Urinary Norepinephrine Levels Research Articles

Effects of dopamine β-hydroxylase inhibition in pressure overload-induced right ventricular failure.

Activation of the sympathetic nervous system is observed in pulmonary arterial hypertension patients. This study investigates whether inhibiting the conversion of dopamine into noradrenaline by dopamine β-hydroxylase (DβH) inhibition with BIA 21-5337 improved right ventricular (RV) function or remodeling in pressure overload-induced RV failure. RV failure was induced in male Wistar rats by pulmonary trunk banding (PTB). Two weeks after the procedure, PTB rats were randomized to vehicle (n = 8) or BIA 21-5337 (n = 11) treatment. An additional PTB group treated with ivabradine (n = 11) was included to control for the potential heart rate-reducing effects of BIA 21-5337. A sham group (n = 6) received vehicle treatment. After 5 weeks of treatment, RV function was assessed by echocardiography, magnetic resonance imaging, and invasive pressure-volume measurements before rats were euthanized. RV myocardium was analyzed to evaluate RV remodeling. PTB caused a fourfold increase in RV afterload which led to RV dysfunction, remodeling, and failure. Treatment with BIA 21-5337 reduced adrenal gland DβH activity and 24-h urinary noradrenaline levels confirming relevant physiological response to the treatment. At end-of-study, there were no differences in RV function or RV remodeling between BIA 21-5337 and vehicle-treated rats. In conclusion, treatment with BIA 21-5337 did not have any beneficial-nor adverse-effects on the development of RV failure after PTB despite reduced adrenal gland DβH activity.

A comparative analysis of surgically excised hereditary and sporadic pheochromocytomas: Insights from a single-center experience.

Pheochromocytoma is a tumor that usually originating from adrenal medullary chromaffin cells and producing one or more catecholamines, can manifest as hereditary or sporadic. While the majority pheochromocytomas are sporadic, hereditary forms are often associated with genetic syndromes such as von Hippel-Lindau, multiple endocrine neoplasia type 2, and neurofibromatosis type 1. This study aims to analyze data from our series of surgically excited pheochromocytoma patients and compare the characteristics between hereditary and sporadic cases. We retrospectively evaluated 33 diagnosed pheochromocytoma patients, documenting clinical features, surgical complications, and tumor characteristics in both hereditary and sporadic cases. Among the patients, 21% (7 individuals) had hereditary pheochromocytoma, while 79% (26 individuals) had sporadic cases. During diagnosis, hereditary pheochromocytoma patients exhibited a significantly lower mean age compared to the sporadic group (26.4 ± 9.9 years vs. 50.4 ± 14.0 years; p < 0.001). The maximum tumor size was also lower in hereditary cases compared to sporadic cases (p = 0.004). Adrenal tumor localization analysis showed that 63.6% were right-sided, 24.2% were left-sided, and 12.1% were bilateral. Laboratory analysis revealed significantly higher urinary norepinephrine levels in hereditary pheochromocytoma patients (p = 0.021). Our findings suggest that hereditary pheochromocytoma cases are characterized by a younger age at diagnosis, smaller tumor size, and a higher prevalence of multiple bilateral adrenal adenomas. We recommend genetic testing for all pheochromocytoma patients, particularly those with early-onset disease and bilateral adrenal tumors.

The effects of renal denervation on blood pressure, cardiac hypertrophy, and sympathetic activity during the established phase of hypertension in spontaneously hypertensive rats.

This study aimed to investigate whether renal denervation (RDN) reduces blood pressure and attenuates cardiac hypertrophy with decreasing sympathetic activity in spontaneously hypertensive rats (SHRs), a model of essential hypertension, during the established phase of hypertension. We performed RDN or sham operation in 15-weeks-old SHRs. Thirty days after RDN, mean blood pressure measured by telemetry, heart weight, left ventricular wall thickness assessed by echocardiography, and urinary norepinephrine levels were significantly decreased in the RDN group compared to the Sham group. Furthermore, oxidative stress, as indicated by thiobarbituric acid reactive substances, in the rostral ventrolateral medulla, a pivotal region regulating basal sympathetic tone, was significantly decreased in the RDN group. In conclusion, RDN reduces blood pressure and attenuates cardiac hypertrophy with sympathoinhibition in the established phase of hypertension in SHRs. These findings highlight the sympathoinhibitory effect of RDN and suggest that RDN may be a potential therapy for hypertensive cardiac hypertrophy. Renal denervation reduces blood pressure and attenuates cardiac hypertrophy with sympathoinhibition in the established phase of hypertension in spontaneously hypertensive rats. This study highlights the sympathoinhibitory effect of renal denervation and suggests that renal denervation may be a potential therapy for hypertensive cardiac hypertrophy.

Deteriorated bone microarchitecture caused by sympathetic overstimulation in pheochromocytoma and paraganglioma.

Despite the potentially destructive effect of sympathetic activity on bone metabolism, its impact on bone microarchitecture, a key determinant of bone quality, has not been thoroughly investigated. This study aims to evaluate the impact of sympathetic activity on bone microarchitecture and bone strength in patients with pheochromocytoma and paraganglioma (PPGL). A cross-sectional study was conducted in 38 PPGL patients (15 males and 23 females). Bone turnover markers serum procollagen type 1 N-terminal propeptide (P1NP) and β-carboxy-terminal crosslinked telopeptide of type 1 collagen (β-CTX) were measured. 24-h urinary adrenaline (24hUE) and 24-h urinary norepinephrine levels (24hUNE) were measured to indicate sympathetic activity. High-resolution peripheral quantitative computed tomography (HR-pQCT) was conducted to evaluate bone microarchitecture in PPGL patients and 76 age-, sex-matched healthy controls (30 males and 46 females). Areal bone mineral density (aBMD) was measured by dual-energy X-ray absorptiometry (DXA) simultaneously. PPGL patients had a higher level of β-CTX. HR-pQCT assessment revealed that PPGL patients had notably thinner and more sparse trabecular bone (decreased trabecular number and thickness with increased trabecular separation), significantly decreased volume BMD (vBMD), and bone strength at both the radius and tibia compared with healthy controls. The deterioration of Tt.vBMD, Tb.Sp, and Tb.1/N.SD was more pronounced in postmenopausal patients compared with the premenopausal subjects. Moreover, subjects in the highest 24hUNE quartile (Q4) showed markedly lower Tb.N and higher Tb.Sp and Tb.1/N.SD at the tibia than those in the lowest quartile (Q1). Age-related bone loss was also exacerbated in PPGL patients to a certain extent. PPGL patients had significantly deteriorated bone microarchitecture and strength, especially in the trabecular bone, with an increased bone resorption rate. Our findings provide clinical evidence that sympathetic overstimulation may serve as a secondary cause of osteoporosis, especially in subjects with increased sympathetic activity.

Psychobiological stress response to a lung cancer diagnosis: a prospective study of patients in Iceland and Sweden

Background A diagnostic work-up leading to a lung cancer diagnosis is a severely stressful experience that may impact tumor progression. Yet, prospective data are scarce on psychological and biological components of stress at the time of lung cancer diagnosis. The aim of this study was to assess pre-to-post diagnosis change in psychological distress and urinary excretion of catecholamines in patients with suspected lung cancer. Methods Participants were 167 patients within the LUCASS study, recruited at referral for suspected lung cancer to University Hospitals in Iceland and Sweden. Patients completed questionnaires on perceived distress (Hospital Anxiety and Depression Scale, HADS) before and after diagnosis of lung cancer or a non-malignant origin. A subpopulation of 85 patients also provided overnight urine for catecholamine analysis before and at a median of 24 days after diagnosis but before treatment. Results A lung cancer diagnosis was confirmed in 123 (73.7%) patients, with a mean age of 70.1 years. Patients diagnosed with lung cancer experienced a post-diagnosis increase in psychological distress (p = 0.010), while patients with non-malignant lung pathology showed a reduction in distress (p = 0.070). Both urinary epinephrine (p = 0.001) and norepinephrine (p = 0.032) levels were higher before the diagnosis among patients eventually diagnosed with lung cancer compared to those with non-malignant lung pathology. We observed indications of associations between pre-to-post diagnosis changes in perceived distress and changes in urinary catecholamine levels. Conclusion Receiving a lung cancer diagnosis is associated with an increase in psychological distress, while elevated catecholamine levels are evident already before lung cancer diagnosis.

Sex Effects on the Relationship between Stress and Psychosis in Schizophrenia

Stress has an important role in schizophrenia symptomology and many stress-related biological and psychological responses are sex-specific. Previous studies have established links between schizophrenia and stress-related hormones, subjectively experienced stress, and history of stressful experiences respectively. We hypothesized that the relationship between stress and psychosis in schizophrenia would be sex-dependent. N=52 patients with schizophrenia (38.4±14.0 years, 37 males) and N=41 healthy controls (45.3±15.4 years, 17 males) were evaluated for stress and symptoms. Stress was quantified by overnight urinary norepinephrine (NE) levels, the Perceived Stress Scale (PSS), the Major Life Events Checklist (MLEs) and the Childhood Trauma Questionnaire (CTQ). Symptoms severity was assessed using the psychosis subscale of the Brief Psychiatric Rating Scale (BPRS) and the Brief Negative Symptom Scale (BNSS). We examined the relationship between NE, PSS, MLEs, and CTQ and the BPRS psychosis and BNSS total scores and evaluated the significance of sex by stress interaction. Patients had significantly higher PSS, MLEs, and CTQ (all p < 0.05) and trend-level higher NE (p = 0.06) than controls. Significant sex by stress interaction was observed for BPRS psychosis in patients. For male, BPRS psychosis was significantly positively associated with urinary NE (p = 0.004) and the CTQ total score (p = 0.0003). For female, BPRS psychosis was significantly positively associated with total PSS (p = 0.02). Preliminary analyses supported sex-dependent relationship between stress and psychotic symptoms in patients with schizophrenia. Replication in a larger sample was necessary to confirm these sex-dependent relationships.

Kininase I inhibition reduces B1R mediated signaling and attenuates angiotensin II-induced hypertension

Objectives: Kininase I, or carboxypeptidase M and N (CPM/CPN), metabolizes bradykinin and kallidin into endogenous kinin B1 receptor (B1R) agonists. B1R expression in the brain is linked to neuroinflammation and autonomic dysfunction, and the development of hypertension. The metalloprotease aminopeptidase N (CD13) can interact with B1R to enhance proinflammatory cytokine production. However, the exact role of kininase I in the development of hypertension has not been yet investigated. In the present study, we tested the hypothesis that inhibition of kininase I will prevent the activation of the B1R, and reduce CD13 signaling, thus ultimately attenuating the progression of hypertension. Methods and Results: To inhibit the kininase I activity, we have utilized carboxypeptidase N gene deleted knockout (CPNKO) mice. Twelve-week-old male and female C57BL/6NJ wild-type (WT) and CPNKO mice, were administered angiotensin II (Ang II, 600 ng/kg/min; 2 weeks) or saline (vehicle) via osmotic minipumps. The mean arterial blood pressure (MAP) was measured using radio telemetry probes for 2 weeks. CPNKO mice did not show any significant differences in MAP at baseline. Ang II-infusion significantly increased the MAP in WT mice compared to saline infused control mice (147 ±5 vs 102 ±2 mmHg, n=5, p&lt;0.05), which was attenuated in CPNKO mice (125 ±4 mmHg, n=5, p&lt;0.01). Interestingly, there were no significant differences in MAP following Ang II-infusion in male and female CPNKO mice. Ang II treatment resulted in sympathoexcitation in WT mice, as indicated by increased urinary norepinephrine levels (446 ±38 ng/ml, p&lt;0.05 vs. control), but this increase was blunted in CPNKO mice infused with Ang II (246 ±14 ng/ml, p&lt;0.05 vs. WT+Ang II). WT mice treated with Ang II had increased inflammation, as shown by elevated gene expression (measured by qRT-PCR) of TNF, IL-1β and IL-6 (5-, 3.6-, and 4-fold, respectively, n=6, p&lt;0.01 vs. WT) in the hypothalamic paraventricular nucleus (PVN). The expression of these inflammatory genes was attenuated in CPNKO mice with Ang II infusion. Immunofluorescence staining showed that Ang II-infusion also significantly increased the expression of B1R, CPM, and CD13 in the PVN, a central regulatory center for cardiovascular and autonomic control. CPM has been shown to interact directly with B1R. To further determine interactions between B1R and CPM, we used proximity ligation assay (PLA) to elucidate close (&lt;40 nM) protein-protein interactions, as indicated by fluorescent PLA signals. Our data suggest that direct B1R-CPM interactions occurring within the PVN as the PLA signals are significantly increased by Ang II treatment in WT mice (p&lt;0.05, n=3), and blunted in CPNKO mice. Conclusions: Kininase I inhibition by CPN gene deletion attenuates Ang II-induced hypertension by reducing B1R and CD13 acti vation, sympathoexcitation, and inflammation. Our data suggest that targeting kininase I may be a novel therapeutic target for hypertension. Funding: This study was supported by NHLBI/NIH 5R01HL153115 (S. Sriramula). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Activation of TRPV1-Expressing Renal Sensory Nerves of Rats with N-Oleoyldopamine Attenuates High-Fat-Diet-Induced Impairment of Renal Function.

Enhanced renal sympathetic nerve activity (RSNA) contributes to obesity-induced renal disease, while the role of afferent renal nerve activity (ARNA) is not fully understood. The present study tested the hypothesis that activating the transient receptor potential vanilloid 1 (TRPV1) channel in afferent renal nerves suppresses RSNA and prevents renal dysfunction and hypertension in obese rats. N-oleoyldopamine (OLDA, 1 ng/kg, daily) was administrated intrathecally (T8-L3) via an indwelled catheter to chronically activate, TRPV1-positive afferent renal nerves in rats fed a chow diet or high-fat diet (HFD) for 8 weeks. HFD intake significantly increased the body weight, impaired glucose and insulin tolerance, decreased creatinine clearance, and elevated systolic blood pressure in rats compared with the levels of the chow-fed rats (all p < 0.05). An intrathecal OLDA treatment for 8 weeks did not affect the fasting glucose level, glucose tolerance, and insulin tolerance in rats fed either chow or HFD. As expected, the chronic OLDA treatment significantly increased the levels of plasma calcitonin gene-related peptide and substance P and ARNA in the HFD-fed rats (all p < 0.05). Interestingly, the OLDA treatment decreased the urinary norepinephrine level and RSNA in rats fed HFD (both p < 0.05). Importantly, the OLDA treatment attenuated HFD-induced decreases in creatinine clearance and urinary Na+ excretion and increases in the plasma urea level, urinary albumin level, and systolic blood pressure at the end of an 8-week treatment (all p < 0.05). Taken together, the intrathecal administration of OLDA ameliorates the enhancement of RSNA, renal dysfunction, and hypertension in obese rats. These findings shed light on the roles of TRPV1-positive renal afferent nerves in obesity-related renal dysfunction and hypertension.

Genetic Study in Pheochromocytoma: Is It Possible to Stratify the Risk of Hereditary Pheochromocytoma?

Introduction: It is estimated that 30–40% of patients with apparently sporadic pheochromocytomas (PHEOs) have an inherited predisposition syndrome. The aim of our study was to develop a predictive model of hereditary PHEO based on the clinical, hormonal, and radiological features present at the diagnosis of patients with PHEOs. Methods: A retrospective multicenter cohort study of patients with PHEOs with available genetic study from 18 tertiary hospitals. Clinical, biochemical, and radiological features were used to build a multivariate logistic regression model. The estimation of all possible equations was used to select the model with the best diagnostic accuracy (lower Akaike index). Results: A total of 245 patients were included: 169 (69.0%) patients with sporadic PHEOs and 76 (31%) with hereditary PHEOs. The parsimonious predictive model with the highest diagnostic accuracy for the prediction of hereditary PHEO combined the variables age, non-cardiovascular disease, urinary norepinephrine levels, and tumor size. The area under the ROC curve of this model was 0.800 (0.705–0.887). Based on the predictive model, the probability of hereditary PHEO in patients older than 60 years with cardiovascular disease, high levels of urinary norepinephrine and unilateral PHEOs >60 mm was <2%. And if the age was above 80 years, lower than 1%. The probability of sporadic PHEO linearly increased with age (MH Test for linear Trend: χ2 (1) = 30.05; p < 0.001). Conclusion: In certain populations such as old patients with cardiovascular disease, with high levels of urinary norepinephrine and large tumors in which the probability of hereditary PHEO is very low, genetic testing could be avoided in the absence of specific suspicion.

Contribution of afferent renal nerve signals to acute and chronic blood pressure regulation in stroke-prone spontaneously hypertensive rats.

The activation of sympathetic nervous system plays a critical role in the development of hypertension. The input from afferent renal nerves may affect central sympathetic outflow; however, its contribution to the development of hypertension remains unclear. We investigated the role of afferent renal nerves in acute and chronic blood pressure regulation using normotensive Wistar-Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). Acute chemical stimulation of afferent renal nerves elicited larger increases in blood pressure and renal sympathetic nerve activity in young 9-week-old SHRSP compared to WKY. Selective afferent renal denervation (ARDN) and conventional total renal denervation (TRDN) ablating both afferent and efferent nerves in young SHRSP revealed that only TRDN, but not ARDN, chronically attenuated blood pressure elevation. ARDN did not affect plasma renin activity or plasma angiotensin II levels, whereas TRDN decreased both. Neither TRDN nor ARDN affected central sympathetic outflow and systemic sympathetic activity determined by neuronal activity in the parvocellular region of hypothalamic paraventricular nucleus and rostral ventrolateral medulla and by plasma and urinary norepinephrine levels, respectively. Renal injury was not apparent in young SHRSP compared with WKY, suggesting that renal afferent input might not be activated in young SHRSP. In conclusion, the chronic input from afferent renal nerves does not contribute to the development of hypertension in SHRSP despite the increased blood pressure response to the acute stimulation of afferent renal nerves. Efferent renal nerves may be involved in the development of hypertension via activation of the renin-angiotensin system in SHRSP.

Longitudinal changes in the hypothalamic-pituitary-adrenal axis and sympathetic nervous system are related to the prognosis of stroke.

Background and purposeThis study sought to improve methods to identify biomarkers in the neuroendocrine system related to stroke progression to improve the accuracy of traditional tools for evaluating stroke prognosis.MethodsSeventy-four stroke patients and 237 healthy controls were prospectively included. We measured urinary epinephrine (E), noradrenaline (NE), dopamine (DA) and cortisol (F) on days 1, 3, and 5 after stroke onset and plasma F, adrenocorticotropic hormone (ACTH), thyrotropin (TSH), prolactin (PRL), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and growth hormone (GH). The correlation between these hormone levels and 90-day prognosis was analyzed, their value in assessing prognosis was compared with lesion volume and National Institutes of Health Stroke Scale (NIHSS) scores using receiver operating characteristic (ROC) curves, and their correlation with conventional clinical variables was assessed.ResultsLevels of F, 24-h urinary free cortisol(UFC), E, NE, DA, and GH on days 1, 3, and 5 were significantly higher in stroke patients than in controls (P < 0.01), while ACTH and TSH decreased, gradually approaching normal within 5 days of onset. Levels of E, NE, F, and 24-h UFC were proportional to severity, and all gradually decreased within 5 days of onset in patients with a good prognosis and gradually increased or remained high in those with a poor prognosis. After adjustment for age, sex, NIHSS, or Glasgow Coma Scale (GCS) score, F > 13.6 μg/dL, ACTH > 22.02 pg/mL and NE > 123.5 μg/ 24 h were identified as risk factors for a poor prognosis 90 days after stroke (P < 0.05). The combination of F, ACTH, NE, white blood cell count (WBC), glucose (Glu), and hemoglobin (Hb) was significantly more accurate than lesion volume (AUC: 0.931 vs. 0.694 P = 0.019) and NIHSS score (AUC: 0.931 vs. 0.746 P = 0.034) in predicting poor prognosis of stroke 1 day after onset. Hormones and traditional clinical variables were correlated to varying degrees, with NE correlating most strongly with 24-h UFC (r = 0.54) and moderately positively with lesion volume (r = 0.40) and NIHSS score (r = 0.45).ConclusionsStroke causes significant time-phased dynamic changes in the hypothalamic–pituitary–adrenal axis and sympathetic nervous system, and plasma F, ACTH, and urinary NE levels can be used to assess stroke severity and prognosis.Chinese clinical trial registryRegistration Number: ChiCTR1900024992. Registration Date: 2019/8/6.

Alterations in Microbiota‐Gut‐Brain Axis and Susceptibility or Resilience to Traumatic Stress

Post‐Traumatic Stress Disorder (PTSD) is a severe and long‐lasting outcome of exposure to traumatic life event. Exposure to trauma induces PTSD only in a sub‐population of individuals while others remain resilient. The mechanisms and contributing factors differentiating between stress resilient and stress susceptible subjects are still unclear. We hypothesize that inter‐individual differences in the microbiome composition and its function contribute to host resilience or susceptibility to stress induced psychopathologies. The current study aimed to characterize differences in the gut microbial community structure and function that mediate vulnerability or resilience to traumatic stress in the Single Prolonged Stress (SPS) animal model of PTSD. Sprague‐Dawley male rats were divided into unstressed controls and SPS experimental group. After 14 days, behavioral analyses were performed using Open Field, Social Interaction and Elevated Plus Maze tests. Based on the anxiety measures, the SPS group was further subdivided into SPS‐resilient (R) and SPS‐susceptible (S) subgroups. After the last behavioral test, the animals were sacrificed and cecum, colon, hippocampus, and medial prefrontal cortex were collected. Prior to SPS and immediately after Open Field test, fecal samples were collected from each rat for 16S V3‐V4 ribosomal sequencing; whereas urine samples were collected before SPS, 90 minutes into immobilization and on the day of dissection to measure urinary epinephrine (epi) and norepinephrine (norepi) levels. Analyses of the fecal microbiota revealed significant differences among the groups before and after SPS stressors. Before SPS, the SPS‐S subgroup harbored microbiota with an overall pro‐inflammatory phenotype, such as significantly increased levels of Clostridia, and decreased levels of Lactobacillusand Barnesiella compared to the SPS‐R subgroup. After SPS, among the many changes observed were significant shifts in the abundance of Firmicutes and Bacteroidetes in SPS subgroups. Urinary epi and norepi levels were also different among the groups, with SPS‐S subgroup having higher baseline catecholamines levels. In line with the alterations seen in the gut microbiota, the levels of cecal short chain fatty acids were also altered, with SPS‐S subgroup having significantly lower levels of Acetate, Valerate and Caproate. Interestingly, the levels of acetate inversely correlated with anxiety index. The colon length and permeability were also altered, with SPS‐S having significantly shorter colon and increased permeability as measured by Claudin‐1 expression. Finally, analyses of different brain regions also revealed significant increases in blood brain barrier permeability in SPS‐S subgroup as determined by Claudin‐5 expression. Taken together, our results suggest microbiota is a potential factor in predisposing subjects either to stress susceptibility or resilience. Moreover, SPS triggered significant shifts in the gut microbiota, their metabolites and brain and gut permeability. These findings could lead to new therapeutic directions for PTSD possibly through the controlled manipulation of gut microbiota. It may enable early identification of individuals more likely to develop prolonged anxiolytic symptoms following traumatic stress.

Predictors of prolonged hypotension requiring vasopressor support after resection of pheochromocytoma and paraganglioma.

Prolonged hypotension is a common complication after resection of pheochromocytoma (PCC) or paraganglioma (PGL). The objective of our study was to identify preoperative or intraoperative clinical factors that can predict prolonged hypotension after PCC/PGL resection. A total of 414 patients who underwent resection of PCC or PGL at our institution between January 2013 and January 2020 were included. Patients were divided into two groups according to whether or not vasopressor support was required postoperatively. Associations between preoperative and intraoperative variables and prolonged hypotension were evaluated. Two hundred and one (48.6%) patients had postoperative hypotension that required vasopressor support with a median duration of 20 h. Multivariable analysis demonstrated that increased 24-hurinary norepinephrine (NE) levels (odds ratio [OR] = 1.091, 95% confidence interval [CI]: 1.052-1.132, p < .001), longer operative time (OR = 1.008, CI: 1.004-1.011, p < .001)and lower preoperative phenoxybenzamine dose (OR = 0.336, CI: 0.150-0.753, p = .008) were predictors of prolonged hypotension. Moreover, operative time, body mass index, 24-hurinary level of NEand preoperative phenoxybenzamine dose were significantly correlated with the duration of postoperative vasopressor support. Increased urine NE level, longer operative timeand lower preoperative phenoxybenzamine dose were predictors of prolonged hypotension requiring vasopressor support. Clinicians can identify these factors to manage their patients better and prevent severe complications.

Moderating Effect of BMI on the Relationship Between Sympathetic Activation and Blood Pressure in Males with Obstructive Sleep Apnea.

BackgroundSympathetic activation is a primary mechanism mediating increased blood pressure (BP) in obstructive sleep apnea (OSA). However, the relationships between overweight/obesity, sympathetic activation and BP in OSA are not well understood. We hypothesized that increased sympathetic drive is associated with increased BP in normal weight, but not in overweight/obese males with OSA. We therefore examined the effects of body mass index (BMI) on the association between sympathetic activation and BP in males with OSA.MethodsWe studied 115 males with OSA recruited consecutively from clinic. Twenty-four-hour urinary norepinephrine was used to assess sympathetic activation. Blood pressure was measured both in the evening and in the morning. Hypertension was defined based on either BP measurements or an existing diagnosis. Linear and logistic regressions were conducted to examine the associations between sympathetic activation and both BP and risk of hypertension.ResultsWe found 24-hour urinary norepinephrine levels were associated with systolic and diastolic BP (SBP, β=0.157, p=0.082; DBP, β=0.212, p=0.023) and mean arterial pressure (MAP, β=0.198, p=0.032) after adjusting for confounders. Interestingly, these associations were modified by overweight/obesity. After adjusting for confounders, increased 24-hour urinary norepinephrine levels were significantly associated with elevated SBP (β=0.454, p=0.012), DBP (β=0.399, p=0.041), and MAP (β=0.432, p=0.023) in normal weight, but not in overweight/obese patients (all p>0.2). Similar findings were observed in the associations between 24-hour urinary norepinephrine levels and hypertension.ConclusionSympathetic activation is associated with elevated BP in normal weight but not in overweight/obese males with OSA, suggesting that BMI may moderate the association between sympathetic activation and BP in males with OSA.

Circulating Levels of the Heparan Sulfate Proteoglycan Syndecan-4 Positively Associate with Blood Pressure in Healthy Premenopausal Women.

Syndecans (SDCs) are transmembrane proteins that are present on most cell types where they play a role in multiple physiological processes, including cell–matrix adhesion and inflammation. Growing evidence suggests that elevated levels of both shed SDC1 and SDC4 are associated with hypertension and cardiovascular diseases, but their relationships with cardiovascular risk factors in healthy individuals are unknown. The primary objective of this study was to investigate whether serum levels of SDC4 and SDC1 were associated with body composition, hemodynamic parameters, pro-inflammatory cytokine concentrations, and urinary noradrenaline and dopamine levels in healthy women (17 African American and 20 European American) between the ages of 20 and 40 years old. Univariate analyses revealed only a significant (p < 0.05) inverse correlation between serum SDC1 and body fat percentage. On the other hand, serum SDC4 was positively correlated with systolic blood pressure, diastolic blood pressure, and urinary levels of noradrenaline and dopamine. Serum SDC4 was also a significant predictor of systolic blood pressure in a multivariate regression model that included fat-free mass and urinary dopamine levels as significant independent variables. The result did not change even adjusting for race. Our findings indicate that SDC4 has an important role in the physiological regulation of blood pressure.

Exposure to volatile organic compounds – acrolein, 1,3-butadiene, and crotonaldehyde – is associated with vascular dysfunction

BackgroundCardiovascular disease (CVD) is the leading cause of mortality worldwide. Exposure to air pollution, specifically particulate matter of diameter ≤2.5 μm (PM2.5), is a well-established risk factor for CVD. However, the contribution of gaseous pollutant exposure to CVD risk is less clear. ObjectiveTo examine the vascular effects of exposure to individual volatile organic compounds (VOCs) and mixtures of VOCs. MethodsWe measured urinary metabolites of acrolein (CEMA and 3HPMA), 1,3-butadiene (DHBMA and MHBMA3), and crotonaldehyde (HPMMA) in 346 nonsmokers with varying levels of CVD risk. On the day of enrollment, we measured blood pressure (BP), reactive hyperemia index (RHI – a measure of endothelial function), and urinary levels of catecholamines and their metabolites. We used generalized linear models for evaluating the association between individual VOC metabolites and BP, RHI, and catecholamines, and we used Bayesian Kernel Machine Regression (BKMR) to assess exposure to VOC metabolite mixtures and BP. ResultsWe found that the levels of 3HPMA were positively associated with systolic BP (0.98 mmHg per interquartile range (IQR) of 3HPMA; CI: 0.06, 1.91; P = 0.04). Stratified analysis revealed an increased association with systolic BP in Black participants despite lower levels of urinary 3HPMA. This association was independent of PM2.5 exposure and BP medications. BKMR analysis confirmed that 3HPMA was the major metabolite associated with higher BP in the presence of other metabolites. We also found that 3HPMA and DHBMA were associated with decreased endothelial function. For each IQR of 3HPMA or DHBMA, there was a −4.4% (CI: −7.2, −0.0; P = 0.03) and a −3.9% (CI: −9.4, −0.0; P = 0.04) difference in RHI, respectively. Although in the entire cohort the levels of several urinary VOC metabolites were weakly associated with urinary catecholamines and their metabolites, in Black participants, DHBMA levels showed strong associations with urinary norepinephrine and normetanephrine levels. DiscussionExposure to acrolein and 1,3-butadiene is associated with endothelial dysfunction and may contribute to elevated risk of hypertension in participants with increased sympathetic tone, particularly in Black individuals.

Silencing Epidermal Growth Factor Receptor in Hypothalamic Paraventricular Nucleus Reduces Extracellular Signal-regulated Kinase 1 and 2 Signaling and Sympathetic Excitation in Heart Failure Rats

Activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling in cardiovascular regulatory regions of the brain contributes to sympathetic excitation in myocardial infarction (MI)-induced heart failure (HF) by increasing brain renin-angiotensin system (RAS) activity, neuroinflammation, and endoplasmic reticulum (ER) stress. The mechanisms eliciting brain ERK1/2 signaling in HF are still poorly understood. We tested the involvement of the epidermal growth factor receptor (EGFR) which, upon activation, stimulates ERK1/2 activity. Adult male Sprague-Dawley rats received bilateral microinjections of a lentiviral vector encoding a small interfering RNA (siRNA) for EGFR, or a scrambled siRNA, into the hypothalamic paraventricular nucleus (PVN), a recognized source of sympathetic overactivity in HF. One week later, coronary artery ligation was performed to induce HF. Four weeks later, the EGFR siRNA-treated HF rats, compared with the scrambled siRNA-treated HF rats, had lower mRNA and protein levels of EGFR, lower levels of phosphorylated (p-) EGFR and p-ERK1/2 and lower mRNA levels of the inflammatory mediators TNF-α, IL-1β and cyclooxygenase-2, the RAS components angiotensin-converting enzyme and angiotensin II type 1a receptor and the ER stress markers BIP and ATF4 in the PVN. They also had lower plasma and urinary norepinephrine levels and improved peripheral manifestations of HF. Additional studies revealed that p-EGFR was increased in the PVN of HF rats, compared with sham-operated control rats. These results suggest that activation of EGFR in the PVN triggers ERK1/2 signaling, along with ER stress, neuroinflammation and RAS activity, in MI-induced HF. Brain EGFR may be a novel target for therapeutic intervention in MI-induced HF.

Seasonal variation of blood pressure in children

Seasonal blood pressure (BP) variation is mostly found between the summer and winter months. Guidelines for diagnosis and treatment of hypertension in children have not considered this variation until recently. This review aims to present an overview of seasonal BP variation in childhood along with potential underlying pathophysiological mechanisms and long-term implications as well as conclusions for future studies. In pediatric cohorts, seven studies investigated seasonal changes in BP. These changes amount to 3.4–5.9 mmHg (or 0.5–1.5 mmHg per − 1 °C difference in environmental temperature) in systolic BP with a peak in fall or winter. Potential mechanisms and mediators of seasonal BP variation include sympathetic activation of the nervous system with an increase of urinary and plasma norepinephrine levels in the winter season. Additionally, the physical activity among children and adolescents was inversely correlated with BP levels. Temperature sensitivity of BP and pediatric BP levels predict future systolic BP and target-organ damage. Therefore, cardiovascular events may even be long-term complications of seasonal BP variation in pediatric hypertensive patients. Overall, these data strongly suggest an important effect of ambient temperature on BP in children. Additional studies in pediatric cohorts are needed to define how best to incorporate such variation into clinical practice.

Meta-analysis of changes in the levels of catecholamines and blood pressure with continuous positive airway pressure therapy in obstructive sleep apnea.

Stress from obstructive sleep apnea (OSA) stimulates catecholamine release consequently exacerbating hypertension. However, different studies have shown a conflicting impact of continuous positive airway pressure (CPAP) treatment in patients with OSA on catecholamine levels and blood pressure. We aimed to examine changes to catecholamine levels and blood pressure in response to CPAP treatment. We conducted a meta‐analysis of data published up to May 2020. The quality of the studies was evaluated using standard tools for assessing the risk of bias. Meta‐analysis was conducted using RevMan (v5.3) and expressed in standardized mean difference (SMD) for catecholamines and mean difference (MD) for systolic (SBP) and diastolic blood pressure (DBP). A total of 38 studies met our search criteria; they consisted of 14 randomized control trials (RCT) totaling 576 participants and 24 prospective cohort studies (PCS) of 547 participants. Mean age ranged between 41 and 62 year and body mass index between 27.2 and 35.1 kg/m2. CPAP treatment reduced 24‐hour urinary noradrenaline levels both in RCT (SMD = −1.1; 95% confidence interval (CI): −1.63 to − 0.56) and in PCS (SMD = 0.38 (CI: 0.24 to 0.53). SBP was also reduced by CPAP treatment in RCT (4.8 mmHg; CI: 2.0‐7.7) and in PCS (7.5 mmHg; CI: 3.3‐11.7). DBP was similarly reduced (3.0 mmHg; CI: 1.4‐4.6) and in PCS (5.1 mmHg; CI: 2.3‐8.0). In conclusion, CPAP treatment in patients with OSA reduces catecholamine levels and blood pressure. This suggests that sympathetic activity plays an intermediary role in hypertension associated with OSA‐related stress.

TRPV1 Activation Prevents Renal Ischemia-Reperfusion Injury-Induced Increase in Salt Sensitivity by Suppressing Renal Sympathetic Nerve Activity.

: BackgroundSalt sensitivity is increased following renal Ischemia-Reperfusion (I/R) injury. We tested the hypothesis that high salt intake induced increase in Renal Sympathetic Nerve Activity (RSNA) after renal I/R can be prevented by activation of Transient Receptor Potential Vanilloid 1 (TRPV1).MethodsRats were fed a 0.4% NaCl diet for 5 weeks after renal I/R, followed by a 4% NaCl diet for 4 more weeks in four groups: sham, I/R, I/R +High Dose Capsaicin (HDC), and I/R+Low Dose Capsaicin (LDC). The low (1mg/kg) or high (100mg/kg) dose of capsaicin was injected subcutaneously before I/R to activate or desensitize TRPV1, respectively.ResultsSystolic blood pressure was gradually elevated after fed on a high-salt diet in the I/R and I/R+HDC groups but not in the I/R+LDC group, with a greater increase in the I/R+HDC group. Renal function was impaired in the I/R group and was further deteriorated in the I/R+HDC group but was unchanged in the I/R+LDC group. At the end of high salt treatment, afferent renal nerve activity in response to unilateral intra-pelvic administration of capsaicin was decreased in the I/R group and was further suppressed in the I/R+HDC group but was unchanged in the I/R+LDC group. RSNA in response to intrathecal administration of muscimol, a selective agonist of GABA-A receptors, was augmented in the I/R group and further intensified in the I/R+HDC group but was unchanged in the I/R+LDC group. Similarly, urinary norepinephrine levels were increased in the I/R group and were further elevated in the I/R+HDC group but unchanged in the I/R+LDC group.ConclusionThese data suggest that TRPV1 activation prevents renal I/R injury-induced increase in salt sensitivity by suppressing RSNA.