Norepinephrine Values Research Articles

Divergent roles of purinergic 2X receptors in the pressor response to treadmill exercise in male and female rats

Our objective was to investigate the role played by ATP sensitive purinergic 2X (P2X) receptors in evoking the pressor response to treadmill running in male and female rats with and without simulated peripheral artery disease (PAD). We hypothesized that PPADS (P2X receptor antagonist, 10 mg i.v.), would reduce the pressor and end-exercise plasma norepinephrine (NE) response to four minutes of treadmill exercise (15 m×min−1; 1° incline) in male and female rats with a greater magnitude of effect in rats with simulated PAD compared to sham-operated rats. Methods: Ten rats had both femoral arteries ligated ~72 hours prior to experimental protocols. Fourteen rats had sham procedures performed in which the femoral arteries were exposed, and 5-0 suture was passed under the arteries but not tied. These groups are referred to as “ligated” and “sham”, respectively. In all rats, the right carotid artery was cannulated (PE-25) for blood pressure measurement and arterial blood samples and the right jugular vein was cannulated (PE-25) for administration of PPADS. After the rats recovered (~2 hrs), treadmill exercise was initiated (15 m·min−1, 1° incline) and the rat completed a four minute exercise bout. While the rat was still running, an arterial blood sample (~100 μl) was drawn for plasma NE assessment. Following a 20 minute rest, PPADS (10 mg, dissolved in 0.2 mL saline) was infused into the jugular vein over 10 min. After PPADS infusion, a second treadmill exercise bout and blood collection were performed as described for the control condition. The pressor and plasma NE responses to submaximal treadmill running before and after the injection of PPADS (10 mg) were compared. Data are expressed as mean ± SD. Statistical significance was defined as P≤0.05. Results: In male rats, PPADS significantly reduced the mean arterial pressure (MAP) response to exercise in both sham ( n=6, Peak ΔMAP control: 19±6; PPADS: 11±9 mmHg; P=0.033) and ligated rats ( n=4; control: 24±3 mmHg; PPADS: 16±6 mmHg; P=0.021) with a similar magnitude of effect observed between groups (p=0.544). In female rats, PPADS had no effect on the MAP response to exercise in either sham (n=6, 13±8; PPADS: 10±5 mmHg; P=0.171) or ligated (n=6, 17±5; PPADS: 18±6 mmHg; P=0.375) rats. When NE values were grouped by sex independent of ligation/sham status, PPADS significantly reduced end-exercise plasma NE concentration in both male (n=11, 200±131; PPADS: 139±61 pg/mL; P=0.016) and female (n=10, 199±133; PPADS: 140±101 pg/mL; P=0.027) rats. Conclusions: The data indicate that P2X receptors contribute to the sympathetic response to exercise in both male and female sham and ligated rats, but that sympathoexcitatory roles for P2X receptors translates into an obligatory role in the blood pressure response to treadmill exercise in male but not female rats. National Institutes of Health R01HL161160. This is the full abstract presented at the American Physiology Summit 2024 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.

Sex differences in the purinergic 2 receptor-mediated blood pressure response to treadmill exercise in rats with simulated peripheral artery disease.

We investigated the role played by ATP-sensitive purinergic 2 (P2) receptors in evoking the pressor response to treadmill exercise in male and female rats with and without femoral arteries that were ligated for ∼72 h to induce simulated peripheral artery disease (PAD). We hypothesized that PPADS (P2 receptor antagonist, 10 mg iv) would reduce the pressor response to 4 min of treadmill exercise (15 m·min-1, 1° incline) and steady-state exercise plasma norepinephrine (NE) values in male and female rats, and that the magnitude of effect of PPADS would be greater in rats with simulated PAD ("ligated") than in sham-operated rats. In males, PPADS significantly reduced the difference between steady-state exercise and baseline mean arterial pressure (ΔMAP) response to treadmill exercise in sham (n = 8; pre-PPADS: 12 ± 2, post-PPADS: 1 ± 5 mmHg; P = 0.037) and ligated (n = 4; pre-PPADS: 20 ± 2, post-PPADS: 11 ± 3 mmHg; P = 0.028) rats with a similar magnitude of effect observed between groups (P = 0.720). In females, PPADS had no effect on the ΔMAP response to treadmill exercise in sham (n = 6; pre-PPADS: 9 ± 2, post-PPADS: 7 ± 2 mmHg; P = 0.448) or ligated (n = 6; pre-PPADS: 15 ± 2, post-PPADS: 16 ± 3 mmHg; P = 0.684) rats. When NE values were grouped by sex independent of ligation/sham status, PPADS significantly reduced plasma NE in male (P = 0.016) and female (P = 0.027) rats. The data indicate that P2 receptors contribute to the sympathetic response to exercise in both male and female rats but that the sympathoexcitatory role for P2 receptors translates into an obligatory role in the blood pressure response to exercise in male but not in female rats.NEW & NOTEWORTHY Here, we demonstrate that purinergic 2 (P2) receptors contribute significantly to the blood pressure response to treadmill exercise in male rats both with and without simulated PAD induced by femoral artery ligation. We found no role for P2 receptors in the blood pressure response to treadmill exercise in female rats, thus revealing clear sex differences in P2 receptor-mediated blood pressure control during exercise.

Synthesis of Tin Doped Copper Oxide Nanocomposites for Electrochemical Sensor Application

Abstract Poly (Tin-doped copper oxide nanocomposites modified glassy carbon electrode) (Poly (Sn-doped CuO nanocomposite)-MGCE) made sensors were confirmed by electrochemical finding of norepinephrine (NE). The Sn-doped CuO nanocomposites were made by precipitation technique. This nanocomposite was described through scanning electron microscope and X-ray diffraction methods. To find the doped properties of the Poly (Sn-doped CuO nanocomposite)-MGCE were studied by cyclic voltammetry studies. The above studies prove that the altered electrodes have wide electroactive external area, and the reduction and oxidation peak appeared at pH 7.4 supportive electrolyte concentration 0.2 M phosphate buffer solution. Poly(Sn-doped CuO nanocomposite)-MGCE as limit of detection was low value for NE was found to be 2.22 µM and the limit of quantification values for NE was appeared as 7.41 µM, wide linear range, high sensitivity (20 to 350 µM), functional to the injection mockup analysis and the attained outcomes are acceptable, excellent reproducibility displays excessive potential in practical applications.

Hemoadsorption as Adjuvant Therapy in Acute Respiratory Distress Syndrome (ARDS): A Systematic Review and Meta-Analysis.

Acute respiratory distress syndrome (ARDS) is often a consequence of a dysregulated immune response; therefore, immunomodulation by extracorporeal cytokine removal has been increasingly used as an adjuvant therapy, but convincing data are still missing. The aim of this study was to investigate the effects of adjunctive hemoadsorption (HA) on clinical and laboratory outcomes in patients with ARDS. We performed a systematic literature search in PubMed, Embase, CENTRAL, Scopus, and Web of Science (PROSPERO: CRD42022292176). The population was patients receiving HA therapy for ARDS. The primary outcome was the change in PaO2/FiO2 before and after HA therapy. Secondary outcomes included the before and after values for C-reactive protein (CRP), lactate, interleukin-6 (IL-6), and norepinephrine (NE) doses. We included 26 publications, with 243 patients (198 undergoing HA therapy and 45 controls). There was a significant improvement in PaO2/FiO2 ratio following HA therapy (MD = 68.93 [95%-CI: 28.79 to 109.06] mmHg, p = 0.005) and a reduction in CRP levels (MD = -45.02 [95%-CI: -82.64; -7.39] mg/dL, p = 0.026) and NE dose (MD = -0.24 [95%-CI: -0.44 to -0.04] μg/kg/min, p = 0.028). Based on our findings, HA resulted in a significant improvement in oxygenation and a reduction in NE dose and CRP levels in patients treated with ARDS. Properly designed RCTs are still needed.

Endogenous Catecholamine Release in COVID-19 Related Acute Respiratory Distress Syndrome: Link between Enhanced Sympathetic Stimulation, Cardiac Dysfunction and Outcome

The aim of this study was to measure the serum levels of catecholamines in patients admitted to intensive care unit (ICU) with COVID-19-related acute respiratory distress syndrome (ARDS) and describe their relation with clinical, inflammatory and echocardiographic parameters. Serum levels of endogenous catecholamines (norepinephrine, epinephrine and dopamine) were measured at ICU admission. We enrolled 71 patients consecutively admitted to ICU due to moderate to severe ARDS. 11 patients (15.5%) died during the admission in ICU. Serum levels of endogenous catecholamines were significantly elevated. Norepinephrine levels were higher in those with RV and LV systolic dysfunction, higher CRP, and higher IL-6. Patients with higher mortality rate were those with norepinephrine values ≥ 3124 ng/mL, CRP ≥ 17.2 mg/dL and IL-6 ≥ 102 pg/mL. Univariable analysis by Cox proportional hazards regression modelling showed that norepinephrine, IL-6 and CRP had the highest risk of acute mortality. Multivariable analysis showed that only norepinephrine and IL-6 retained in the model. Marked increase of serum catecholamine levels is present during acute phase of critically ill COVID-19 and it is associated with inflammatory and clinical parameters.

A Preliminary Study on the Interplay between the Serum Levels of Neurotransmitters and Thyroid Hormones for the Evaluation of the Behavioral Phenotype of Dogs.

A total of 112 dogs (49 males and 63 females) belonging to different breeds (i.e., Boxer, Cirneco dell'Etna, Fonni's Dog, Labrador, Crossbreed, German Shepherd, Pit Bull, Shar-Pei, Yorkshire) were analyzed to compare the serum concentration of serotonin, dopamine, norepinephrine, prolactin, beta-endorphins, thyroxine (T4), triiodothyronine (T3), thyroid-stimulating hormone (TSH), and assess whether these parameters can be correlated with the behavioral phenotype of the investigated breeds. T4 was above or below the threshold in 61% and 14% of dogs, respectively; T3, in contrast, 41% of dogs showed values below the limit, while 26% above it. TSH was within the reference range in 58% of dogs; 94% of the dogs had prolactin in the reference range and only five animals showed values above the limit. For beta-endorphins, 49% of dogs had values above the limit, while 46% had values within the reference range. Serotonin and dopamine values below physiological limits were found in 62% and 70% of dogs, respectively. Finally, 61% of the dogs showed norepinephrine values within the reference range. The study confirmed that the assessment of the serum values of hormones and neurotransmitters in dogs could be useful to better understand the behavioral phenotype of the animal and could be useful for breeders and trainers for the selection of the most suitable subjects for specific tasks.

Determination of the Relative Potency of Norepinephrine and Phenylephrine Given as Infusions for Preventing Hypotension During Combined Spinal-Epidural Anesthesia for Cesarean Delivery: A Randomized Up-And-Down Sequential Allocation Study.

Purpose: The relative potency of norepinephrine and phenylephrine given as boluses to treat hypotension during spinal anesthesia for cesarean delivery has been reported but few data are available for infusions. This study aimed to determine the relative potency of norepinephrine and phenylephrine when given by infusion for preventing hypotension during combined spinal-epidural anesthesia for cesarean delivery. Methods: This was a prospective, randomized, double-blind, up-and-down sequential allocation study. Patients were randomly allocated to receive a prophylactic infusion of norepinephrine or phenylephrine started immediately after induction of anesthesia. The first patients received either norepinephrine 0.1 μg/kg/min or phenylephrine 0.5 μg/kg/min. An effective infusion rate was defined when no hypotension occurred before delivery. For each subsequent patient, the norepinephrine infusion rate was decreased or increased by 0.01 μg/kg/min or the phenylephrine infusion rate was decreased or increased by 0.05 μg/kg/min according to whether the infusion was effective or ineffective respectively in the previous patient. Values for the infusion rate that was effective in preventing hypotension in 50% of patients (ED50) for norepinephrine and phenylephrine were estimated using up-and-down sequential analysis and relative potency was estimated. Probit regression was used as a backup and sensitivity analysis. Results: The ED50 values for norepinephrine and phenylephrine calculated by the up-and-down method were 0.061 (95% CI 0.054–0.068) μg/kg/min and 0.368 (95% CI 0.343–0.393) μg/kg/min respectively. The estimated relative potency ratio for ED50 for norepinephrine to phenylephrine was 6.03:1 (95% CI 5.26:1 to 6.98:1). Conclusion: Under the conditions of this study, norepinephrine given by infusion was about 6 times more potent than phenylephrine. This information is useful for clinical practice and further comparative studies of norepinephrine versus phenylephrine. Clinical Trial Registration: http://www.chictr.org.cn/showproj.aspx, identifier [ChiCTR2200056237]

Antagonism of α1-adrenoceptors by β3-adrenergic agonists: Structure–function relations of different agonists in prostate smooth muscle contraction

Effects of β3-adrenergic agonists on prostate smooth muscle contraction are poorly characterized, although mirabegron is used for treatment of lower urinary tract symptoms. Off-target effects of several β3-adrenergic agonists include antagonism of α1-adrenoceptors. Proposed, but unconfirmed explanations include phenylethanolamine backbones, found in some β3-adrenergic agonists and imparting interaction with catecholamine binding pockets of adrenoceptors. Here, we examined effects of β3-adrenergic agonists on contractions of human prostate tissues, including ZD7114 (without phenylethanolamine moiety), ZD2079 (phenylethanolamine backbone), BRL37344 and CL316243 (chloride-substituted phenylethanolamine deriatives). Prostate tissues were obtained from radical prostatectomy. Contractions by α1-adrenergic agonists and electric field stimulation (EFS) were studied in an organ bath. ZD7114 (10 µM) right-shifted concentration responses curves for α1-adrenergic agonists, resulting in increased EC50 values for phenylephrine, methoxamine and noradrenaline up to one magnitude, without affecting Emax values. ZD7114 (10 µM) inhibited EFS-induced contractions, resulting in reduced Emax values. All effects of ZD7114 were resistant to the β3-adrenergic antagonist L-748337, including increases in EC50 values for α1-adrenergic agonists, up to more than two magnitudes. Using 10 µM, neither ZD2079, BRL37344 or CL316243 affected α1-adrenergic or EFS-induced contractions. At escalated concentrations, BRL37344 (200 µM) right-shifted concentration response curves for phenylephrine, increased EC50 values for phenylephrine, and inhibited EFS-induced contractions, while CL316243 (300 µM) did not affect phenylephrine- or EFS-induced contractions. In conclusion, phenylethanolamine backbones are not decisive to impart α1-adrenoceptor antagonism to β3-agonists. Effects of β3-adrenergic agonists on prostate smooth muscle contraction are limited to off-target effects, including α1-adrenoceptor antagonism by ZD7114 and BRL37344.

Prikaz prve laparoskopske adrenalektomije zbog feohromocitoma u pedijatrijskoj populaciji u Republici Srbiji

Pheochromocytoma is a tumor that arises from adrenal medulla and it is characterized by increased secretion of catecholamines. The incidence of pheochromocytoma is 3 to 8 cases per million inhabitants, of which about 10 to 20% of diagnosed pheochromocytomas occurs in the pediatric population, with a higher frequency in boys. In 1.7% of the pediatric population with hypertension, the cause of hypertension is pheochromocytoma. Due to headaches and verified hypertension on twenty-four-hour holter blood pressure monitoring, the 13-year-old female patient underwent ultrasound, followed by scintigraphy and magnetic resonance imaging of the abdomen, which described an oval change above the right kidney about 4.5 cm in diameter suspected of pheochromocytoma. Twenty-four-hour urine cateholamines showed elevated noradrenaline values as much as 45 times higher than the reference range, as well as elevated Dopamine values. After adequate preparation with phenoxybenzamine and bisoprolol for two weeks, a right laparoscopic adrenalectomy was performed at the University Children's Clinic in Tirsova, which is also the first operation of this type in the pediatric population. Intraoperatively, the maximum value of tension was 180/120 mmHg. Pathohistological findings confirmed pheochromocytoma. Although a rare cause of hypertension in the pediatric population, young patients with newly diagnosed hypertension should be examined for possible pheochromocytoma. Laparoscopic adrenalectomy through both the lateral transabdominal and posterior retroperitoneoscopic approach is the gold standard for the treatment of pheochromocytomas in both the adult and pediatric populations.

594 Impact of admission hyperglycaemia on heart failure events and mortality in patients with Takotsubo syndrome at long-term follow-up: data from the high-Glucotako investigators

Abstract Aims As known, Takotsubo Syndrome (TTS) can occur during stressful events that result in sympathetic overactivity. No studies have investigated the sympathetic activity and long-term prognosis in patients with TTS and admission hyperglycaemia vs. normoglycaemia. Moreover, whether hyperglycaemia may serve as a metabolic trigger to unbalance the sympathetic system axis as well as through over-inflammation is not fully understood. To investigate admission hyperglycaemia effects on the sympathetic system and long-term prognosis in Takotsubo syndrome (TTS). Methods and results In this multicentre study, we screened 4783 patients undergoing coronary angiography within the first 72 h of hospitalization for suspected acute coronary syndrome between January 2015 and January 2018. All enrolled patients met the InterTAK diagnostic criteria proposed in the European Society of Cardiology position statement for the diagnosis of TTS. Exclusion criteria encompassed patients with previous myocardial infarction, TTS events, or chronic kidney or liver disease. Patients with TTS were divided into those with hyperglycaemia vs. those with normoglycaemia according to a cutoff admission blood glucose value of 140 mg/dl. Sympathetic activity was assayed by blood values of norepinephrine and 123I-labelled metaiodobenzylguanidine (MIBG) cardiac scintigraphy with late heart-to-mediastinum ratio (H/Mlate) and washout rate (WR), performed in 30 patients who did not present any contraindication to the examination, evaluated at baseline and at follow-up. Similarly, systemic inflammatory markers [C-reactive protein (CRP), white blood cell count (leukocytes and neutrophils), tumour necrosis factor-alpha (TNF-a)] and B-type natriuretic peptide (BNP) were assessed. Prespecified endpoints [heart failure (HF) and all-cause deaths] were assessed at long-term follow-up (12 and 24 months). At hospitalization, TTS patients with hyperglycaemia (N = 28) vs. those with normoglycaemia (M = 48) had significantly higher levels of inflammatory markers and B-type natriuretic peptide and lower left ventricular ejection fraction. Admission glucose values were correlated with norepinephrine levels (R2 = 0.39; P = 0.001). In 30 patients with TTS, 123I-MIBG cardiac scintigraphy showed lower late heart-to-mediastinum ratio values in the acute phase (P < 0.001) and at follow-up (P < 0.001) in those with hyperglycaemia. Patients with hyperglycaemia had higher rates of HF (P < 0.001) and death events (P < 0.05) after 24 months. In multivariate Cox regression analysis, hyperglycaemia (P = 0.008), tumour necrosis factor-alpha (P = 0.001), and norepinephrine (P = 0.035) were independent predictors of HF events. Conclusions Patients with TTS and hyperglycaemia exhibit sympathetic overactivity with a hyperglycaemia-mediated proinflammatory pathway, which could determine a worse prognosis during follow-up.

The Role of the Noradrenergic System in Eating Disorders: A Systematic Review.

Noradrenaline (NE) is a catecholamine acting as both a neurotransmitter and a hormone, with relevant effects in modulating feeding behavior and satiety. Several studies have assessed the relationship between the noradrenergic system and Eating Disorders (EDs). This systematic review aims to report the existing literature on the role of the noradrenergic system in the development and treatment of EDs. A total of 35 studies were included. Preclinical studies demonstrated an involvement of the noradrenergic pathways in binge-like behaviors. Genetic studies on polymorphisms in genes coding for NE transporters and regulating enzymes have shown conflicting evidence. Clinical studies have reported non-unanimous evidence for the existence of absolute alterations in plasma NE values in patients with Anorexia Nervosa (AN) and Bulimia Nervosa (BN). Pharmacological studies have documented the efficacy of noradrenaline-modulating therapies in the treatment of BN and Binge Eating Disorder (BED). Insufficient evidence was found concerning the noradrenergic-mediated genetics of BED and BN, and psychopharmacological treatments targeting the noradrenergic system in AN. According to these data, further studies are required to expand the existing knowledge on the noradrenergic system as a potential target for treatments of EDs.

PD11-07 MIRABEGRON INHIBITS NEUROGENIC AND α 1 -ADRENERGIC HUMAN PROSTATE SMOOTH MUSCLE CONTRACTIONS, WITH SIMILAR PHARMACOLOGIC PATTERNS AS α 1 -BLOCKERS

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology (PD11)1 Sep 2021PD11-07 MIRABEGRON INHIBITS NEUROGENIC AND α1-ADRENERGIC HUMAN PROSTATE SMOOTH MUSCLE CONTRACTIONS, WITH SIMILAR PHARMACOLOGIC PATTERNS AS α1-BLOCKERS Ru Huang, Yuhan Liu, Bingsheng Li, Ruixiao Wang, Alexander Tamalunas, Raphaela Waidelich, Frank Strittmatter, Christian G. Stief, and Martin Hennenberg Ru HuangRu Huang More articles by this author , Yuhan LiuYuhan Liu More articles by this author , Bingsheng LiBingsheng Li More articles by this author , Ruixiao WangRuixiao Wang More articles by this author , Alexander TamalunasAlexander Tamalunas More articles by this author , Raphaela WaidelichRaphaela Waidelich More articles by this author , Frank StrittmatterFrank Strittmatter More articles by this author , Christian G. StiefChristian G. Stief More articles by this author , and Martin HennenbergMartin Hennenberg More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001986.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Mirabegron inhibits detrusor smooth muscle contractions and is available for treatment of overactive bladder. Consequently, its effects on lower urinary tract symptoms (LUTS) suggestive of bengin prostatic hyperplasia (BPH) were subject of recent trials. However, available results are not yet conclusive, and effects of mirabegron on human prostate smooth muscle contraction are hardly characterized. Voiding symptoms suggestive of BPH may be driven by increased prostate smooth muscle tone. Here, we examined effects of mirabegron on contractions of human prostate tissues. METHODS: Human prostate tissues were obtained from radical prostatectomy. Contractions were studied in an organ bath. Comparisons were performed between whole groups (one-way ANOVA), and at single frequencies and agonist concentrations (multivariate analysis). RESULTS: Electric field stimulation (EFS) induced neurogenic, frequence-dependent contractions, while agonists induced concentration-dependent contractions. Mirabegron (10 µM) inhibited EFS-induced contractions (p <0.001 for controls vs. mirabegron between whole groups), which was observed at different frequencies and reflected by reduced Emax values calculated by curve fitting (contractions in controls 84±11% of KCl-induced contractions, but 14±2% after mirabegron, p <0.01). Miragebron increased the EC50 values for noradrenaline (controls 0.55±0.32 µM, mirabegron 5.1±2.4 µM, p <0.004), resulting in rightshifts of concentration response curves for noradrenaline-induced contractions (p <0.001) and in reduced contractions up to 10 µM noradrenaline, but in recovery at higher noradrenaline concentrations and unchanged Emax values. Similarly, EC50 values for the α1-adrenergic agonist phenylephrine were increased by mirabegron (controls 7.4±4.1 µM, mirabegron 29.2±8.9 µM, p=0.05), resulting in rightshifts of concentration response curves for phenylephrine (p <0.001) and in reduced contractions up to 30 µM phenylephrine, but in recovery at higher phenylephrine concentrations and in unchanged Emax values. Mirabegron slightly reduced contractions induced by the thromboxane A2 analog U46619 (p <0.03), without changing EC50 values. Contractions induced by endothelin-1 remained unchanged by mirabegron. CONCLUSIONS: Mirabegron inhibits neurogenic and α1-adrenergic smooth muscle contractions in the human prostate. Surprisingly, the pharmacologic pattern is similar to that of α1-blockers, including rightshifts of α1-adrenergic concentration response curves, reduced Emax values for neurogenic contractions, and lacking or small effects on non-adrenergic contractions. Source of Funding: China Scholarship Council (CSC) © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e200-e200 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ru Huang More articles by this author Yuhan Liu More articles by this author Bingsheng Li More articles by this author Ruixiao Wang More articles by this author Alexander Tamalunas More articles by this author Raphaela Waidelich More articles by this author Frank Strittmatter More articles by this author Christian G. Stief More articles by this author Martin Hennenberg More articles by this author Expand All Advertisement Loading ...

Prophylactic norepinephrine infusion for postspinal anesthesia hypotension in patients undergoing cesarean section: A randomized, controlled, dose-finding trial.

Prophylactic norepinephrine infusion effectively lowers the incidence of postspinal anesthesia hypotension. The optimal prophylactic dose of norepinephrine remains undefined. The purpose of this study was to investigate the optimal prophylactic dose of norepinephrine to prevent postspinal anesthesia hypotension in patients undergoing cesarean section. Prospective, double-blind, randomized, controlled, dose-finding trial. Operating room from March 2020 to June 2020. Ninety nine primipara or multipara women 18 - 40 years of age, singleton pregnancy ≥ 37 weeks, American Society of Anesthesiologists' physical status 1 or 2, scheduled for elective cesarean section under spinal anesthesia were included in this study. Patients were randomly assigned into groups to receive normal saline (NS) or one of four different prophylactic doses (0.025 [NE25], 0.05 [NE50], 0.075 [NE75], and 0.1 [NE100] ug/kg/min) of norepinephrine. The primary end point was the incidence of postspinal anesthesia hypotension (systolic blood pressure [SBP] < 80% of baseline) within 15 min after spinal anesthesia. Secondary outcomes included the overall stability of SBP control versus baseline (median performance error [MDPE] and median absolute performance error [MDAPE]), the dose that would be effective in preventing postspinal anesthesia hypotension in 50% (effective dose, ED 50) and 90% (ED90) of patients, other adverse events (bradycardia, nausea, vomiting, hypertension, and the total additional bolus of norepinephrine and atropine), and neonatal outcomes (blood gas values and Apgar scores). The incidence of postspinal anesthesia hypotension in NS, NE25, NE50, NE75, and NE100 groups was 68.42% (13/19), 40.00% (8/20), 20.00% (4/20), 15.00% (3/20), and 10.00% (2/20), respectively. With increasing prophylactic doses of norepinephrine, the incidence of postspinal anesthesia hypotension decreased (p < 0.001), SBP was maintained closer to the baseline (MDPE, p < 0.001; MDAPE, p = 0.001), and the total additional bolus of norepinephrine decreased (p < 0.001). The ED50 and ED90 values of norepinephrine were 0.016 (95% CI: -0.014 - 0.033) and 0.088 (95% CI: 0.068 - 0.133) ug/kg/min, respectively. Other adverse effects, neonatal outcomes, and the total additional bolus of atropine did not differ among the five groups. A prophylactic dose of 0.05 or 0.075 μg/kg/min norepinephrine prevents postspinal anesthesia hypotension in patients undergoing cesarean section.

The clinical effect of dexmedetomidine combined with parecoxib sodium on sedation, antianxiety and prevention of intubation stress in patients undergoing functional endoscopic sinus surgery: a randomised controlled trial

BackgroundTo investigate the effect of intravenous injection of dexmedetomidine combined with parecoxib sodium on sedation and anxiety and stress response of tracheal intubation in patients undergoing functional endoscopic sinus surgery.MethodsOne hundred twenty patients undergoing endoscopic sinus surgery were randomly divided into four groups: group DP, group D, group P and group N. The blood pressure (BP), heart rate (HR), blood oxygen saturation (SPO2), EEG, bispectral index (BIS), Ramsay sedation score and state anxiety questionnaire (SAI) were recorded before administration (T0), 10 min (T1), 20 min (T2) and 30 min (T3) after administration. After 30 min, endotracheal intubation was performed after anesthesia induction. The BP, HR, SPO2 were recorded 1 min before intubation (T4), intubation (T5), 3 min (T6) after intubation, 5 min (T7) after intubation, and blood samples were collected from patients before administration and after intubation 2 min to detect serum cortisol (Cor), adrenalin (E) norepinephrine (NE) and blood glucose (BS).ResultsThere was no significant difference in Ramsay sedation score before anesthesia, but the Ramsay sedation score in group D、DP was significantly higher than that in group P and group N, the BIS, BP, HR and anxiety scores were significantly lower than those in the group P and group N (p < 0.05). There was no significant difference in Ramsay sedation score, BIS value, anxiety score and BP, HR between group D and group DP (p > 0.05). Compared with T4, there was no significant difference in BIS and BP, HR in group D, group DP and group P (p > 0.05), but the BIS, BP and HR in group N were significantly higher than T4, (p < 0.05). Three minutes after intubation there was no statistical difference in the changes of Cor, E, NE and BS values compared with before intubation in group P and group DP (p > 0.05), but the changes of Cor, E, NE and BS values were significantly lower than that in group N (p < 0.05). Compared with T0, the values of NE, E, Cor, BS decreased in group D, DP and P at T4, group DP decreased more significantly than group D (p < 0.05). while the NE, E, Cor, BS of T6 are at the same level as the base value. In group N, the NE, E, Cor, BS of T4 were at the same level of T0, but significantly higher at T6.And at T6, NE and E in group D, P and N were significantly different from those in group DP (p < 0.05).ConclusionPreoperative intravenous infusion of dexmedetomidine combined with parecoxib sodium by functional nasal endoscopy can not only calm and resist anxiety, but also better prevent stress response of endotracheal intubation, which is a safe and effective way of preoperative medication.Trial registrationChiCTR-OPN-17010444. Prospectively registered on 16 January 2017.

In utero inflammatory challenge induces an early activation of the hepatic innate immune response in late gestation fetal sheep.

Chorioamnionitis is associated with inflammatory end-organ damage in the fetus. Tissues in direct contact with amniotic fluid drive a pro-inflammatory response and contribute to this injury. However, due to a lack of direct contact with the amniotic fluid, the liver contribution to this response has not been fully characterized. Given its role as an immunologic organ, we hypothesized that the fetal liver would demonstrate an early innate immune response to an in utero inflammatory challenge. Fetal sheep (131 ± 1 d gestation) demonstrated metabolic acidosis and high cortisol and norepinephrine values within 5 h of exposure to intra-amniotic LPS. Likewise, expression of pro-inflammatory cytokines increased significantly at 1 and 5 h of exposure. This was associated with NF-κB activation, by inhibitory protein IκBα degradation, and nuclear translocation of NF-κB subunits (p65/p50). Corroborating these findings, LPS exposure significantly increased pro-inflammatory innate immune gene expression in fetal sheep hepatic macrophages in vitro. Thus, an in utero inflammatory challenge induces an early hepatic innate immune response with systemic metabolic and stress responses. Within the fetal liver, hepatic macrophages respond robustly to LPS exposure. Our results demonstrate that the fetal hepatic innate immune response must be considered when developing therapeutic approaches to attenuate end-organ injury associated with in utero inflammation.

395-P: N-hydroxyethyl-1-deoxynojirimycin (Miglitol) Restores the Sympathoadrenal Response to Hypoglycemia following Antecedent Hypoglycemia in Diabetic Rats

Antecedent hypoglycemia leads to a reduction in the sympathoadrenal response during subsequent hypoglycemia, i.e., HAAF. We’ve shown previously that this can be corrected in nondiabetic rats by portal vein infusion of N-hydroxyethyl-1-deoxynojirimycin (NEOH-DNJ; miglitol). In the current study we examined the efficacy of portal vein NEOH-DNJ infusion in restoring the sympathoadrenal response for diabetic animals. Diabetes was induced in rats via streptozotocin (STZ) injection (65mg/kg) 4 weeks prior to experiments. Conscious, unrestrained STZ-diabetic rats underwent hyperinsulinemic-hypoglycemic clamps on two consecutive days with a glycemic nadir of 2.6 ± 0.04 mM. On Day 2 animals received portal vein miglitol infusions (1.45 μmol/kg/min) either upstream, (PORups) or liver adjacent (PORadj), while hypoglycemic controls (HYPO) received normal saline infusion. Serial plasma samples were assayed for glucose, insulin, epinephrine (EPI) and norepinephrine (NE). On Day1 peak epinephrine (22.7 ± 2.1 nM) and norepinephrine (2.92 ± 0.3 nM) values were not significantly different between HYPO, PORups and PORadj (P&amp;gt;0.38). On Day 2, EPI values for untreated HYPO controls were suppressed by 85% relative to Day 1 (P &amp;lt; 0.0001). In contrast, EPI responses for miglitol infused groups, PORups (21.3 ± 2.2 nM) and PORadj (16.1 ± 2.01 nM) were not significantly different from Day 1 values (P = 0.75 and 0.50, respectively). NE demonstrated similar responses with HYPO suppressed by 63% on Day 2 (P&amp;lt;0.05), while miglitol treated groups, PORups and PORadj, demonstrated Day 2 NE values not significantly different from Day 1 (P&amp;gt;0.85). Conclusion: The impaired sympathoadrenal response following antecedent hypoglycemia is restored in STZ-diabetic rats by miglitol (NEOH-DNJ) treatment during subsequent hypoglycemia. As with nondiabetic rats, STZ-diabetic animals demonstrated no differences between portal miglitol infusion sites. Disclosure C. Donovan: None. A.J. Jokiaho: None. Funding JDRF (3-SRA-2017-486-S-B)

Microglial‐Mediated PVN Inflammation Precedes Sympathoexcitation but not Hypertension in the Development of Gαi2 Protein‐Dependent Salt Sensitive Hypertension

AimPrevious work in our laboratory has established that hypothalamic paraventricular nucleus (PVN) Gαi2 proteins mediate sympathoinhibitory responses to high salt (HS) diets. The inability to upregulate these proteins in response to a HS diet results in salt sensitive hypertension (ssHTN). Additionally, we have demonstrated that microglial‐mediated PVN inflammation correlates with Gαi2 protein dependent ssHTN. We hypothesize that microglial‐mediated PVN inflammation precedes sympathoexcitation in the development of Gαi2 protein‐dependent ssHTN.MethodsThree‐month‐old male Sprague Dawley rats were implanted with ICV cannulas fitted to osmotic minipumps to deliver an infusion of either targeted Gαi2, which downregulate CNS Gαi2 proteins by ~85%, or scrambled (SCR) oligodeoxynucleotides (ODN) (25μg/5μl/day) and were then put on a 24‐hour or 7‐day normal (NS; 0.6% NaCl) or high (HS; 4% NaCl) salt diet (n=5 per group). Rats were transcardially perfused and brains were extracted and fixed in paraformaldehyde and sucrose. Immunohistochemistry (IHC) was performed to assess PVN microglial activation and for protein levels of pro‐inflammatory cytokines (PIC) IL‐1β, and IL‐6. We ran additional groups in the same manner, previously fitted with radiotelemeters to assess MAP, and sacrificed these groups on day 1 and 7 to obtain whole blood for ELISA plasma norepinephrine (NE) analysis as a measure of sympathetic tone.ResultsIn SCR ODN infused rats, HS diet evoked no change in MAP or microglial reactivity compared to NS control. In rats lacking central Gαi2 proteins, a 24‐hour HS diet evoked significant increases in blood pressure (MAP, mmHg; Gαi2 ODN HS 115 ± 2 vs Gαi2 ODN NS 103 ± 1 p&lt;0.05) and percent activated PVN microglia (% active per sample region; Gαi2 ODN HS 25.1% ± 3 vs Gαi2 ODN NS 16.8 ± 3.7 p&lt;0.05) compared to Gαi2 ODN NS control and SCR ODN rats. Additionally, immunofluorescence detected qualitative increases in IL‐6 and IL‐1β expression in rats lacking central Gαi2 proteins compared to SCR ODN. Plasma NE values were significantly lower in SCR ODN infused animals on HS (plasma NE, nmol/L; SCR ODN HS 43 ± 4.6 vs. SCR ODN NS 65 ± 5.0, p&lt;0.05) than NS control. Gαi2 ODN and HS infused animals on day 1 showed no change in plasma NE levels compared to Gαi2 NS control, but showed significantly lower NE levels than Gαi2 HS on day 7 (plasma NE, nmol/L; Gαi2 ODN day 1 56 ± 6.0 vs. Gαi2 ODN day 7 91 ± 3.2, p&lt;0.05).ConclusionsWhile SCR ODN infused animals inhibit sympathetic activity after 1 day HS and remain normotensive, Gαi2 ODN infused animals fail to do so. Gαi2 ODN infused animals do not, however, exhibit sympathoexcitation on day 1, yet demonstrate increases in MAP, PVN microglial activation, and PVN inflammation. This suggests inflammation may precede sympathoexcitation in Gαi2 protein‐dependent ssHTN.Support or Funding InformationR01 HL139867, R01 HL141406, R56 AG057687, T32 HL007224 MAP, inflammation, and sympathetic characteristics of rats with and without central Gαi2 proteins Gαi2 ODN, 0.6% NaCl diet baseline Gαi2 ODN, 4% NaCl diet day 1 Gαi2 ODN, 4% NaCl diet day 7 SCR ODN, 0.6% NaCl diet baseline SCR ODN, 4% NaCl diet day 1 SCR ODN, 4% NaCl diet day 7 Mean Arterial Pressure (mmHg) 103 ± 1 115 ± 2 * 128 ± 2 * # 102 ± 1 103 ± 2 103 ± 1 Plasma NE (nmol/L) 67 ± 6.0 56 ± 6.0 91 ± 3.2 * # 65 ± 5.0 43 ± 4.6 * 37 ± 2.4 * # Microglia in 200 μm × 200 μm sample area in PVN 22.0 ± 3.1 22.6 ± 2.1 35.33 ± 3.1 * # 26.6 ± 4.2 17.4 ± 2.0 20.5 ± 2.7 % Microglia activated in 200 μm × 200 μm sample area in PVN 16.8 ± 3.7 25.1 ± 3.0 * 29.2 ± 2.5 * 18.0 ± 2.4 11.4 ± 3.5 15.6 ± 2.5 Data presented as mean ± SD, *p&lt;0.05 vs NS baseline within ODN group; #p&lt;0.05 vs. HS day 1 within ODN group

Quantitative sensory testing predicts histological small fiber neuropathy in postural tachycardia syndrome.

Retrospective investigation of the somatosensory profile and prediction of histologic small fiber neuropathy (SFN) in postural orthostatic tachycardia syndrome (POTS) was performed using quantitative sensory testing (QST) as a standardized noninvasive test. In this investigation, full data sets from 30 patients (age: 34.03 ± 10.82 years, n = 6 males), including results of autonomic function testing, norepinephrine values, skin biopsy, and QST, were retrospectively analyzed. The QST data were compared with healthy controls (HCs) (age: 34.20 ± 10.5 years, n = 6 males, t test: 0.95). The evaluation of all QST parameters in POTS compared with HCs yielded differences in all thermal parameters (cold detection threshold: p < 0.05, warm detection threshold: p < 0.001, thermal sensory limen: p < 0.001, cold pain threshold: p < 0.05, and heat pain threshold: p < 0.001) and in paradoxical heat sensations (p < 0.05). Differences in nonpainful stimuli (mechanical detection threshold: p < 0.05 and vibration detection threshold: p < 0.001) were also detected. All patients who had clinical signs of SFN in combination with impairment of small fibers in QST also had SFN on skin biopsy. These results suggest that a non-region-specific SFN in POTS compared with controls can be detected by noninvasive QST that predicts histologic small fiber pathology.

Modulation and role of brain neurotransmitters in pilocarpine-induced seizures in the rat

Epilepsy, a group of serious disorders of the central nervous system characterized by a predisposition to recurrent unprovoked seizures due to abnormal excessive synchronous neural activity. Animal models of pilocarpine-induced seizures have been employed to demonstrate that ongoing epileptic activity in the brain can affect both excitatory and inhibitory synapses and thus neuronal plasticity. Neurotransmitters play a vital role in the functioning of brain. Our study aimed to investigate the changes in brain neurotransmitters in Wistar rat models of pilocarpine-induced seizures. Total 75 animals of pilocarpine-induced seizures models for epilepsy were studied. Behavioral, electroencephalographic and morphological changes induced by systemic administration of pilocarpine hydrochloride were studied in 3–90-day-old rats. Pilocarpine, 100, 200 and 380 mg/kg, presented a characteristic array of behavioral patterns in developing rats. Determination of brain norepinephrine, Gamma-aminobutyric acid (GABA), dopamine and serotonin was carried out using high performance liquid chromatography (HPLC) system, Agilent technologies 1100 series. The mean values of brain norepinephrine, dopamine and serotonin levels in pilocarpine-induced seizures rat brain were significantly increased compared to control group, which consequently, may reduce seizure susceptibility and epilepsy comorbidities. There was a significant decrease in Gamma-aminobutyric acid (GABA) values in treatment group compared to control. Neurotransmitters play a vital role in brain functioning and also have important function in epilepsy status.

Noninvasive Stereotactic Radiotherapy for Renal Denervation in a Swine Model

BackgroundCatheter-based renal denervation (RDN) has achieved promising outcomes to treat hypertension in recent randomized controlled trials. ObjectivesThe purpose of this study was to assess the feasibility, efficacy, and safety of noninvasive stereotactic body radiotherapy (SBRT) as an approach for RDN. MethodsSBRT was performed in 24 renal arteries from 12 normotensive swine at doses of 25, 35, and 45 Gy (n = 4 each), and an additional 4 swine served as controls. Blood pressure (BP), renal function, and serum norepinephrine (NE) values were obtained at baseline and at 7 days, 1 month, and 3 months after SBRT. Abdominal contrast-enhanced computed tomography (CT) was performed after 3 months before euthanasia. Renal NE concentration was determined, and histological analysis and immunohistochemistry against tyrosine hydroxylase were performed. ResultsSBRT procedure was successful in all 12 swine. BP was comparable among groups. Serum and renal NE levels at 3 months were significantly lower in treatment groups compared with control group. Furthermore, SBRT resulted in significantly greater nerve injury score and lower tyrosine hydroxylase score compared with control subjects, whereas there were no statistical differences between SBRT groups. Circumferential lesions created with 35 and 45 Gy were significantly greater than with 25 Gy. CT and histology analysis revealed that animals receiving 35 and 45 Gy experienced more collateral damage, which was minimal in the 25-Gy group. ConclusionsNoninvasive SBRT was feasible and effective for complete, circumferential RDN in a swine model, with dosage at 25 Gy providing the safest short-term profile.