Plasma Norepinephrine Concentrations 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.

A mouse model of chronic primary pain that integrates clinically relevant genetic vulnerability, stress, and minor injury.

Chronic primary pain conditions (CPPCs) affect over 100 million Americans, predominantly women. They remain ineffectively treated, in large part because of a lack of valid animal models with translational relevance. Here, we characterized a CPPC mouse model that integrated clinically relevant genetic (catechol-O-methyltransferase; COMT knockdown) and environmental (stress and injury) factors. Compared with wild-type mice, Comt+/- mice undergoing repeated swim stress and molar extraction surgery intervention exhibited pronounced multisite body pain and depressive-like behavior lasting >3 months. Comt+/- mice undergoing the intervention also exhibited enhanced activity of primary afferent nociceptors innervating hindpaw and low back sites and increased plasma concentrations of norepinephrine and pro-inflammatory cytokines interleukin-6 (IL-6) and IL-17A. The pain and depressive-like behavior were of greater magnitude and longer duration (≥12 months) in females versus males. Furthermore, increases in anxiety-like behavior and IL-6 were female-specific. The effect of COMT genotype × stress interactions on pain, IL-6, and IL-17A was validated in a cohort of 549 patients with CPPCs, demonstrating clinical relevance. Last, we assessed the predictive validity of the model for analgesic screening and found that it successfully predicted the lack of efficacy of minocycline and the CB2 agonist GW842166X, which were effective in spared nerve injury and complete Freund's adjuvant models, respectively, but failed in clinical trials. Yet, pain in the CPPC model was alleviated by the beta-3 adrenergic antagonist SR59230A. Thus, the CPPC mouse model reliably recapitulates clinically and biologically relevant features of CPPCs and may be implemented to test underlying mechanisms and find new therapeutics.

Behavioral and physiological responses of horses to ground-based adaptive horsemanship lessons for veterans with post-traumatic stress disorder (PTSD)

Little literature exists on horses in adaptive horsemanship (AH) despite concerns about their well-being. The study objective was to evaluate behavioral and physiological responses of horses to ground-based AH lessons for veterans with post-traumatic stress disorder (PTSD). Lessons were expected to alter horses’ hormone concentrations, behavior, and muscle activity. Geldings were assigned to AH (n=6; 20.3 ± 1.9 yrs., mean ± SE) or control (CON; stall in arena, n=6; 13.8 ± 1.7 yrs.) conditions for 8-week sessions based on current occupation (AH = equine-assisted services; CON = recreational riding). Plasma cortisol, epinephrine, norepinephrine, and oxytocin concentrations from samples at 0 (start of lesson), 3, 5, 25, and 30 (end) min were determined using assays validated in horses. Surface electromyography (sEMG) (masseter and brachiocephalic; Noraxon, Scottsdale, AZ, USA) and video were recorded continuously. Average rectified values (ARV) and median frequency (MF) were calculated (100 ms) after sEMG data were normalized, rectified, and filtered. The number, number of unique, and duration of stress related behaviors (ethogram) were recorded by three trained (ĸ ≥ 0.7) observers. Data were analyzed with repeated measures ANOVAs (significance P ≤ 0.05) with fixed effects of treatment, time point, week, and their interactions as appropriate and random effect of horse. CON horses had elevated cortisol concentrations (P = 0.0023) at 25 and 30 min. AH horses displayed fewer (P ≤ 0.0491) stress related and unique behaviors. CON horses were described as more (P < 0.0001) anxious, nervous, and stressed than AH horses (calm, comfortable, patient, and relaxed) in qualitative behavior analysis (22 observers). AH horses were less stressed than CON horses.

Fasting for 48h induced similar glucose intolerance in both sexes despite greater perceived stress and decreased estradiol levels in females.

The purpose of this study was to compare the effects of fasting for 48 h on the evoked insulin and glucose responses in males and females, and to explore factors such as stress and estrogen levels that might influence these responses. Healthy, nonobese male (n = 14) and female (n = 14) subjects underwent 48-h fasting trial. Changes in glucose tolerance and insulin levels in response to the oral glucose tolerance test, subjectively perceived stress and catecholamine concentrations were measured in all participants. Estrogen levels were also measured in the female participants during the 48-h fast. Glucose area under the curve (AUC) values increased similarly in both sexes after 48-h fasting (P < 0.05), but females displayed a greater rise in insulin AUC values than males (P < 0.05). Fasting increased plasma epinephrine concentrations in both sexes (P < 0.05), whereas plasma norepinephrine concentrations and subjective stress increased only in females (P < 0.05). Plasma 17-β-estradiol concentrations in females decreased after fasting (P < 0.05). Fasting for 48h induced a similar glucose intolerance in females and males, despite decreased 17-β-estradiol levels and greater psychological and physiological stress in females. These differences represent a plausible explanation for the gender-based differences observed in insulin responses. Retrospectively registered on ClinicalTrials.gov(NCT05545943) in September 19, 2022.

ВЗАИМОСВЯЗЬ ПОКАЗАТЕЛЕЙ НАПРЯЖЕННОСТИ СИМПАТОАДРЕНАЛОВОЙ СИСТЕМЫ У ПАЦИЕНТОВ С ФИБРИЛЛЯЦИЕЙ ПРЕДСЕРДИЙ ДО И ПОСЛЕ ХИРУРГИЧЕСКОГО ЛЕЧЕНИЯ

Introduction. It is known that cardiovascular diseases, including cardiac arrhythmias, are accompanied by increased activation of the sympathetic-adrenal system (SAS). Hyperactivation of the SAS causes an increase in the level of circulating catecholamines - adrenaline and norepinephrine, resulting in desensitization of β-adrenergic receptors (β-AR), aggravation of myocardial contractile dysfunction and the development of arrhythmia. Indicators of SAS tension are β-adrenergic reactivity of erythrocyte membranes (β-ARM) and the level of circulating catecholamines. One of the most common arrhythmias is atrial fibrillation (AF), which leads to a decrease in the quality of life, disability and high mortality. Therefore, among patients with AF, it is important to study the functional viability of β-AR in different periods of the disease. Purpose: to evaluate β-ARM and the level of adrenaline, norepinephrine in patients with AF before and after surgical treatment. Materials and methods. The sample included 47 patients - 31 men and 16 women, the age in the sample was 51 (26; 77) years. All patients were diagnosed with AF based on ECG and 24-hour monitoring. Among the entire sample, 59.6% of patients had paroxysmal, 25.5% persistent, 14.9% long-term persistent forms of AF. All patients underwent surgical treatment of AF using radiofrequency or cryoablation. β-ARM was determined by the method of assessing changes in erythrocyte osmotic resistance as a result of blockade of β-AR in vitro with a selective β-adrenergic blocker (Β-ARM, AGAT, Russia). Plasma epinephrine and norepinephrine concentrations were determined by enzyme-linked immunosorbent assay using Adrenalin ELISA and Noradrenalin ELISA kits (Tecan IBL International, Germany). The parameters were studied in all patients before treatment, in 44 patients after 3 days, in 18 patients after 3 months and in 9 patients after 12 months after ablation. The significance of changes in β-ARM and catecholamine levels before and after ablation was assessed using the Wilcoxon test. The strength of the linear relationship between quantitative indicators was assessed using the Spearman rank correlation coefficient. Results. In the study sample, there were no statistically significant changes in β-ARM and adrenaline levels before and at different times after ablation. Thus, the level of β-ARM before surgery was 18.2 (12.6; 25.4), after 3 days - 22.3 (14.4; 26.6), after 3 months - 20.3 (9.3 ; 29.3), and 12 months after the operation - 27.7 (16.8; 36.7). The level of adrenaline before surgery, 3 days, 3 months and 12 months after surgery was 4.4 (3.7; 6.9), 4.7 (3.0; 6.4), 4.6 (2 .5; 6.6), 5.6 (9.1; 8.8). However, an increase in the level of norepinephrine was found 12 months after ablation compared with the values before treatment and 3 days after treatment by 1.7 and 1.8 times, respectively (p = 0.028). The level of norepinephrine before surgery, 3 days, 3 months and 12 months after surgery was 40.9 (18.7; 56.6), 38.6 (14.8; 49.6), 46.7 (25 .6; 57.3), 69.3 (65.1; 80.1). Before surgery, β-ARM and norepinephrine levels were linearly correlated (r = 0.335, p = 0.037), but after treatment, the linear correlation disappeared. At 3 and 12 months after ablation, there was a strong linear correlation between adrenaline and norepinephrine levels (r = 0.611, p = 0.012; r = 0.786, p = 0.036, respectively). Conclusion. In the sample of patients with AF, β-ARM and norepinephrine levels were linearly correlated before treatment, but after ablation, the correlation disappeared. At the same time, the values of β-ARM do not change statistically significantly, and the level of norepinephrine increases during a 12-month follow-up. Thus, 12 months after treatment in patients with AF, the activity of the CAS increases, but the functional viability of beta-AR does not change significantly.

Effects of the menstrual cycle on EPOC and fat oxidation after low-volume high-intensity interval training.

Low-volume high-intensity interval training (HIIT) for weight loss has become prevalent in recent years, with increased excess post-exercise oxygen consumption (EPOC) as the mechanism. However, the influence of the menstrual cycle on EPOC and fat oxidation following low-volume HIIT is unclear. This study aimed to investigate the effect of the menstrual cycle on the increase in EPOC and fat oxidation after low-volume HIIT. Twelve eumenorrheic women participated during their early follicular and luteal phases. On each experimental day, they performed low-volume HIIT comprising fifteen repeated 8 s sprint cycling tests with 12 s rests, for 5 min. Expired gas samples were collected before and every 60 min until 180 min post-exercise. EPOC was defined as the increase in oxygen consumption from the resting state, and the total EPOC and fat oxidation were calculated from the total time of each measurement. Blood samples for serum estradiol, progesterone, free fatty acids, blood glucose, lactate, and plasma noradrenaline were collected and assessed before immediately after, and at 180 min post-exercise and were assessed. Serum estradiol and progesterone were significantly higher in the luteal phase than the follicular phase (P<0.01 for both). No significant differences in total EPOC and fat oxidation were found between the menstrual phases. Serum free fatty acid, blood glucose, lactate, and plasma noradrenaline concentrations were not affected by the menstrual cycle. These results suggest that the menstrual cycle does not affect the increase in EPOC or fat oxidation after low-volume HIIT.

Sympathetic and hemodynamic responses to exercise in heart failure with preserved ejection fraction.

Excessive sympathetic activity during exercise causes heightened peripheral vasoconstriction, which can reduce oxygen delivery to active muscles, resulting in exercise intolerance. Although both patients suffering from heart failure with preserved and reduced ejection fraction (HFpEF and HFrEF, respectively) exhibit reduced exercise capacity, accumulating evidence suggests that the underlying pathophysiology may be different between these two conditions. Unlike HFrEF, which is characterized by cardiac dysfunction with lower peak oxygen uptake, exercise intolerance in HFpEF appears to be predominantly attributed to peripheral limitations involving inadequate vasoconstriction rather than cardiac limitations. However, the relationship between systemic hemodynamics and the sympathetic neural response during exercise in HFpEF is less clear. This mini review summarizes the current knowledge on the sympathetic (i.e., muscle sympathetic nerve activity, plasma norepinephrine concentration) and hemodynamic (i.e., blood pressure, limb blood flow) responses to dynamic and static exercise in HFpEF compared to HFrEF, as well as non-HF controls. We also discuss the potential of a relationship between sympathetic over-activation and vasoconstriction leading to exercise intolerance in HFpEF. The limited body of literature indicates that higher peripheral vascular resistance, perhaps secondary to excessive sympathetically mediated vasoconstrictor discharge compared to non-HF and HFrEF, drives exercise in HFpEF. Excessive vasoconstriction also may primarily account for over elevations in blood pressure and concomitant limitations in skeletal muscle blood flow during dynamic exercise, resulting in exercise intolerance. Conversely, during static exercise, HFpEF exhibit relatively normal sympathetic neural reactivity compared to non-HF, suggesting that other mechanisms beyond sympathetic vasoconstriction dictate exercise intolerance in HFpEF.

Distinct Mechanisms Responsible for the Increase in Glucose Production and Ketone Formation Caused by Empagliflozin in T2DM Patients.

To examine the mechanisms responsible for the increase in glucose and ketone production caused by empagliflozin in patients with type 2 diabetes mellitus (T2DM). Twelve subjects with T2DM participated in two studies performed in random order. In study 1, endogenous glucose production (EGP) was measured with 8-h infusion of 6,6,D2-glucose. Three hours after the start of 6,6,D2-glucose infusion, subjects ingested 25 mg empagliflozin (n = 8) or placebo (n = 4), and norepinephrine (NE) turnover was measured before and after empagliflozin ingestion with 3H-NE infusion. Study 2 was similar to study 1 but performed under pancreatic clamp conditions. When empagliflozin was ingested under fasting conditions, EGP increased by 31% in association with a decrease in plasma glucose (-34 mg/dL) and insulin (-52%) concentrations and increases in plasma glucagon (+19%), free fatty acid (FFA) (+29%), and β-hydroxybutyrate (+48%) concentrations. When empagliflozin was ingested under pancreatic clamp conditions, plasma insulin and glucagon concentrations remained unchanged, and the increase in plasma FFA and ketone concentrations was completely blocked, while the increase in EGP persisted. Total-body NE turnover rate was greater in subjects receiving empagliflozin (+67%) compared with placebo under both fasting and pancreatic clamp conditions. No difference in plasma NE concentration was observed in either study. The decrease in plasma insulin and increase in plasma glucagon concentration caused by empagliflozin is responsible for the increase in plasma FFA concentration and ketone production. The increase in EGP caused by empagliflozin is independent of the change in plasma insulin or glucagon concentrations and is likely explained by the increase in NE turnover.

Compound lidocaine/prilocaine cream combined with tetracaine prevents cough caused by extubation after general anaesthesia: a randomised controlled trial

BackgroundCoughing caused by tracheal extubation is common following general anaesthesia. Heavy aerosol production by coughing during recovery from general anaesthesia in patients with respiratory infections (especially COVID-19) may be one of the highest risk factors for infection in healthcare workers. The application of local anaesthetics to the endotracheal tube is an effective method to reduce coughing. The most commonly used anaesthetics are compound lidocaine/prilocaine cream and tetracaine spray. However, coughing still occurs when the two anaesthetics are used alone. We speculated that the application of compound lidocaine/prilocaine combined with tetracaine spray would better prevent coughing caused by tracheal extubation.MethodsPatients scheduled for laparoscopic cholecystectomy or cholecystectomy combined with common bile duct exploration under general anaesthesia were randomly assigned to Group C (saline spray), Group L (2 g compound lidocaine/prilocaine cream contains 5 mg of lidocaine and 5 mg prilocaine)), Group T (tetracaine) and Group F (compound lidocaine/prilocaine cream combined with tetracaine). The incidence of coughing, the endotracheal tube tolerance assessment, the incidence of agitation, the active extubation rate, the incidence of postoperative pharyngeal pain and the incidence of postoperative cough were recorded and analysed. Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and the plasma concentrations of epinephrine and norepinephrine were measured immediately before extubation and 1 min after extubation.ResultsA total of 211 patients were randomly assigned to Group C (53 cases), Group L (52 cases), Group T (52 cases) and Group F (54 cases). The primary result is assessment of the incidence of cough. The patients emerged from general anaesthesia, 96% of Group C had cough, which was significantly reduced in Group L (61.5%, P < 0.001), Group T (75%, P < 0.05) and Group F (22.2%, P < 0.001). Group F had a significantly reduced incidence of cough compared to Group L and Group T (P < 0.05 or P < 0.01, respectively). The secondary results were assessed. The endotracheal tube tolerance score in Group C ((1, 3) 4, P < 0.001) was higher than Group L ((0, 1) 2), Group T ((0, 1.25) 3) and Group F ((0, 0) 1). Group F had a significantly lower score than Group L and Group T (P < 0.05, P < 0.01, respectively). The incidence of agitation and the active extubation rate were also higher in Group C (96.2% and 71.7%, respectively, P < 0.001) than Group L (48.1% and 15.4%, respectively), Group T (61.5% and 26.9%, respectively) and Group F (17.3% and 7.7%, respectively). Blood pressure, HR and plasma concentrations of epinephrine and norepinephrine were significantly higher in Group C than in all other groups at the time of extubation and 1 min after extubation (P < 0.001). Group F exhibited significantly reduced blood pressure, heart rate and plasma concentrations of epinephrine and norepinephrine compared to Group L and Group T (P < 0.05, P < 0.01 or P < 0.001, respectively). The incidence of postoperative pharyngeal pain and the incidence of postoperative cough were not significantly different among the groups.ConclusionsCompound lidocaine/prilocaine cream combined with tetracaine may be a more effective approach for preventing coughing and stabilising circulation during extubation following general anaesthesia. This may play an important role in preventing medical staff from contracting respiratory infectious diseases.Trial registrationChinese Clinical Trial Registry: ChiCTR2200058429 (registration date: 09–04-2022) “retrospectively registered”.

PS-BPB07-2: AFFERENT RENAL NERVES CONTRIBUTE TO LEFT VENTRICULAR DYSFUNCTION THROUGH HYPOTHALAMIC VASOPRESSIN-MEDIATED CENTRAL SYMPATHOEXCITATION IN HYPERTENSIVE HEART FAILURE MODEL

Objective: Afferent renal nerves may contribute to the development and progression of heart failure, which, however, has not been well investigated. This study aimed to examine whether the afferent renal nerve input contributes to hypertensive cardiac dysfunction. Design and method: Male Dahl salt-sensitive rats were fed 0.3% low-salt diet (LS) or 8% high-salt diet (HS) from 6 weeks of age. HS-fed rats were divided into selective afferent renal denervation (HS-ARDN) or sham operation (HS-Sham) at 9 weeks. The effects of ARDN on central sympathetic regulation were investigated at 12 weeks. In another cohort, its effects on the cardiac phenotypes were evaluated at 16 weeks, with adding total renal denervation (HS-TRDN) group. Results: At 12 weeks, systolic blood pressure (SBP) measured by tail-cuff method was significantly increased in HS-Sham compared to LS, while there was no significant difference between HS-Sham and HS-ARDN. Plasma norepinephrine concentration was increased in HS-Sham compared to LS and was attenuated in HS-ARDN. The c-Fos expression, a neuronal activation marker, in presympathetic neurons within hypothalamic paraventricular nucleus (PVN) and rostral ventral lateral medulla (RVLM) was also increased in HS-Sham and attenuated in HS-ARDN, which was in parallel with the c-Fos expression in vasopressin-expressing neurons within PVN. At 16 weeks, SBP was similarly increased in HS-Sham, HS-ARDN, and HS-TRDN compared to LS. Although the parameters of left ventricular (LV) hypertrophy, such as LV wall thickness by echocardiography and LV weight, were significantly increased in HS-Sham, HS-ARDN, and HS-TRDN compared to LS, there was no significant difference between HS-fed three groups. Echocardiographic LV fractional shortening was significantly decreased in HS-Sham compared to LS, and was attenuated to the same extent in HS-ARDN and HS-TRDN. Histological LV fibrosis determined by Masson trichrome staining and mRNA expression of ANP and CTGF in LV were significantly increased in HS-Sham compared to LS; these changes were similarly ameliorated in both HS-ARDN and HS-TRDN. Conclusion: The input from renal afferent nerves contributes to sympathoexcitation and cardiac dysfunction independently of SBP in Dahl salt-sensitive hypertensive heart failure model. Vasopressin production in PVN may be involved in the renal afferents-mediated sympathetic regulation.

Relationship between haemodynamic indicators and haemogram in patients with heart failure.

Pulmonary congestion, reduced cardiac output, neurohumoral factor activation, and decreased renal function associated with decreased cardiac function may have various effects on haemograms. The relationship between these factors and haemograms in patients with heart failure has not been sufficiently investigated. Recently, it was suggested that the lungs are an important site for platelet (Plt) biosynthesis and that it is necessary to study the relationship between pulmonary congestion and Plt count in heart failure in detail. In this study, we examined the relationship between various haemodynamic indicators and haemograms in detail using statistical analyses. A total of 345 patients who underwent cardiac catheterization for the evaluation of cardiac function between 1 January 2015 and 31 December 2020 were included in the study. Haemodynamic indices, including left ventricular end-diastolic pressure (LVEDP) and cardiac index (CI), were measured. Plasma noradrenaline (Nor) concentration, estimated glomerular filtration rate (eGFR), white blood cell (WBC) count, haemoglobin (Hb) level, and Plt count were measured using blood samples collected at the same time. Structural equation modelling (SEM) was used to examine the relationship between LVEDP, CI, plasma Nor concentration, eGFR, WBC count, Hb level, and Plt count. Bayesian inference using SEM was performed for Plt count. A total of 345 patients (mean age: 66.0±13.2years) were included in this study, and 251 (73%) patients were men. After simple and multiple regression analyses, path diagrams were drawn and analysed using SEM. LVEDP showed a significant negative relationship with Plt count (standardized estimate: -0.129, P=0.015), and CI showed a significant negative relationship with Hb level (standardized estimate: -0.263, P<0.001). Plasma Nor concentration showed a significant positive relationship with WBC count (standardized estimate: 0.165, P=0.003) and Plt count (standardized estimate: 0.198, P<0.001). The eGFR had a significant positive relationship with Hb level (standardized estimate: 0.274, P<0.001). Bayesian inference using SEM revealed no relationship between LVEDP and Hb level or WBC count but a significant negative relationship between LVEDP and Plt count. LVEDP, CI, plasma Nor concentration, and eGFR were related to WBC count, Hb level, and Plt count in patients with heart failure. There was a strong relationship between elevated LVEDP and decreased Plt count, suggesting that pressure overload on the lungs may interfere with the function of the lung as a site of Plt biosynthesis.

α-Adrenergic blockade prevented environmental temperature reduction-induced transient portal pressure surge in cirrhotic and portal hypertensive rats.

Exposure to low temperatures has been associated with increased gastroesophageal variceal bleeding in patients with cirrhosis and portal hypertension; however, the mechanism remains unclear. Therefore, the aim of the present study was to evaluate the impact of environmental temperature reduction on portal hypertension and the role of adrenergic signaling pathways in this phenomenon. Male Sprague-Dawley rats underwent common bile duct ligation or partial portal vein ligation to induce liver cirrhosis and/or portal hypertension. The impacts of acute or chronic changes in environmental temperature were surveyed. The results showed that acute cooling from 25 to 15°C and 5°C increased the portal pressure by 10.6% and 15.5% in cirrhotic rats, and by 22.2% and 36.1% in portal hypertensive rats, respectively. The transient portal pressure surge started shortly after cooling, reached a peak within 5 min and returned to baseline after 10 min. Systemic vascular resistance, mean arterial pressure and splanchnic blood flow increased significantly at the same time. Plasma epinephrine and norepinephrine concentrations, phospholipase C, protein kinase C activity and myosin phosphorylation of peripheral arteries increased significantly in response to cooling. Phentolamine (an α-blocker) but not propranolol (a non-selective β-blocker) dose-dependently inhibited the transient portal pressure surge and aforementioned molecular changes. In conclusion, environmental temperature reduction induced peripheral vasoconstriction via α-adrenergic pathways, and redistribution of blood flow to the splanchnic system led to a surge in transient portal pressure. Treatment with α-adrenergic receptor antagonists may exert additional benefits in controlling portal hypertension, especially on exposure to low temperatures.

Application of Preoperative Adductor Canal Block Coupled with General Anaesthesia in Elderly Patients Undergoing Total Knee Arthroplasty.

Objective To investigate the clinical application of preoperative adductor canal block combined with general anaesthesia in elderly patients with total knee arthroplasty. Methods Seventy-four patients scheduled for elective TKA in Shaanxi Nuclear Industry Hospital No. 215 were selected and were assigned into group A (continuous ACB prior to the induction of anaesthesia) and group B (continuous ACB after extraction of the tracheal catheter post-operatively) according to the random number table method. Pre and postoperative plasma adrenaline and noradrenaline levels were measured; mean arterial pressure (MAP) and heart rate (HR) were recorded at the admission and the surgical skin incision; intraoperative sufentanil dosage, number of analgesic pump presses at 48 h postoperatively; postoperative adverse effects and length of stay were recorded; resting and active VAS pain scores were assessed at 4, 8, 12, 24, and 48 h postoperatively. Results Group B experienced a substantial increase in MAP and HR at the time of surgical skin incision, while group A registered a smaller change and a stable haemodynamic profile (P < 0.05). The plasma adrenaline and norepinephrine concentrations in group B were elevated compared to the preoperative period, differentially with group A. Group A received less intraoperative sufentanil than Group B (P < 0.05). Conclusion Collectively, postoperative resting VAS scores and active VAS scores remained lower in TKA patients who were subjected to preoperative and postoperative ACB, while preoperative ACB in conjunction with general anaesthesia decreased intraoperative sufentanil dosage, contained the surgical stress response, and maintained a stable intraoperative haemodynamic state, in what is probably a preferable option for elderly patients undergoing TKA. This study has served as a reference for postoperative patients to reduce their medication and for clinicians in the treatment going forward.

Effect of Green Tea Extract Ingestion on Fat Oxidation during Exercise in the Menstrual Cycle: A Pilot Study.

In women, fat oxidation during exercise changes with the menstrual cycle. This study aimed to investigate the effect of green tea extract (GTE) ingestion on fat oxidation during exercise depending on the menstrual cycle phase. Ten women with regular menstrual cycles participated in this randomized, double-blind, crossover study. GTE or placebo was administered during the menstrual cycle’s follicular phase (FP) and luteal phase (LP). Participants cycled for 30 min at 50% maximal workload, and a respiratory gas analysis was performed. Serum estradiol, progesterone, free fatty acid, plasma noradrenaline, blood glucose, and lactate concentrations were assessed before, during, and after the exercise. Fat oxidation, carbohydrate oxidation, and the respiratory exchange ratio (RER) were calculated using respiratory gas. Fat oxidation during the exercise was significantly higher in the FP than in the LP with the placebo (p < 0.05) but did not differ between the phases with GTE. Carbohydrate oxidation, serum-free fatty acid, plasma noradrenaline, blood glucose, and lactate concentrations were not significantly different between the phases in either trial. Our results suggest that GTE ingestion improves the decrease in fat oxidation in the LP.

Importance of catecholamine signaling in the development of platelet exhaustion after traumatic injury

BackgroundImpaired ex vivo platelet aggregation is common in trauma patients. The mechanisms driving these impairments remain incompletely understood, but functional platelet exhaustion due to excessive in vivo activation is implicated. Given platelet adrenoreceptors and known catecholamine surges after injury, impaired ex vivo platelet aggregation in trauma patients may be linked to catecholamine‐induced functional platelet exhaustion. ObjectiveTo determine the relationship of catecholamines with platelet‐dependent hemostasis after injury and to model catecholamine‐induced functional platelet exhaustion in healthy donor platelets. Patients/MethodsWhole blood was collected from 67 trauma patients as part of a prospective cohort study. Platelet aggregometry and rotational thromboelastometry were performed, and plasma epinephrine (EPI) and norepinephrine (NE) concentrations were measured. The effect of catecholamines on healthy donor platelets was examined in a microfluidic model, with platelet aggregometry, and by flow cytometry examining surface markers of platelet activation. ResultsIn trauma patients, EPI and NE were associated with impaired platelet aggregation (both p < 0.05), and EPI was additionally associated with decreased viscoelastic clot strength, increased fibrinolysis, and mortality (all p < 0.05). In healthy donors, short duration incubation with EPI enhanced platelet aggregation, platelet adhesion under flow, and increased glycoprotein IIb/IIIa activation, while weaker effects were observed with NE. Compared with short incubation, longer incubation with EPI resulted in decreased platelet adhesion, platelet aggregation, and surface expression of glycoprotein IIb/IIIa. ConclusionsThese findings suggest sympathoadrenal activation in trauma patients contributes to impaired ex vivo platelet aggregation, which mechanistically may be explained by a functionally exhausted platelet phenotype under prolonged exposure to high plasma catecholamine levels.

Improvement of several stress response and sleep quality hormones in men and women after sleeping in a bed that protects against electromagnetic fields

BackgroundThe electromagnetic fields (EMFs) emitted by the technologies affect the homeostatic systems (nervous, endocrine, and immune systems) and consequently the health. In a previous work, we observed that men and women, after 2 months of using a bed with a registered HOGO system, that prevents and drain EMFs, improved their immunity, redox and inflammatory states and rejuvenated their rate of aging or biological age. Since, EMFs can act as a chronic stressor stimulus, and affect the sleep quality. The objective of this work was to study in men and women (23–73 years old) the effect of sleeping for 2 months on that bed in the blood concentrations of several hormones related to stress response and sleep quality as well as to corroborate the rejuvenation of their biological age.MethodsIn 18 men and women, plasma concentration of cortisol, dehydroepiandrosterone (DHEA), catecholamines (epinephrine, norepinephrine and dopamine), serotonin, oxytocin and melatonin were analyzed before and after 2 months of using the HOGO beds. A group of 10 people was used as placebo control. In another cohort of 25 men (20 experimental and 5 placebo), the effects of rest on the HOGO system on the concentration of cortisol and testosterone in plasma were studied. In all these volunteers, the biological age was analyzed using the Immunity Clock model.ResultsThere is a significant increase in plasma concentration of DHEA, norepinephrine, serotonin, oxytocin, and melatonin as well as in testosterone, after resting for 2 months in that bed with the EMFs avoiding system. In addition, decreases in Cortisol/DHEA and Testosterone/cortisol ratio and plasma dopamine concentration were observed. No differences were found in placebo groups. In all participants that slept on HOGO beds, the biological age was reduced.ConclusionsSleeping in a bed that isolates from EMFs and drain them can be a possible strategy to improve the secretion of hormones related to a better response to stress and sleep quality, which means a better endocrine system, and consequently better homeostasis and maintenance of health. This fact was confirmed with the slowdown in the rate of aging checked with a rejuvenation of the biological age.

54-LB: Distinct Mechanisms Are Responsible for the Increase in Endogenous Glucose Production and Ketone Formation following Empagliflozin in T2DM Patients

Aim: To examine the mechanisms responsible for the increase in glucose and ketone production caused by SGLT2 inhibition with empagliflozin in T2DM patients. Research Design and Methods: 12 T2DM subjects (Age = 53; BMI = 31.7; HbA1c = 7.4%) participated in two studies performed in random order. At 0700h following an overnight fast subjects received an 8-hour infusion of 6,6D2-glucose to measure endogenous (hepatic) glucose production. At 0900 h an infusion of 3H-norepinephrine was started. At 1000h subjects ingested 25 mg of empagliflozin (n=8) or matching placebo (n=4) and were followed for 5 hours (1500 h) . Within 1 week subjects returned for a repeat study with pancreatic clamp to maintain plasma insulin and glucagon concentrations constant at the basal level. As per study one, subjects ingested empagliflozin 25 mg or placebo prior to the pancreatic clamp. Results: When empagliflozin was ingested under fasting conditions, EGP increased by 31% in association with a decrease in plasma glucose (-34 mg/dl) and insulin (-52%) concentrations and increases in plasma glucagon (+19%) , FFA (+29%) and β-hydroxybutyrate (β-HB) (+48%) concentrations. When empagliflozin was ingested under pancreatic clamp conditions, plasma insulin and glucagon concentrations remained unchanged, and the increase in plasma FFA and ketone concentrations was completely blocked, while the increase in EGP persisted. Total-body NE turnover rate increased significantly in subjects receiving empagliflozin (+67%) compared to placebo under both fasting and pancreatic clamp conditions. No difference in plasma norepinephrine concentration was observed in either study. Conclusion: The decrease in plasma insulin and increase in plasma glucagon concentration caused by empagliflozin is responsible for the increase in plasma FFA concentration and ketone production. The increase in EGP caused by empagliflozin is independent of the change in plasma insulin or glucagon concentrations and is explained by the increase in total-body NE turnover. Disclosure S. Abdelgani: None. J. M. Adams: None. G. Daniele: n/a. F. Almulla: None. R. A. Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck &amp; Co., Inc., Speaker’s Bureau; AstraZeneca. M. Abdul-ghani: None. M. Abu-farha: None. S. Del prato: Advisory Panel; Applied Therapeutics, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Consultant; Menarini Group, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Speaker’s Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck &amp; Co., Inc., Sanofi, Stock/Shareholder; Novo Nordisk A/S. Funding National Institute of Health, Boehringer Ingelheim provided empagliflozin and placebo

Electroacupuncture Decreases Chronic Inflammation, Sympathetic Activities, and Blood Pressure in Dahl Salt‐Sensitive Hypertensive Rats

Low grade chronic inflammation is detected in hypertensive patients. The dahl salt‐sensitive hypertensive (DSS HTNive) rat model has been investigated on different pathways how excessive salt intake induces elevation in blood pressure (BP). Previous studies have demonstrated low grade chronic inflammation and elevated sympathetic outflow in DSS HTNive rats. We have shown in series of studies that sympathoinhibitory electroacupuncture (SI‐EA) at acupoints ST36‐37 suppresses sympathoexcitatory cardiovascular responses and reduces BP in HTNive rats and patients. Other researchers reported that EA at acupoints SP6‐7 as well as ST 36‐37 decreases inflammation. Therefore, we hypothesized that combined EA (cEA) at ST36‐37 and SP6‐7 induces greater reduction in BP than SI‐EA through the modification of chronic inflammation and elevated sympathetic activity in DSS HTNive rats. DSS rats (n=36) were fed with 4% salt diet and treated with SI‐EA, cEA or Sham‐EA (without electrical stimulation) twice weekly for five weeks once the rats developed moderate HTN (SBP 160±5 mmHg). Systolic/diastolic BP (SBP/DBP) and heart rate (HR) were measured by weekly tail‐cuff non‐invasively. Upon completion of different treatments, cardiac perfusion was performed under anesthesia, and plasma samples were collected to measure the concentration of high‐sensitivity c‐reactive protein (hs‐CRP), an indicator of low‐grade chronic inflammation, and norepinephrine (NE) by ELISA. We observed that DSS rats fed with 4% salt diet developed moderate HTN (SBP 163±3.8 mmHg) in five weeks compared to those fed with standard rat chow (SBP 129±5.4 mmHg). After five weeks of treatments, the EA treated rats displayed significantly lowered SBP (138±4.7 mmHg for cEA group, 147±4.2 mmHg for SI‐EA group) compared to the Sham‐EA treated rats (SBP 191±6.8 mmHg). The cEA group showed greater reduction in SBP by 28% than the SI‐EA group (23%) compared to Sham‐EA group. The DBP but not HR among the groups exhibited similar trends. Furthermore, we observed that plasma NE concentrations showed greater reduction in the cEA group by 24.5% than the SI‐EA group (11.4% decrease) compared to the Sham‐EA group. In addition, the rats treated with cEA displayed lowest concentration of plasma hs‐CRP (225 ug/mL) in the three hypertensive groups. As such, our findings suggest that cEA at ST36‐37 and SP6‐7 induces larger BP‐lowering effect than SI‐EA in DSS HTNive rats and was associated with reduction of biomarkers of chronic inflammation and sympathetic outflow.

Clinical study on effect of wrist-ankle acupuncture on incidence of hypertension after intubation during induction of general anesthesia

ABSTRACT Objective To observe the effect of wrist-ankle acupuncture on the incidence of hypertension after tracheal intubation during induction of general anesthesia. Methods 200 patients receiving selective surgery under tracheal intubation and general anesthesia in our Hospital were selected and divided into control group and wrist-ankle acupuncture group using the random number table method, with 100 patients in each group. Sufentanil, cisatracurium besilate, remifentanil, etomidate and lidocaine hydrochloride were used for anesthesia induction, and intravenously injected according to the onset time of drugs, successively. The wrist-ankle acupuncture group was needled in bilateral upper 1, 2 and 3 areas, while the control group was treated with false acupuncture.Blood pressure and related blood biochemical indexes were measured and observed at different stages in each group. Result The incidence of blood pressure exceeding 20% and 30% of basal blood pressure within 5 minutes after intubation was as follows:wrist-ankle acupuncture group 11.83% and 6.45%; control group 29.79% and 22.34%, The incidence in the study group was lower than that in the control group. Norepinephrine concentration in the wrist-ankle acupuncture group was significantly lower than that before induction (P < .05), and plasma Norepinephrine concentration in the wrist-ankle acupuncture group was significantly lower than that in the control group after intubation (P < .05). The plasma Norepinephrine concentration in the wrist-ankle acupuncture group was significantly lower than that in the control group after intubation (P < .05) Conclusion wrist-ankle acupuncture can prevent hypertension after intubation during anesthesia induction. Moreover, it is safe, effective, minimally invasive. Therefore, it is easy to be popularized in clinical practice.

Effect of liver resection-induced increases in hepatic venous pressure gradient on development of postoperative acute kidney injury

BackgroundThe impact of changes in portal pressure before and after liver resection (defined as ΔHVPG) on postoperative kidney function remains unknown. Therefore, we investigated the effect of ΔHVPG on (i) the incidence of postoperative AKI and (ii) the renin-angiotensin system (RAAS) and sympathetic nervous system (SNS) activity.MethodsWe included 30 patients undergoing partial liver resection. Our primary outcome was postoperative AKI according to KDIGO criteria. For our secondary outcome we assessed the plasma renin, aldosterone, noradrenaline, adrenaline, dopamine and vasopressin concentrations prior and 2 h after induction of anaesthesia, on the first and fifth postoperative day. HVPG was measured prior and immediately after liver resection.ResultsΔHVPG could be measured in 21 patients with 12 patients HVPG showing increases in HVPG (∆HVPG≥1 mmHg) while 9 patients remained stable. AKI developed in 7/12 of patients with increasing HVPG, but only in 2/9 of patients with stable ΔHVPG (p = 0.302). Noradrenalin levels were significantly higher in patients with increasing ΔHVPG than in patients with stable ΔHVPG. (p = 0.009). Biomarkers reflecting RAAS and SNS activity remained similar in patients with increasing vs. stable ΔHVPG.ConclusionsPatients with increased HVPG had higher postoperative creatinine concentrations, however, the incidence of AKI was similar between patients with increased versus stable HVPG.