Epinephrine Concentrations Research Articles

Paliperidone-Induced Acute Hyperglycemia Is Caused by Adrenaline Secretion via the Activation of Hypothalamic AMP-Activated Protein Kinase.

Although paliperidone-related hyperglycemia has been extensively examined, the underlying mechanisms have not yet been elucidated. We investigated the effects of a single intravenous injection of paliperidone (0.2, 0.4, or 0.6 mg/kg) on serum concentrations of glucose and other endogenous metabolites in rats. We also examined the effects of a single intravenous injection of paliperidone (0.4 mg/kg) on AMP-activated protein kinase (AMPK) activity in the hypothalamus and liver. To clarify the relationship between AMPK activity and adrenaline secretion, the effects of berberine, which inhibits hypothalamic AMPK, on paliperidone-induced hyperglycemia were assessed. Significant increases were observed in serum glucose, adrenaline, and insulin concentrations following intravenous injections of paliperidone at doses of 0.4 and 0.6 mg/kg. A propranolol pretreatment attenuated paliperidone-induced increases in serum concentrations of glucose, but not adrenaline. Significant increases were also noted in phosphorylated AMPK concentrations in the hypothalamus following the administration of paliperidone at a dose of 0.4 mg/kg. A berberine pretreatment attenuated paliperidone-induced increases in blood concentrations of glucose, adrenaline, and insulin and phosphorylated AMPK concentrations in the hypothalamus. Collectively, the present results demonstrated that an acute treatment with paliperidone induced hyperglycemia, which was associated with the effects of hypothalamic AMPK activation on the secretion of adrenaline.

A randomized clinical trial on effects of alfaxalone combined with medetomidine and midazolam in preventing stress-related neurohormonal and metabolic responses of isoflurane-anesthetized cats undergoing surgery.

To evaluate the effects of IM and IV administration of alfaxalone alone and in combination with medetomidine, midazolam, or both on key stress-related neurohormonal and metabolic changes in isoflurane-anesthetized cats undergoing ovariohysterectomy or castration. 72 client-owned mixed-breed cats undergoing ovariohysterectomy or castration between October 4, 2018, and January 10, 2020. For each type of surgery, cats were assigned to 1 of 6 premedication protocols groups, with 6 cats/group: physiologic saline (0.9% NaCl) solution (0.5 mL, IM) and alfaxalone (5 mg/kg, IV); physiologic saline solution (0.5 mL, IM) and alfaxalone (5 mg/kg, IM); medetomidine (50 μg/kg, IM) and alfaxalone (5 mg/kg, IV); medetomidine (50 μg/kg, IM) and alfaxalone (5 mg/kg, IM); midazolam (0.5 mg/kg, IM), medetomidine (50 μg/kg, IM), and alfaxalone (5 mg/kg, IV); or midazolam (0.5 mg/kg, IM), medetomidine (50 μg/kg, IM), and alfaxalone (5 mg/kg, IM). Venous blood was taken before pretreatment, pre- and postoperatively during anesthesia with isoflurane and oxygen, and during early and complete recovery. Compared with baseline concentrations, plasma adrenaline and noradrenaline concentrations decreased during anesthesia in cats premedicated with alfaxalone alone and in combination with medetomidine. The combination of medetomidine, midazolam, and alfaxalone prevented an excessive increase in catecholamines during anesthesia and surgery in cats. Postoperative plasma cortisol concentration after ovariohysterectomy was lower for cats premedicated with the combination of medetomidine and alfaxalone or the combination of medetomidine, midazolam, and alfaxalone, compared with cats premedicated with alfaxalone alone. Cats treated with combinations that included medetomidine and midazolam had hyperglycemia during anesthesia. Cats treated with medetomidine or medetomidine and midazolam in combination with alfaxalone, compared with alfaxalone alone, had lower concentrations of nonesterified fatty acids during anesthesia. Behavioral recovery scores were lower (better) for cats that received medetomidine in addition to alfaxalone, compared with alfaxalone alone. Results indicated that pretreatments with medetomidine and alfaxalone or with medetomidine, midazolam, and alfaxalone were useful for preventing stress-related hormonal and metabolic responses, other than hyperglycemia, during isoflurane anesthesia and surgery in cats.

EPINEPHRINE NASAL SPRAY (ARS-1) AND INTRAMUSCULAR INJECTION: PHARMACOKINETIC/PHARMACODYNAMIC DIFFERENCES AND DIFFERENTIAL AFFINITIES FOR ADRENERGIC RECEPTORS

<h3>Introduction</h3> Although considered clinically indistinguishable, pharmacokinetics (PK) and pharmacodynamics (PD) between epinephrine intramuscular (IM) injection devices and manual IM injection are different. Differences in PD profiles of epinephrine products affecting blood pressure (BP) were investigated. <h3>Methods</h3> This integrated analysis was based on 4 randomized, cross-over, phase 1 studies (175 participants) comparing epinephrine manual IM 0.3 mg injection, epinephrine 0.3 mg injection devices, and epinephrine 1 mg nasal spray (ARS-1) once and twice dosing. IRB approval was obtained by all clinical sites. <h3>Results</h3> Highest mean C_max values (pg/mL) were observed following epinephrine auto-injector (503), with ARS-1 (258) comparable to manual IM (254), with the trend similar with twice-dosing. Mean systolic BP (SBP) E_max change from baseline (mm Hg) and heart rate (HR) E_max change from baseline (bpm) were comparable between ARS-1 (16.9 and 13.6, respectively) and epinephrine auto-injector (18.1 and 14.4, respectively) compared to IM (10.9 and 12.8, respectively), despite expecting that HR would correlate with epinephrine concentration due to lower affinity of β-adrenergic receptors. This trend was observed with twice dosing where mean C_max with ARS-1 and epinephrine auto-injector were 486 pg/mL versus 654 pg/mL, respectively, and mean SBP E_max (mm Hg) and HR Emax (bpm), respectively, were 25.9 and 22.6 with ARS-1 and 26.7 and 22.7 with epinephrine auto-injector. <h3>Conclusion</h3> ARS-1 increased BP more efficiently than epinephrine auto-injector or manual IM injection despite differences in C_max and t_max. This is likely due to bypassing β2 receptor-mediated vasodilatation in the skeletal muscle and stimulating β1 receptors to increase HR.

IVABRADINE-INDUCED HEART RATE REDUCTION INCREASES THE SEVERITY OF POSTRESUSCITATION MYOCARDIAL DYSFUNCTION IN A RAT MODEL OF CARDIOPULMONARY RESUSCITATION.

Aims: A rapid heart rate (HR) that occurs after cardiopulmonary resuscitation (CPR) is a short-term compensatory mechanism preserving cardiac output. However, if of long duration, it is unfavorable for myocardial function postresuscitation because of disrupted balance between myocardial oxygen supply and demand. This raises the assumption that such a sustained fast HR should be regulated. The present study aimed to investigate the follow-on effect of ivabradine (a specific inhibitor of the I f current of the sinoatrial node)-induced HR reduction (HRR) on postresuscitation myocardial function in a rat model of CPR. Methods and results: Six minutes of ventricular fibrillation and 8 min of CPR were performed on Sprague-Dawley rats. All 32 resuscitated animals were then randomized into saline and ivabradine groups, each group having nonsurvival and survival subgroups (n = 8 each). Saline or ivabradine (0.5 mL/kg) was administered at 1 h postresuscitation. Heart rate, myocardial function as expressed by cardiac output, ejection fraction, and myocardial performance index were assessed at baseline and hourly from 1 to 5 h postresuscitation. Heart rate variability was analyzed at baseline and at 1, 3, and 5 h postresuscitation. Serum epinephrine and cardiac troponin I at baseline and at 1, 3, and 5 h postresuscitation in nonsurvival subgroup were measured. Survival duration in the survival subgroup was observed. The baseline HR was approximately 390 beats/min (bpm). After resuscitation, an average increase of Δ ≈ +15 bpm (relative ratio ≈ +3.8%) with a resultant HR of 405 bpm lasting more than 5 h occurred. Ivabradine group achieved a steady HRR of Δ ≈ -30 bpm (relative ratio ≈ -7.4%) as compared with saline group ( P < 0.01). Postresuscitation myocardial function was significantly worse in the ivabradine group (all P < 0.01). Heart rate variability was significantly impaired in the ivabradine group (all P < 0.05). Serum cardiac troponin I and epinephrine concentration were significantly higher in the ivabradine group (all P < ?0.01). Survival duration was significantly shortened in the ivabradine group as compared with the saline group (388 vs. 526 min, P < ?0.01). Conclusions: Ivabradine-induced HRR increases the severity of postresuscitation myocardial dysfunction and shortens survival duration in a rat model of CPR.

Gestational protein restriction alters early amygdala neurochemistry in male offspring

ABSTRACT Background Gestational protein intake restriction-induced long-lasting harmful outcomes in the offspring's organs and systems. However, few studies have focused on this event's impact on the brain's structures and neurochemical compounds. Aim The present study investigated the effects on the amygdala neurochemical composition and neuronal structure in gestational protein-restricted male rats' offspring. Methods Dams were maintained on isocaloric standard rodent laboratory chow with regular protein [NP, 17%] or low protein content [LP, 6%]. Total cells were quantified using the Isotropic fractionator method, Neuronal 3D reconstruction, and dendritic tree analysis using the Golgi–Cox technique. Western blot and high-performance liquid chromatography performed neurochemical studies. Results The gestational low-protein feeding offspring showed a significant decrease in birth weight up to day 14, associated with unaltered brain weight in youth or adult progenies. The amygdala cell numbers were unchanged, and the dendrites length and dendritic ramifications 3D analysis in LP compared to age-matched NP progeny. However, the current study shows reduced amygdala content of norepinephrine, epinephrine, and dopamine in LP progeny. These offspring observed a significant reduction in the amygdala glucocorticoid (GR) and mineralocorticoid (MR) receptor protein levels. Also corticotrophin-releasing factor (CRF) amygdala protein content was reduced in 7 and 14-day-old LP rats. Conclusion The observed amygdala neurochemical changes may represent adaptation during embryonic development in response to elevated fetal exposure to maternal corticosteroid levels. In this way, gestational malnutrition stress can alter the amygdala's neurochemical content and may contribute to known behavioral changes induced by gestational protein restriction.

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.

Physiological levels of adrenaline fail to stop pancreatic beta cell activity at unphysiologically high glucose levels.

Adrenaline inhibits insulin secretion from pancreatic beta cells to allow an organism to cover immediate energy needs by unlocking internal nutrient reserves. The stimulation of α2-adrenergic receptors on the plasma membrane of beta cells reduces their excitability and insulin secretion mostly through diminished cAMP production and downstream desensitization of late step(s) of exocytotic machinery to cytosolic Ca2+ concentration ([Ca2+]c). In most studies unphysiologically high adrenaline concentrations have been used to evaluate the role of adrenergic stimulation in pancreatic endocrine cells. Here we report the effect of physiological adrenaline levels on [Ca2+]c dynamics in beta cell collectives in mice pancreatic tissue slice preparation. We used confocal microscopy with a high spatial and temporal resolution to evaluate glucose-stimulated [Ca2+]c events and their sensitivity to adrenaline. We investigated glucose concentrations from 8-20 mM to assess the concentration of adrenaline that completely abolishes [Ca2+]c events. We show that 8 mM glucose stimulation of beta cell collectives is readily inhibited by the concentration of adrenaline available under physiological conditions, and that sequent stimulation with 12 mM glucose or forskolin in high nM range overrides this inhibition. Accordingly, 12 mM glucose stimulation required at least an order of magnitude higher adrenaline concentration above the physiological level to inhibit the activity. To conclude, higher glucose concentrations stimulate beta cell activity in a non-linear manner and beyond levels that could be inhibited with physiologically available plasma adrenaline concentration.

Important Hormones Regulating Lipid Metabolism.

There is a wide variety of kinds of lipids, and complex structures which determine the diversity and complexity of their functions. With the basic characteristic of water insolubility, lipid molecules are independent of the genetic information composed by genes to proteins, which determine the particularity of lipids in the human body, with water as the basic environment and genes to proteins as the genetic system. In this review, we have summarized the current landscape on hormone regulation of lipid metabolism. After the well-studied PI3K-AKT pathway, insulin affects fat synthesis by controlling the activity and production of various transcription factors. New mechanisms of thyroid hormone regulation are discussed, receptor α and β may mediate different procedures, the effect of thyroid hormone on mitochondria provides a new insight for hormones regulating lipid metabolism. Physiological concentration of adrenaline induces the expression of extrapituitary prolactin in adipose tissue macrophages, which promotes fat weight loss. Manipulation of hormonal action has the potential to offer a new therapeutic horizon for the global burden of obesity and its associated complications such as morbidity and mortality.

Low and Moderate Doses of Caffeinated Coffee Improve Repeated Sprint Performance in Female Team Sport Athletes.

Simple SummaryThe bulk of research on caffeine as an ergogenic aid has been on endurance performance, however there is evidence that caffeine can enhance short-term high-intensity performance. Caffeine may have an ergogenic impact during anaerobic exercise by facilitating central effects by antagonizing adenosine receptors, hence decreasing the detrimental effects of adenosine on neurotransmission, arousal, and pain perception. Caffeine intake also activates the central nervous system, which promotes alertness and concentration. Additionally, athletes typically consume coffee containing caffeine. To date, the bulk of study has focused on the administration of 3–9 mg/kg of anhydrous caffeine, as opposed to the readily accessible source of caffeine, coffee, and has mostly been conducted on males. Consequently, there is a dearth of study evaluating the ergogenic impact of caffeine on females, particularly when consuming alternative caffeine delivery methods, such as coffee. The current study is the first to investigate the effects of low (3 mg/kg) and moderate (6 mg/kg) doses of caffeine from coffee on repeated sprint performance in females.The aim of this study was to determine the effect of low and moderate doses of caffeine ingestion via caffeinated coffee on repeated sprint test (RST) and plasma catecholamine concentration in trained female team-sport athletes. In a randomized, double-blind, crossover design, 13 female team-sport athletes (VO2max: 48.7 ± 4 mL·kg·min−1) completed three RST trials, separated by 4-day, 60 min post-ingestion of either 3 mg·kg−1 (LCOF) or 6 mg·kg−1 (MCOF) or placebo (PLA). The RST consisted of 12 × 4 s sprints on a cycle ergometer interspersed with 20 s of active recovery. Blood lactate (BLa) and glucose (GLU) and epinephrine and norepinephrine concentrations were collected before and 60 min after coffee ingestion, and after RST. Heart rate (HR) and ratings of perceived exertion (RPE) were measured at the beginning of RST, and after the 6th and 12th sprints. Average peak power score during RST was significantly improved after LCOF (p = 0.016) and MCOF (p = 0.041) compared to PLA, but peak and mean power output of the individual sprints, and fatigue index were not different between trials (all p > 0.05). Epinephrine and norepinephrine concentrations were significantly higher before and after RST in LCOF and MCOF compared to PLA (all p < 0.05). BLa was also higher after RST in both LCOF and MCOF compared to PLA (p = 0.005). HR, RPE, and GLU were not different between conditions (p > 0.05). In conclusion, low and moderate dose of caffeine ingestion can enhance the average peak power score during repeated sprints. These findings partly support low and moderate doses of caffeine supplementation via coffee as a nutritional ergogenic aid for trained female team-sport players during repeated sprint exercise.

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.

Laparoscopic Radical Resection versus Routine Surgery for Colorectal Cancer.

For patients with colorectal cancer, minimally invasive surgical methods, particularly laparoscopic methods, are now the preferred course of therapy. This research is performed to investigate the effects of laparoscopic radical resection on patients with colorectal cancer. A total of 100 colorectal cancer patients treated in our hospital from January 2017 to January 2019 were enrolled. The subjects were divided into observation (n = 50) and control (n = 50) groups and treated with laparoscopic surgery and laparotomy, respectively. As well as postoperative complications and survival rates, the levels of inflammatory substances, stress response, immunological function, and perioperative markers were compared between the two groups. There was no significant difference in the postoperative exhaust time between the two groups (P > 0.05). Compared with the control group, the observation group showed longer operation time, faster recovery of intestinal function, shorter hospital stay, and less intraoperative bleeding amount (P < 0.05). The serum contents of hs-CRP, TNF-α, IL-6, norepinephrine, adrenaline, and cortisol at 1 d, 3 d, and 5 d after surgery were significantly higher than before in both groups (P < 0.05). Moreover, the serum contents of hs-CRP, TNF-α, IL-6, norepinephrine, adrenaline, and cortisol in the observation group were significantly lower than that in the control group (P < 0.05). At 10 days following surgery, immune index levels had dramatically increased in both groups, with noticeably higher immune index levels in the observation group than in the control group (P < 0.05). There were no appreciable differences in the two groups' 2-year survival rates (P > 0.05), but the complication rate was much greater in the control group (P < 0.05). To sum up, after laparoscopic surgery, patients had fewer complications, shorter hospital stay, lower inflammatory factor expression, less stress response, better immune function, less trauma, faster recovery, and improved quality of life.

Matrix Metalloproteinases and Stress Hormones in Lung Cancer Progression.

Several matrix metalloproteinases (MMPs) and psychological stress are associated with poor cancer prognosis. The current work goal was to determine MMPs' and stress hormones' blood concentrations from lung adenocarcinoma (LAC) patients. Patients were divided into the following groups: tobacco smokers (TS), wood smoke-exposed (W), passive smokers (PS), TS exposed to wood smoke (TW), and patients with no recognizable risk factor (N). MMPs, tissue inhibitors of metalloproteinases (TIMPs), adrenaline, noradrenaline, and cortisol blood concentrations were measured by ELISA. Zymography and Western blot assays were performed to determine MMP-2 and MMP-9 active and latent forms. MMP-2, MMP-3, MMP-9, and TIMP-1 blood concentrations, and MMP-9 gelatinase activity were augmented, while MMP-12, MMP-14, and TIMP-2 were diminished in LAC patients. Cortisol was increased in LAC samples. Adrenaline concentrations were higher in W, TS, and TW, and noradrenaline was increased in W and N groups. Positive correlations were observed among cortisol and TIMP-1 (rs = 0.392) and TIMP-2 (rs = 0.409) in the W group and between noradrenaline and MMP-2 (rs = 0.391) in the N group. MMPs' blood concentration increments can be considered as lung cancer progression markers. Although stress hormones were also augmented, only weak correlations were observed between them and MMPs and TIMPs.

Pre-treatment strategies based on aqueous two-phase systems comprising ionic liquids to improve the adrenal cancer diagnosis

Cancer remains the cause of millions of deaths every year worldwide, and reliable early-stage diagnosis methods are essential to prevent them. Cancer biomarkers quantification in human fluids has gained relevance in detecting cancer in an early-stage. Among these, the levels of the biomarkers epinephrine, norepinephrine and vanillylmandelic acid in urine have been used for the diagnosis of adrenal cancer. However, due to their low levels in human fluids, expensive and multistep pretreatment methods are necessary to increase their concentration to meet the detection limits of the analytical equipments. In this work, we propose the use of aqueous two-phase systems (ATPS) composed of ionic liquids (ILs), K3PO4 and synthetic/natural urine as an alternative pretreatment strategy to improve the concentration of adrenal cancer biomarkers from human fluids. The ATPS ternary phase diagrams, as well as the respective tie-lines and tie-line lengths, were determined at 25 °C. The performance of these IL-based ATPS for the extraction and concentration of epinephrine, norepinephrine and vanillylmandelic acid from human urine was then evaluated. The obtained results show that in the studied systems, with the exception of IL-based ATPS constituted by ILs with longer alkyl side chains at the cation, all the studied cancer biomarkers preferably migrate to the IL-rich phase. The best ATPS investigated is constituted by 1-ethyl-3-methylimidazolium methylsulfate ([C2mim][CH3SO4]) that allows the complete extraction of all cancer biomarkers to the IL-rich phase in a single-step and a concentration factor up to 500-fold. All biomarkers were accurately quantified in the IL-rich phase after the extraction from urine and the concentration step by UHPLC. According to the obtained results, IL-based ATPS could be used as a novel and effective method for the pretreatment and concentration of cancer biomarkers from human fluids to improve cancer diagnosis.

PSIII-A-5 Blood Catecholamine Profiling of Transportation Stress in Goats Previously Habituated to Livestock Trailer

Abstract Long distance transportation can cause significant physiological changes in goats that can impact their wellbeing. This experiment was conducted to determine the effects of habituation to livestock trailer on plasma catecholamine profile in goats transported for long periods. A total of 168 intact male Spanish goats were separated into two treatment (TRT) groups and maintained on two different paddocks in a split-plot design. Concentrate supplement was fed to one group inside two livestock trailers (5.0 × 2.3 m each; habituated group, H), while the other group received the concentrate supplement, but not inside the trailers (non-habituated, NH). After 4 weeks of habituation period, goats were subjected to a 10-hour transportation stress in 4 replicates (n = 21 goats/replicate/TRT). Blood samples were collected prior to loading (Preload), 20 min after loading (0 h), and at 2, 4, 6, 8, and 10 h of transportation (Time) for catecholamine analysis using a sensitive, high-throughput GC-MS/MS method. Habituation did not have any significant effect on dopamine, norepinephrine, and normetanephrine concentrations, while there was a tendency for TRT effect (P &amp;lt; 0.1) on epinephrine, tyramine, and metanephrine concentrations. Phenyethylamine and 5-methoxytryptamine concentrations were significantly higher (P &amp;lt; 0.05) in the H group compared to the NH group, which may enhance emotional wellbeing and energy levels. While both dopamine and 5-methoxytryptamine concentrations decreased (P &amp;lt; 0.05) with transportation time, dopamine concentrations increased again at 10 h. Plasma metanephrine concentrations were 0.86, 0.85, 4.22, 3.68, 2.30, 2.05, 2.14 (SEM = 0.327) nM, respectively at Preload, 0, 2, 4, 6, 8, and 10 h, indicating that stress peaked during the initial hours and decreased thereafter. Interaction effects were not significant. Habituation to trailer may be beneficial in mood and energy stabilization in goats during long-distance transportation. Metanephrine concentrations may more accurately reflect stress levels in goats.

Effects of Left Atrial Appendage Closure on Neuroendocrine Function in Patients with Nonvalvular Atrial Fibrillation.

BackgroundThe left atrial appendage (LAA) is an organ with neuroendocrine function. It remains unclear whether left atrial appendage closure (LAAC) has physiological effects on neuroendocrine function in patients with nonvalvular atrial fibrillation (NVAF). In the present study, we aimed to investigate the effects of LAAC on neuroendocrine function in patients with NVAF.Material/MethodsWe enrolled 20 patients with NVAF treated by LAAC in Jiangsu Taizhou People’s Hospital from October 2019 to October 2020. Blood samples were collected 1 day before LAAC and 12 months after LAAC. Plasma concentrations of adrenaline, aldosterone, pro-atrial natriuretic peptide (NT-proANP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured.ResultsLAAC was successfully performed in all patients, without serious complications. Compared with the preoperative levels, there was no significant difference in the levels of NT-proANP, NT-proBNP, and epinephrine at 12 months after LAAC (P>0.05). However, there was a significant decrease in aldosterone level at 12 months post-procedure (209.04±132.98 pg/ml) compared with pre-procedure baseline (279.08±166.88 pg/ml, P=0.04). There was no correlation between the compression rate of the occlusion and the reduction of aldosterone (Kendall’s Tau-b=0.159, P=0.351).ConclusionsLAAC can be safely and effectively performed in NVAF patients, and showed no significant effect on the adrenergic system and natriuretic peptides, but had an influence on the RAAS.

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.

The physiological role of melatonin in oxidative stress during the embryonic period of development

Introduction. Melatonin, being a powerful endogenous antioxidant, provides healthy course of pregnancy and childbirth. Decrease of melatonin levels in blood correlates with severity of preeclampsia. Currently, melatonin is viewed as a perspective antioxidant, able to improve mother’s condition during preeclampsia and protect fetus from unfavorable intrauterine environment.The objective was to study melatonin effects on remodeling of chicken embryo heart tissue under normal conditions and under oxidative stress model.Materials and methods. The study was performed using organotypic culture of heart tissue of 10–12-day-old chicken embryos. Oxidative stress was modeled by adding epinephrine 10–4 М or homocysteine thiolactone 10–3 М to culture medium.Results. The trophotropic effects of melatonin was detected at a concentration of 10–6 M. Drug stimulated heart tissue explants’ growth on 20 %. Epinephrine showed cardiotoxic effects at concentrations of 10–4 and 10–6 М. Melatonin (10–6 М) neutralized cardiotoxic effects of epinephrine (10–4 M). Cardiotoxic effects of homocysteine thiolactone (10–3 М) preserved in presence of melatonin (10–6 М).Conclusion. During embryonic period, melatonin neutralizes cardiotoxic effects of oxidative stress caused by a high concentration of epinephrine, but not by homocysteine thiolactone.

Endothelin-1 as a novel target for the prevention of metabolic dysfunction with intermittent hypoxia in male participants.

We examined the effect of intermittent hypoxia (IH, a hallmark feature of sleep apnea) on adipose tissue lipolysis and the role of endothelin-1 (ET-1) in this response. We hypothesized that IH can increase ET-1 secretion and plasma free fatty acid (FFA) concentrations. We further hypothesized that inhibition of ET-1 receptor activation with bosentan could prevent any IH-mediated increase in FFA. To test this hypothesis, 16 healthy male participants (32 ± 5 yr, 26 ± 2 kg/m2) were exposed to 30 min of IH in the absence (control) and presence of bosentan (62.5 mg oral twice daily for 3 days prior). Arterial blood samples for ET-1, epinephrine, and FFA concentrations, as well as abdominal subcutaneous adipose tissue biopsies (to assess transcription of cellular receptors/proteins involved in lipolysis), were collected. Additional proof-of-concept studies were conducted in vitro using primary differentiated human white preadipocytes (HWPs). We show that IH increased circulating ET-1, epinephrine, and FFA (P < 0.05). Bosentan treatment reduced plasma epinephrine concentrations and blunted IH-mediated increases in FFA (P < 0.01). In adipose tissue, bosentan had no effect on cellular receptors and proteins involved in lipolysis (P > 0.05). ET-1 treatment did not directly induce lipolysis in differentiated HWP. In conclusion, IH increases plasma ET-1 and FFA concentrations. Inhibition of ET-1 receptors with bosentan attenuates the FFA increase in response to IH. Based on a lack of a direct effect of ET-1 in HWP, we speculate the effect of bosentan on circulating FFA in vivo may be secondary to its ability to reduce sympathoadrenal tone.

Взаимосвязь анатомии области расположения и особенностей формирования третьего моляра нижней челюсти с частотой развития альвеолита его лунки

INTRODUCTION: Socket alveolitis is the most unpleasant and frequent complication of the tooth extraction operation. According to the data of numerous studies, it most often occurs after extraction of the third mandibular molar. The causes of inflammation of the extracted tooth socket are well known. They include absence (“dry socket”) or decay of a blood clot which forms immediately after the operation and performs protective and reparative function during physiological healing of the socket. In turn, the risk factors provoking “dry socket” formation or blood clot fibrinolysis are mechanical injury of the socket, use of high concentration of adrenaline in local anesthetic solution, inadequate socket curettage, bleeding in the postoperative period, technically complicated surgical procedure and many others. However, all the mentioned factors leading to alveolitis, equally influence the inflammatory activity in the socket of any extracted tooth, including the lower third molar. Consequently, the anatomical location of the lower wisdom tooth, its germ and formation, have some peculiarities. The data analysis was carried out in the following Internet resources: eLibrary, Cyberleninka, disserCat, National Library of Medicine, ResearchGate (48 sources for the time period from 1967 to 2021). In the review article, the collected data of different studies on the frequency of alveolitis after tooth extraction, after the third lower molar extraction, on the main causes of the socket inflammation are given; generalized information of the anatomical characteristics of third molar location, its germ and formation is presented. CONCLUSION: The highest incidence of alveolitis of the mandibular wisdom tooth socket is probably associated with peculiarities of its supply with blood, the existence of high quantity of adipose tissue and loose connective tissue around it, difficult rupture and other anatomical and physiological parameters, which create conditions for development of intensive inflammatory process.

Genome-wide association study for circulating FGF21 in patients with alcohol use disorder: Molecular links between the SNHG16 locus and catecholamine metabolism

ObjectiveAlcohol consumption can increase circulating levels of fibroblast growth factor 21 (FGF21). The effects of FGF21 in the central nervous system are associated with the regulation of catecholamines, neurotransmitters that play a crucial role in reward pathways. This study aims to identify genetic variants associated with FGF21 levels and evaluate their functional role in alcohol use disorder (AUD). MethodsWe performed a genome-wide association study (GWAS) using DNA samples from 442 AUD subjects recruited from the Mayo Clinic Center for the Individualized Treatment of Alcoholism Study. Plasma FGF21 levels were measured using Olink proximity extension immunoassays. Alcohol consumption at time of entry into the study was measured using the self-reported timeline followback method. Functional genomic studies were performed using HepG2 cells and induced pluripotent stem cell (iPSC)-derived brain organoids. ResultsPlasma FGF21 levels were positively correlated with recent alcohol consumption and gamma-glutamyl transferase levels, a commonly used marker for heavy alcohol use. One variant, rs9914222, located 5’ of SNHG16 on chromosome 17 was associated with plasma FGF21 levels (p = 4.60E-09). This variant was also associated with AUD risk (β: −3.23; p:0.0004). The rs9914222 SNP is an eQTL for SNHG16 in several brain regions, i.e., the variant genotype was associated with decreased expression of SNHG16. The variant genotype for the rs9914222 SNP was also associated with higher plasma FGF21 levels. Knockdown of SNHG16 in HepG2 cells resulted in increased FGF21 concentrations and decreased expression and enzyme activity for COMT, an enzyme that plays a key role in catecholamine metabolism. Finally, we demonstrated that ethanol significantly induced FGF21, dopamine, norepinephrine, and epinephrine concentrations in iPSC-derived brain organoids. ConclusionsGWAS for FGF21 revealed a SNHG16 genetic variant associated with FGF21 levels which are associated with recent alcohol consumption. Our data suggest that SNHG16 can regulate FGF21 concentrations and decrease COMT expression and enzyme activity which, in turn, have implications for the regulation of catecholamines.(The ClinicalTrials.gov Identifier: NCT00662571)