Higher Epinephrine Levels Research Articles

12394 "Sugar And Tumors: A Case Report On New-onset Diabetes In Metastatic Pheochromocytoma With Elevated Dopamine Levels"

Abstract Disclosure: B. Agrawal: None. V. mehta: None. R. naseem: None. M. Renzu: None. R. rashid: None. Introduction: Metastatic pheochromocytoma is a rare neuroendocrine tumor with potential complication of new-onset diabetes mellitus (DM). We present a case highlighting the challenges in managing a patient with metastatic pheochromocytoma and concurrent DM. Case presentation: A 66-year-old male with a history of hypertension and gout initially presented in 2010 with an adrenal mass, later identified as pheochromocytoma and resected. In 2018, he presented with bilateral leg pain, revealing metastatic disease-causing spinal cord compression along with metastatic lung nodules and metastasis in adrenalectomy bed. Despite interventions including T6,7,8 laminectomy in 2020 and radiation therapy, metastases persisted. In 2024, he presented with polyuria, polydipsia, and hyperglycemia (blood glucose >500 mg/dL). Laboratory findings showed elevated a1c of 15 in addition to elevated normetanephrines, metanephrines, and dopamine with levels of 3880, 48 and 488 respectively. He was diagnosed with new-onset DM and started on insulin therapy in addition to metformin and jardiance. Discussion: Secondary diabetes mellitus (DM) in secretory pheochromocytoma occurs in approximately 50% of cases, manifesting from mild insulin resistance to severe presentation like DKA. Epinephrine-secreting tumors contribute to glucose intolerance by activating beta receptors, thereby stimulating gluconeogenesis. Patients with higher levels of epinephrine and preoperative glucose intolerance were more prone to developing postoperative hypoglycemia, requiring close monitoring during the postoperative period. Additionally, research by DiSalvo et al. Epinephrine-secreting tumors have a more significant impact on hyperglycemia by impairing insulin secretion and stimulation GLP-1. Tumor resection has been found to be more effective effective in restoring normal glucose homeostasis in these patients. Dopamine-secreting pheochromocytomas are rare neoplasms characterized by the presence of immature catecholamine vesicles that inhibit dopamine conversio owing to localized dopamine beta hydroxylase. Typically presenting around the age of 48, these tumors often lack excess catecholamines, leading to atypical symptoms such as local discomfort or pain from tumor compression. These neoplasms are less detectable on metaiodobenzylguanidine (MIBG) scans, necessitating positron emission tomography (PET) for accurate diagnosis. Surgical resection is the treatment, with preoperative management involving metyrosine instead of alpha blockers. These tumors are frequently diagnosed late, often in a malignant stage, contributing to poor prognosis Conclusion: Overall, understanding the complex interplay between catecholamines and glucose metabolism is crucial for the comprehensive management of patients with pheochromocytoma and secondary DM. Presentation: 6/1/2024

Chromogranin A Deficiency Attenuates Tauopathy by Altering Epinephrine-Alpha-Adrenergic Receptor Signaling.

Metabolic disorders such as insulin resistance and hypertension are potential risk factors for aging and neurodegenerative diseases. These conditions are reversed in Chromogranin A knockout (CgA-KO) mice. This study investigates the role of CgA in Alzheimer's disease (AD) and corticobasal degeneration (CBD). CgA ablation in tauopathy mice (hTau) (CgA-KO/hTau) exhibited reduced tau aggregation, spreading, extended lifespan, and improved cognitive function. Transcriptomic and metabolite analysis of mouse cortices revealed altered alpha1-adrenergic receptors (Adra1) and high epinephrine (EPI) levels in hTau mice compared to WT mice, mirroring observations in AD and CBD patients. CgA-KO/hTau mice exhibited a reversal of EPI levels in the cortex and the expression of Adra1, nearly returning them to WT levels. Treatment of hippocampal slices with EPI or Adra1 agonist intensified, while an Adra1 antagonist inhibited tau hyperphosphorylation and aggregation. These findings highlight the interplay between the EPI-Adra signaling system and CgA in tauopathy.

Stress system dysfunction and changes in brain volume and functional connectivity in older adults with subclinical depressive symptoms

AbstractBackgroundSubclinical depressive symptoms are associated with increased risk of Alzheimer’s disease (AD). This link could be related to stress system dysfunction, known to occur in both depression and AD, and to depend notably on the hippocampus which is particularly sensitive to AD. We aimed at investigating the links between levels of blood stress markers and changes in brain regions involved in the stress response in older adults with subclinical depressive symptoms.MethodCognitively unimpaired older adults with (DepS; n = 73) or without (NoDepS; n = 58) subclinical depressive symptoms (defined using the 15‐item version of the Geriatric Depression Scale), from the baseline data of the Age‐Well trial (NCT02977819) were included. For each participant, levels of cortisol, epinephrine and norepinephrine were obtained from blood sampling. Moreover, the functional connectivity (FC) between, and the gray matter (GM) volume of, the hypothalamus, hippocampus and hippocampal subfields were extracted from resting‐state functional, and structural T1‐weighted, MRI. Levels of blood stress markers and neuroimaging measures were compared between groups. Regression analyses were then conducted between levels of blood markers and brain measures. Analyses were corrected for age, sex, education and anxiety symptoms with statistical significance set to p<0.05.ResultHigher blood epinephrine level (p<0.024), and FC between the hypothalamus and the CA1 hippocampal subfield (p<0.040), was found in DepS compared to NoDepS (Fig.1). This higher epinephrine level was associated with greater FC between the hypothalamus and the CA1 (p<0.007) and Subiculum (p<0.013) subfields (Fig.2). Lower GM volume in the CA1 (p<0.008) and DG/CA2‐3‐4 (p<0.013) subfields was also found in the DepS group (Fig.3), but was not associated with epinephrine level. No significant between‐group difference in blood cortisol and norepinephrine levels was observed.ConclusionSubclinical depressive symptoms in aging are associated with higher blood epinephrine level related to greater FC between the hypothalamus and hippocampal subfields (CA1 and Subiculum) – suggesting an increased sympathetic nervous system activity. They are also associated with GM atrophy in specific hippocampal subfields, including the CA1 that is sensitive to AD. These two distinct mechanisms at this preclinical stage of depression may at least partly explain that depression is a risk factor for AD.

Influence of Chronic Fatigue Syndrome Codiagnosis on the Relationship between Perceived and Objective Psychoneuro-Immunoendocrine Disorders in Women with Fibromyalgia.

Although the predominant symptom in fibromyalgia (FM) is muscle pain, and fatigue in chronic fatigue syndrome (CFS), differential diagnosis is very difficult. This research investigates the psychoneuroimmunoendocrine disorders of FM patients and ascertains whether a previous CFS diagnosis affected them. Through accelerometry objective parameters, physical activity/sedentarism levels in relation to fatigue are studied, as well as whether perceived levels of stress, anxiety, and pain correspond to objective biomarkers, all of these with respect to a reference group (RG) of women without FM. FM patients have a worse psychological state and perceived quality of life than those with RG. These perceived outcomes are consistent with impaired objective levels of a sedentary lifestyle, higher systemic levels of cortisol and noradrenaline, and lower levels of serotonin. However, FM patients with a previous CFS diagnosis had lower systemic levels of IL-8, cortisol, oxytocin, and higher levels of adrenaline and serotonin than FM patients without diagnosed CFS. In conclusion, while perceived health parameters do not detect differences, when objective neuroimmunoendocrine parameters related to stress, inflammation, pain, and fatigue are used, people with CFS could be overdiagnosed with FM. This reinforces the need for objective biomarker assessment of these patients for better diagnostic discrimination between both syndromes.

Repeated stress-induced crosstalk between the sympathetic nervous system and mast cells contributes to delayed cutaneous wound healing in mice

The study identifies a link between the neuroimmune interaction and the impairment of wound healing induced by repeated stress. Stress increased mast cell mobilization and degranulation, levels of IL-10, and sympathetic reinnervation in mouse wounds. In contrast to mast cells, macrophage infiltration into wounds was significantly delayed in stressed mice. Chemical sympathectomy and the blockade of mast cell degranulation reversed the effect of stress on skin wound healing in vivo. In vitro, high epinephrine levels stimulated mast cell degranulation and IL-10 release. In conclusion, catecholamines released by the sympathetic nervous system stimulate mast cells to secrete anti-inflammatory cytokines that impair inflammatory cell mobilization, leading to a delay in the resolution of wound healing under stress conditions.

Chronic psychological stress aggravates psoriasis-like skin inflammation via overactivation of β2-adrenoceptor and nuclear factor kappa B pathways.

The relationship between psoriasis severity and psychological stress has been described in several studies. However, the mechanism by which chronic stress exacerbates psoriasis is not completely understood. This study aimed at investigating whether chronic psychological stress can aggravate psoriasis-like skin inflammation. Mice were subjected to a restraint stress model and topically treated with imiquimod (IMQ). Differentiated human keratinocytes were treated with high epinephrine levels and IMQ in vitro. Stress aggravated macroscopic features and the increase in epidermal thickness induced by IMQ in mouse skin. The increase in NF-κB and IL-17A expression induced by IMQ was potentiated by chronic stress in mouse skin. The skin of stressed mice treated with IMQ showed higher levels of β2-adrenergic receptors (β2-AR). In human keratinocytes, high epinephrine levels exacerbated the increase in the levels of β2-AR and IL-17A induced by IMQ. β-AR antagonist reversed the effects of chronic stress in IMQ-induced inflammation both in vivo and in vitro. In conclusion, stress-stimulated overactivation of the β2-AR and NF-κB pathways potentiates a Th1/Th17 profile leading to an exacerbation of psoriasis.

Maternal anxiety affects embryo implantation via impairing adrenergic receptor signaling in decidual cells

Recurrent implantation failure (RIF) is defined as the failed pregnancy after good embryo transfer over 3 cycles during in vitro fertilization (IVF).The human endometrium plays a vital role in providing the site for embryo implantation, with several factors implicated in unsatisfactory endometrial receptivity in RIF. Our present results revealed that women with pregnancy loss or infertility have a higher serum epinephrine level, indicating a potential correlation between psychological stress and pregnancy failure. RNA-sequencing of the tissues collected at the endometrial receptive phase in normal and RIF women showed that stress hormones could affect the functional status of endometrial receptivity. Subsequent analysis revealed that the epinephrine signaling acts as an important regulator of endometrial receptivity through the PI3K-AKT and FOXO1 signaling pathways. We also found that patients with RIF show attenuated expression of the alpha-2C-adrenergic receptor (ADRA2C) and that its down regulation induced by high level epinephrine could inhibit the decidualization. Early pregnant mice treated with stress showed high serum epinephrine levels, defective uterine adrenergic receptor expression, and low pregnancy rates. Altogether, our findings indicate that mental stress during early pregnancy can alter the functional status of endometrial receptivity.

DIVE, SURVIVE OR THRIVE: A Prescription for Post-Traumatic Thriving

Medical problems and procedures, along with a host of other issues, can be traumatizing. The fallout for post-traumatic effects can linger for decades. In any traumatic episode, the body switches off the parasympathetic (rest and digest) nervous system while turning on the sympathetic (fight-flight-freeze) system. In this mode, the body pumps high levels of adrenaline through the bloodstream. This is a basic survival instinct based on the need to escape the trauma and get to safety. Trauma causes a well-researched chain reaction. It shifts the brain activity from the outer "human brain" to the inner "reptilian brain" that governs instincts. This can result in a blurred and distorted mental state, so when the trauma ends, many patients remain stuck in the sympathetic nervous state. It is somewhat like a car at full throttle while parked in neutral. The human body is not designed to have a continual flow of high adrenaline levels flowing through the bloodstream. Yet, this is precisely what unresolved trauma does. This state of perpetual trauma hurts, so many self-medicate with any of the many harmful activities designed to dull the pain. Of course, self-medication only deadens the hurt but does nothing for the underlying unresolved trauma. Health care professionals have their specialties, yet all should be versed in the fundamental steps patients can take to flip the parasympathetic nervous system back on. Two of the most effective techniques are "grounding" and "sitting in the fire." They are simple practices, can cost nothing, and get right to the heart of healing the unresolved trauma. When included in the overall prescription, both physical and emotional healing can occur.

MON-LB035 Adrenal Venous Sampling in the Lateralization of Acth-Independent Cushing Syndrome With Bilateral Adrenal Masses: A Case With a 5-Year Follow-Up

Background Nearly 25% of adrenal Cushing syndrome (CS) patients with bilateral adrenal masses have unilateral hypercortisolism, making localization crucial for surgical planning. Since there is no standardized protocol for adrenal venous sampling (AVS) in lateralizing adrenal hypercortisolism, we share our experience with a case of CS with bilateral adrenal masses in which lateralization via AVS permitted unilateral adrenalectomy. Clinical Case A 59-year-old woman with hypertension, hyperlipidemia, and prediabetes was hospitalized for worsening back pain and hypertension. Her BMI was 26.5 kg/m2, BP 173/93 mmHg, HR 73/min, she was anxious, diaphoretic, and hirsute. Glucose was 118 mg/dL and HbA1c 6.6%. Abdominal computed tomography revealed a type B aortic dissection with both right (6.1 x 3.1cm and 3.6 x 2.4cm), and left (largest 1.7 cm) sided adrenal masses. Plasma and 24 hour-urine metanephrine, normetanephrine and catecholamines, as well as plasma renin and aldosterone levels, were normal. AM cortisol on three different occasions was 21.30, 20.70, and 21.30 mcg/dL. Midnight cortisol was 17.8 mcg/dL, and 24-hour urine free cortisol on two occasions was 163 mcg (urine volume 3.4L with creatinine 1.14) and 99.2 mcg (urine volume 1.15L). After 1mg dexamethasone her AM ACTH and cortisol were <5 and 18.70 mcg/dL, respectively. Preoperative AVS was performed and 8mg of dexamethasone was administered the night prior to ensure ACTH suppression during the procedure, and epinephrine was measured to ascertain adequate adrenal vein cannulation. Cortisol levels (in mcg/dL) from the common iliac, right and left adrenal veins were 14.7, 61.5, and 23.5 at 0 minute and 15.2, 61.0, and 22.7 at 2 minutes, respectively. Epinephrine levels (in pg/dL) from the common iliac, right and left adrenal veins were 42, 577, and 3225 at 0 minutes, and 46, 718, and 2989 at 2 minutes. Despite higher epinephrine levels from the left adrenal, the cortisol ratio of the right adrenal vein to peripheral vein was 4.18 with the right-to-left ratio of 2.59 and 2.68 at 0 and 2 minutes, suggesting hypersecretion of cortisol from the right adrenal gland. Unilateral right adrenalectomy revealed a 5.6 cm adrenal adenoma arising in a background of adrenal cortical hyperplasia. Morning postoperative cortisol was 2.2 mcg/dL. She was placed on hydrocortisone and tapered over a 10-month period with remission maintained for more than 3.5 years post-operatively. Conclusion This case demonstrates the safety, usefulness, and necessity, of AVS in localizing cortisol production when bilateral adrenal masses are present. In addition, this case suggests that the use of high dose dexamethasone and measurement of catecholamines may be helpful for more accurate interpretation. More data on AVS in CS patients with bilateral adrenal masses is needed so a well-validated and standardized CS-specific ACS protocol can be developed.

Fatal \u03b1-PVP and amphetamine poisoning during a sauna and autoerotic practices

We describe the sudden death of a middle-aged man while having a sauna under the influence of α-pyrrolidinovalerophenone (α-PVP) (PM blood concentration: 0.8 mg/L), amphetamine (0.34 mg/L), and other drugs (buprenorphine, benzodiazepines), and engaging in solitary sexual activities. The drugs’ effects on the cardio-circulatory system and on body thermoregulation combined with the high temperatures are likely to have been central mechanisms leading to death. The high levels of adrenaline triggered by sexual arousal and the respiratory depression caused by buprenorphine, in association with benzodiazepines, may have also contributed to his death. This previously unreported type of accidental autoerotic death illustrates the risk of using amphetamine-like sympathomimetic drugs (e.g. cathinone derivates) in hot environments such as a sauna, and during sexual activities therein.

Plasma epinephrine as a prognostic marker in traumatic brain injury

Background Traumatic brain injury is an international health problem with high morbidity and mortality. It is associated with catecholamine release (catecholamine surge).Objective The purpose of the work was to study plasma epinephrine as a prognostic marker in traumatic brain injury.Patients and methods The authors enrolled 60 adult persons of both sexes [30 patients with diagnosis of isolated traumatic brain injury with Glasgow coma score (GCS) ≤11 and 30 volunteers as a control group]. Plasma epinephrine levels were measured on admission and after 24 h. Then the patients were classified into two groups at the end of the study (3 months) according to the GOS: group I (favorable outcome; GOS IV, V) which included 11 (36.6%) patients and group II (unfavorable outcome; GOS I, II, III) which included 19 (63.3%) patients.Results Receiver operating characteristic curves were used to describe the prognostic value of plasma epinephrine on admission and after 24 h to predict unfavorable outcome and mortality. Higher levels of epinephrine on admission were associated with a higher rate of unfavorable outcome [areas under the curve (AUC)=0.921, confidence interval (CI): 0.828–1.014, P<0.001] and mortality (AUC=0.855, CI: 0.707–1.003, P=0.003). Also, higher levels of epinephrine after 24 h were associated with a higher rate of unfavorable outcome (AUC=0.971, CI: 0.912–1.030, P<0.001) and mortality (AUC=0.884, CI: 0.752–1.02, P=0.002).Conclusion Plasma epinephrine could be used as a prognostic marker in traumatic brain injury.

Olive oil inhibits ageing signs induced by chronic stress in exvivo human skin via inhibition of extracellular-signal-related kinase 1/2 and c-JUN pathways.

Chronic stress-induced oxidative damage and protease synthesis cause a loss of extracellular matrix components promoting human skin ageing. The administration of antioxidant compounds, such as those observed in olive oil, may attenuate stress-induced ageing signs in human skin. Thus, the aim of this study was to investigate the effect of olive oil administration in exvivo stressed human skin. Explants of human skin were treated with high levels of epinephrine (as observed in stressed patients) and olive oil in medium for 13days. Cultures treated with medium alone were used as controls. Olive oil reversed the high epinephrine level-induced reduction in epidermis and dermis thickness and collagen fibre content in exvivo human skin. The increase in the production of reactive oxygen species (ROS) and malondialdehyde levels (an index of lipid peroxidation) promoted by high levels of epinephrine were also attenuated by olive oil in exvivo human skin. Moreover, olive oil was able to reverse the high epinephrine level-induced increase in extracellular signal-related kinase 1/2 (ERK 1/2) and c-JUN (a major component of transcription factor AP-1) phosphorylation and protein matrix metalloproteinase-2 (MMP-2) expression in exvivo human skin. Olive oil attenuates stress-induced ageing signs (thinner dermis and collagen fibre loss) in exvivo human skin by reducing MMP-2 expression, ROS production, and ERK 1/2 and c-JUN phosphorylation.

Photopic light-mediated down-regulation of local \u03b11A-adrenergic signaling protects blood-retina barrier in experimental autoimmune uveoretinitis

We have reported the gateway reflex, which describes specific neural activations that regulate immune cell gateways at specific blood vessels in the central nervous system (CNS). Four types of gateway reflexes exist, all of which induce alterations in endothelial cells at specific vessels of the blood-brain barrier followed by inflammation in the CNS in the presence of CNS-autoreactive T cells. Here we report a new gateway reflex that suppresses the development of retinal inflammation by using an autoreactive T cell-mediated ocular inflammation model. Exposure to photopic light down-regulated the adrenoceptor pathway to attenuate ocular inflammation by suppressing breaching of the blood-retina barrier. Mechanistic analysis showed that exposure to photopic light down-regulates the expression of α1A-adrenoceptor (α1AAR) due to high levels of norepinephrine and epinephrine, subsequently suppressing inflammation. Surgical ablation of the superior cervical ganglion (SCG) did not negate the protective effect of photopic light, suggesting the involvement of retinal noradrenergic neurons rather than sympathetic neurons from the SCG. Blockade of α1AAR signaling under mesopic light recapitulated the protective effect of photopic light. Thus, targeting regional adrenoceptor signaling might represent a novel therapeutic strategy for autoimmune diseases including those that affect organs separated by barriers such as the CNS and eyes.

Olive oil reduces chronic psychological stress-induced skin aging in mice through the NF-κB and NRF2 pathways

Abstract The aim of this study was to investigate whether oral administration of olive oil could attenuate chronic stress-induced signs of aging in mouse skin. The mice were subjected to daily rotational stress and treated with olive oil until the time of euthanasia (28 days). Murine dermal fibroblast cultures were exposed to increased epinephrine levels plus olive oil. Olive oil reduced catecholamine synthesis in the stressed mice. Moreover, olive oil inhibited stress-mediated increases in reactive oxygen species production, lipid peroxidation and protein carbonylation in mouse skin. Olive oil also inhibited stress-induced increases in matrix metalloproteinase-8 protein expression and collagen deposition in mouse skin. Additionally, olive oil reduced nuclear factor kappa B protein expression in the skin of stressed mice. In cultured dermal fibroblasts, olive oil abolished the increase in reactive oxygen species production and nuclear translocation of activated nuclear factor kappa B induced by high epinephrine levels. In conclusion, olive oil may attenuate stress-induced signs of aging in mouse skin.

EFFECT OF UROKINASE GENE KNOCKOUT ON TISSUE LEVELS OF BIOGENIC AMINES IN MICE WITH MELANOMA

The research aim was to study the dynamics of biogenic amines in the brain, tumor and intact skin of urokinase (uPA) gene knockout mice on day 21 of the B16/F10 melanoma growth. Material and methods. The study included male and female uPA gene knockout (-uPA, n = 38) and wild type mice (+uPA, n = 61). Melanoma was transplanted subcutaneously. Levels of biogenic amines were studied by ELISA in tissues obtained on day 21 of carcinogenesis. Results and discussion . Intact (-uPA) mice showed an increased total content of biogenic amines: in the skin - due to noradrenaline increase by 4.8 times in males and by 4.9 times in females, histamine - by 3.6 times in males and by 1.6 times (p < 0.05) in females, serotonin - by 3.4 times in males and by 8.3 times in females; in the brain - due to noradrenaline increase by 3.5 times in males and by 3.2 times in females, dopamine by 2.1 times in males and by 2.9 times in females, while histamine content decreased. Melanoma development in (-uPA) mice was characterized by: lower levels of adrenaline with high NA concentrations and an increase in the serotonin metabolism in the brain; higher histamine concentrations in the tumor and higher serotonin levels in the skin; similar to (+uPA) mice levels of adrenaline (males) and noradrenaline in the tumor and higher levels of adrenaline in the tumor and histamine in the skin in (-uPA) females. Conclusions. The uPA gene knockout limits the development of stress at the central regulatory level due to lower levels of A together with increasing serotoninergic mediation in the brain, as well as modulates the immune antitumor response due to higher levels of histamine in the tumor and 5 serotonin in the skin, as a result of lower monoamine oxidase activity, in mice with B16/F10 melanoma.

Topical retinol attenuates stress-induced ageing signs in human skin ex vivo, throughEGFR activation viaEGF, but notERK andAP-1 activation.

Stress-induced oxidative damage and the inflammatory response lead to degradation of collagen and elastic fibres and wrinkle formation. Topical retinol (or vitamin A) can be a strategy to attenuate the effects of stress in skin as it promotes collagen and elastic fibre production and reduces protease synthesis. This study investigated the effect of topical retinol in stressed human skin using in vitro and ex vivo models. Human skin explants were treated with high levels of epinephrine (as observed in stressed patients) and topically with retinol for 13days. Human dermal fibroblasts were treated with conditioned medium of ex vivo retinol-treated and non-stressed (without epinephrine) human skin for 24hours. In ex vivo human skin, retinol reversed the epinephrine-induced reduction in epidermal proliferation and differentiation, normalizing epidermal thickness. Retinol also inhibited the epinephrine-induced reduction in elastic fibre deposition and organization, restoring dermal thickness. In addition, retinol reversed the epinephrine-induced increase in c-JUN protein expression, but it did not alter extracellular signal-regulated kinase 1/2 (ERK) phosphorylation in ex vivo human skin. Conditioned medium of ex vivo retinol-treated and non-stressed human skin presented an increased protein expression of epidermal growth factor (EGF). In human dermal fibroblasts, conditioned medium of ex vivo retinol-treated and non-stressed human skin increased protein and gene expression of fibrillin-1 and protein expression of EGF receptor (EGFR). In conclusion, topical retinol attenuates stress-induced skin ageing signs in human skin ex vivo, probably through EGFR activation via EGF, but not by the stress-activated ERK 1/2 and c-JUN pathways.

Effects of epinephrine exposure on contractile performance of compact and spongy myocardium from rainbow trout (Oncorhynchus mykiss) during hypoxia

Hypoxia results in elevated circulating epinephrine for many fish species, and this is likely important for maintaining cardiac function. The aims of this study were to assess how hypoxia impacts contractile responses of ventricular compact and spongy myocardium from rainbow trout (Oncorhynchus mykiss) and to assess how and if epinephrine may protect myocardial performance from a depressive effect of hypoxia. Work output and maximum contraction rate of isolated preparations of spongy and compact ventricular myocardium from rainbow trout were measured. Tissues were exposed to the blood PO2 that they experience in vivo during environmental normoxia and hypoxia and also to low (5nM) and high (500nM) levels of epinephrine in 100% air saturation (PO2 20.2kPa) and during hypoxia (PO2 2kPa, 10% air saturation). It was hypothesized that hypoxia would result in a decrease in work output and maximum contraction rate in both tissue types, but that epinephrine exposure would mitigate the effect. Hypoxia resulted in a decline in net work output of both tissue types, but a decline in maximum contraction rate of only compact myocardium. Epinephrine restored the maximum contraction rate of compact myocardium in hypoxia, appeared to slightly enhance work output of only compact myocardium in air saturation but surprisingly not during hypoxia, and restored net work of hypoxic spongy myocardium toward normoxic levels. These results indicate hypoxia has a similar depressive effect on both layers of ventricular myocardium, but that high epinephrine may be important for maintaining inotropy in spongy myocardium and chronotropy in compact myocardium during hypoxia.

Heat stress-induced neuroinflammation and aberration in monoamine levels in hypothalamus are associated with temperature dysregulation

Heat Stress (HS) induces diverse pathophysiological changes, which include brain ischemia, oxidative stress and neuronal damage. The present study was undertaken with the objective to ascertain whether neuroinflammation in Hypothalamus (HTH) caused under HS affects monoamine levels and hence, its physiological role in thermoregulation. Rats were exposed to HS in a heat simulation environmental chamber (Ambient temperature, Ta=45±0.5°C and Relative Humidity, RH=30±10%) with real-time measurement of core temperature (Tc) and skin temperature (Ts). Animals were divided into two subgroups: Moderate HS (MHS) (Tc=40°C) and Severe HS (SHS)/Heat stroke (Tc=42°C). Rats with MHS showed an increase in Mean Arterial Pressure (MAP) and Heart Rate (HR) while fall in MAP and rise in HR was observed in rats with SHS. In addition, oxidative stress and an increase in pyknotic neurons were observed in HTH. High levels of Adrenocorticotropic-hormone (ACTH), Epinephrine (EPI), Norepinephrine (NE) and Dopamine (DA) in the systemic circulation and progressive increase in EPI and DA levels in HTH were recorded after the thermal insult. Moreover, a substantial increase in Glutamate (Glu) level was observed in HTH as well as in systemic circulation of heat stroke rats. We found a rise in NE whereas a fall in Serotonin (5-HT) level in HTH at MHS, without perturbing inflammatory mediators. However, rats with SHS exhibited significant elevations in NF-kB, IL-1β, COX2, GFAP and Iba1 protein expression in HTH. In conclusion, the data suggest that SHS induces neuroinflammation in HTH, which is associated with monoamines and Glu imbalances, leading to thermoregulatory disruption.

Enhanced activity of hormone sensitive lipase (HSL) in mesenteric but not epididymal fat correlates with higher production of epinephrine in mesenteric adipocytes in rat model of cachectic rheumatoid arthritis

Cachectic rheumatoid arthritis, the less frequent form of the disease, is associated with loss of fat mass and often more severe course of the disease. Its experimental model represents rat adjuvant arthritis (AA) characterized by edema, lack of appetite, sharp body weight and fat loss. As individual fat depots display functional differences, here we studied lipolytic activity and sensitivity to lipolytic stimuli of nodeless epididymal fat (eWAT) and perinodal mesenteric fat (mWAT) depots at the peak of AA. We also examined changes in catecholamine and cytokine levels involved in lipolysis in plasma and/or isolated adipocytes from both WATs to identify the contribution of local, adipocyte-based processes and/or systemic events to adiposity loss in cachectic rheumatoid arthritis. AA was induced to male Lewis rats by complete Freund’s adjuvant. Groups of ad libitum-fed and pair-fed controls were used to distinguish the effects of food restriction from inflammation-induced cachexia. Adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL) and its phosphorylated form (pHSL) were analyzed by western blot. CRP and catecholamine levels in plasma or adipocyte lysates were determined using ELISA kits. Cytokine-induced neutrophil chemoattractant-1 (CINC-1/CXCL1), monocyte chemoattractant protein-1 (MCP-1/CCL2), IL-1β, IL-6, IL-10 and leptin in adipocyte lysate were analyzed by quantitative protein microarray. Plasma glycerol and FFA were measured spectrophotometrically. AA rats developed severe cachexia, with lower adiposity in mWAT compared to normal and pair-fed controls, whereas in eWAT the adiposity was similarly reduced in AA and pair-fed groups. ATGL levels in both WATs were not affected by AA or pair feeding. AA upregulated levels of HSL, pHSL and pHSL/HSL ratio in mWAT, whereas none of these parameters has changed in eWAT of AA rats or in either WATs of pair-fed rats. In AA rats plasma glycerol was elevated, whereas FFA concentration was reduced. Plasma norepinephrine and epinephrine were increased in AA compared with both groups of controls. In eWAT adipocytes, AA but not pair feeding, upregulated norepinephrine levels. In mWAT adipocytes, AA rats showed higher epinephrine levels than pair-fed controls. Leptin levels in both WATs were depleted in AA animals in accordance with body weight loss. None of the measured cytokines in eWAT and mWAT was enhanced. Our results demonstrate augmented lipolytic activity in mWAT and not eWAT during cachectic arthritis. The adipocyte-derived cytokines do not seem to contribute to activated lipolysis. We first demonstrated enhanced presence of norepinephrine in perinodal adipocytes that may contribute to the regulation of local lipolytic activity by auto/paracrine fashion and thus provide independent fuel supply to activated lymph nodes.

The Association Between Air Pollution And Stress Hormones: Evidence From The Multi-Ethnic Study Of Atherosclerosis

Introduction: Autonomic nervous system effects have been hypothesized as a mechanism of air pollutant health effects, though scant prior epidemiologic research has examined the association between air pollutants and catecholamines. Methods: We examined the association between air pollutants and urinary catecholamines in the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study with participants from six US areas. Data from two ancillary studies, the MESA Air Study and the MESA Stress Study, provide exposure and outcome data. Dopamine (DA), epinephrine (EPI), norepinephrine (NE) data were collected from 2004 – 2006 from 1002 white, black and Hispanic participants from the New York and Los Angeles study sites. Urinary analyte concentrations were adjusted for creatinine and log-transformed for analysis. Spatio-temporal models incorporated cohort-specific monitoring and modeled estimated annual average pollutant concentrations (PM2.5 and NOx) at participant's homes the year prior to urine collection. Several covariates were considered confounders: age, race, sex, site, socioeconomic status, cardiovascular disease risk factors (smoking, second hand smoke, BMI, alcohol use and hypertension) and psychosocial stressors (depression, social support, anxiety, anger and chronic stress) and linear regression models were employed. Results: Preliminary models show a 40 ppb higher NOx concentration was associated with 10% higher NE (95% confidence interval (CI): 4%, 20%) and 17% higher EPI level (95% CI: 3%, 33%). A 5 µg/m3 higher PM2.5 concentration was associated with 23% higher EPI (95% CI: 8%, 41%) and 14% higher DA level (95% CI: 5%, 23%). Conclusions: We found a cross-sectional association between several urinary catecholamines and long-term residential concentrations of PM2.5 and NOx. These novel finding support the hypothesis that air pollutant exposures are related to sympathetic nervous system activation; however, additional investigation is warranted.