 ± 0.14 nmol/L) compared with the control group (from 1.12 ± 0.24 nmol/L to 1.39 ± 0.32 nmol/L) with analysis of covariance ( P < 0.001). The differences remained significant ( P = 0.01) even after deletion of three subjects in the ω-3 group who had the highest baseline NE values and one in the control group who had the lowest baseline NE value to nullify a significant baseline differences in NE between groups. Conclusion This study demonstrated that EPA plus DHA supplementation lowered plasma NE concentrations in normal volunteers even at the small dose of 762 mg of EPA plus DHA per day. This effect of EPA plus DHA to lower plasma NE concentrations may be important to understand some of the effects of fish oils on diseases.

Nerve Growth Factor-Tyrosine Kinase A Pathway Is Involved in Thermoregulation and Adaptation to Stress: Studies on Patients with Hereditary Sensory and Autonomic Neuropathy Type IV

Hereditary sensory and autonomic neuropathy type IV (HSAN IV) is caused by mutations in the tyrosin kinase A (TrkA) gene, encoding for the high-affinity receptor of nerve growth factor (NGF). The NGF-TrkA system is expressed in many endocrine glands. We hypothesized that HSAN IV represents a natural model for impaired NGF effect on the neuroendocrine system in humans. We have documented the clinical outcome of 31 HSAN IV patients in a single medical center, and investigated their basal endocrine system status. The endocrine system response to thirst was compared between six patients and six healthy children. High rates of mortality (22%) and severe morbidity (30%) have been found in HSAN IV patients. Hypothermia was noted in 40% of the patients and unexplained fever was observed in 56%. Subnormal adrenal function was demonstrated in six (30%) of the patients studied. Furthermore, we found lower plasma norepinephrine (NE) levels in six HSAN IV patients compared with a control group after the thirst test. Our findings emphasize the importance of NGF-TrkA pathway in the physiology of the neuroendocrine system and its response to stress. Inadequate response to stress might contribute to the observed significant mortality, morbidity, and temperature instability in HSAN IV patients.

Clinical pharmacokinetics of the norepinephrine precursor L-threo-DOPS in primary chronic autonomic failure

Oral L-threo-3,4-dihydroxyphenylserine (L-DOPS), a synthetic catechol amino acid, increases standing blood pressure and improves standing ability in patients with neurogenic orthostatic hypotension, by conversion of L-DOPS to norepinephrine (NE) outside the brain. This study assessed the pharmacokinetics of L-DOPS, NE, and dihydroxyphenylglycol (DHPG), the main neuronal metabolite of NE, in patients with primary chronic autonomic failure from pure autonomic failure (PAF) or multiple system atrophy (MSA). In 5 MSA and 4 PAF patients, antecubital venous blood was drawn during supine rest and plasma levels of catechols measured at various times for 48 hours after a single oral dose of 400 mg of L-DOPS. Plasma L-DOPS peaked at 1.9 microg/ml (9 micromol/L) about 3 hours after drug administration, followed by a monoexponential decline with a half-time of 2-3 hours in both patient groups. Plasma NE and DHPG also peaked at about 3 hours, but at much lower concentrations (4 and 42 nmol/L). Compared to the MSA group, the PAF group had a smaller calculated volume of distribution of L-DOPS and up to 10-fold lower plasma NE levels at all time points. Plasma NE was above baseline in MSA even at 48 hours after L-DOPS. The relatively long half-time for disappearance of L-DOPS compared to that of NE explains their very different attained plasma concentrations. The similar NE and DHPG responses in PAF and MSA suggests production of NE from LDOPS mainly in non-neuronal cells. Persistent elevation of plasma NE in MSA suggests residual release of NE from sympathetic nerves.