Plasma Epinephrine Concentrations Research Articles

The protective and hemodynamic effects of dexmedetomidine on hypertensive cerebral hemorrhage patients in the perioperative period.

The aim of the present study was to analyze the protective and hemodynamic effects of dexmedetomidine in hypertensive cerebral hemorrhage (HCH) patients during perioperative period. In total, 50 HCH patients were selected and randomly divided into two groups, one group was administered with dexmedetomidine and the other groups with midazolam. The mean arterial pressure (MAP), heart rate (HR) and blood oxygen saturation (SpO2) were monitored in the two groups of patients before and during the operation. The MAP, HR, SpO2 and PETCO2 recorded 5 min after admission into the operation room was considered T1, the same parameters recorded 10 min after drug administration were considered T2, just after starting the operation were considered T3 and 30 min after start of operation were considered T4. The preoperative sedation and analgesia were evaluated by the Ramsay scoring method and the neuron-specific enolase (NSE) and S100 protein (S100β) were estimated using ELISA. The patients of the midazolam group experienced mild respiratory depression during the period of sedation. Levels of, MAP, HR and PETCO2 were significantly increased whereas SPO2 was decreased (P<0.05). The MAP, HR, SPO2 and PETCO2 were stable during the period of sedation (P>0.05). The plasma concentrations of epinephrine and norepinephrine at T1 were similar in the two groups (P>0.05), but decreased after drug administration. This decrease was more prominent in the dexmedetomidine group patients (P<0.05) than midazolam group patients. The epinephrine and norepinephrine concentrations just after starting operation (T3) were higher than the basal level (T1) in the midazolam group, but close to the basal level in the dexmedetomidine group (P<0.05). The serum concentration of NSE and S100β in the two groups showed no difference (P>0.05) at the end of operation (T5), but after 24 h of operation (T7) NSE and S100β in the dexmedetomidine group were significantly lower compared to the midazolam group (P<0.05). In conclusion, the administration of dexmedetomidine for patients with HCH during perioperative period is safe and serves as an effective sedative, without causing respiratory depression and does not influence stable haemodynamics with certain brain protective effect.

Abstract P633: Resistance Training Counteracts The Systemic Catecholaminergic Hyperactivation Associated With Experimental Diabetes, But Not Normalize Cardiac Sympathetic Outflow

Previous studies from our laboratory have demonstrated that chronic diabetes in rats results in cardiomyopathy, associated with sympathetic nervous system (SNS) hyperactivity. On the other hand, it is well known that the beneficial cardiovascular effects of exercise training in diabetes are due in part to normalization of the sympathetic outflow and improvement in the responsiveness of the myocardium to autonomic stimulation. Recently, resistance training (RT) has been recognized as a useful therapeutic tool for the treatment of chronic diseases and similar to aerobic exercise, has been reported to improve metabolic profile and body composition. Therefore, the aim of this study was to evaluate the effect of moderate-intensity RT on circulating and cardiac catecholamines concentration, to understand whether this type of exercise is also associated with cardiovascular protection. Wistar rats (3 months old) were randomized into: control (C), diabetic (D), diabetic + RPT (DR) and diabetic + APT (DA). Animals were made diabetic with a single tail injection of streptozotocin (STZ, 50 mg/Kg). Resistance exercise training was performed on a vertical ladder (5 days/week, 8 weeks) at 40-60% maximal load, and moderate aerobic training was performed on a treadmill (5 days/week, 8 weeks). Diabetes significantly increased plasma concentration of adrenaline (D: 5.3 ± 1.0 vs. C: 4.1 ± 0.6 ng/mL) and noradrenaline (D: 14.5 ± 0.2 vs. C: 3.1± 0.8 ng/mL), and both exercise modalities induced a significant reduction of them: adrenaline (DR: 1.1 ± 0.3; DA: 0.7 ± 0.16 vs. D: 5.3 ± 1.0 ng/mL) and noradrenaline (DR: 1.0 ± 0.2; DA: 0.7 ± 0.1 vs. D: 14.5 ± 0.2 ng/mL). Cardiac concentration of noradrenaline was also increased in diabetic group (D: 62 ± 7 vs. CS: 34 ± 6 pg/g) and only aerobic exercise was capable to reduce its concentration in heart tissue (DA: 30 ± 6 vs. D: 62 ± 7; DR: 55 ± 7 pg/g). The results from the present study show for the first time additional beneficial effects of RT on modulating SNS activity in diabetes. Moreover, considering that RT does not modulate cardiac catecholaminergic secretion, it also highlights the importance of aerobic training in diabetes treatment. Financial Support: FAPESP, CAPES, CNPq

Acute arterial baroreflex-mediated changes in plasma catecholamine concentrations in a chronic rat model of myocardial infarction.

While it may be predictable that plasma norepinephrine (NE) concentration changes with efferent sympathetic nerve activity (SNA) in response to baroreceptor pressure inputs, an exact relationship between SNA and plasma NE concentration remains to be quantified in heart failure. We examined acute baroreflex‐mediated changes in plasma NE and epinephrine (Epi) concentrations in normal control (NC) rats and rats with myocardial infarction (MI) (n = 6 each). Plasma NE concentration correlated linearly with SNA in the NC group (slope: 2.17 ± 0.26 pg mL−1 %−1, intercept: 20.0 ± 18.2 pg mL−1) and also in the MI group (slope: 19.20 ± 6.45 pg mL−1 %−1, intercept: −239.6 ± 200.0 pg mL−1). The slope was approximately nine times higher in the MI than in the NC group (P < 0.01). Plasma Epi concentration positively correlated with SNA in the NC group (slope: 1.65 ± 0.79 pg mL−1 %−1, intercept: 115.0 ± 69.5 pg mL−1) and also in the MI group (slope: 7.74 ± 2.20 pg mL−1 %−1, intercept: 24.7 ± 120.1 pg mL−1). The slope was approximately 4.5 times higher in the MI than in the NC group (P < 0.05). Intravenous administration of desipramine (1 mg kg−1) significantly increased plasma NE concentration but decreased plasma Epi concentration in both groups, suggesting that neuronal NE uptake had contributed to the reduction in plasma NE concentration. These results indicate that high levels of plasma catecholamine in MI rats were still under the influence of baroreflex‐mediated changes in SNA, and may provide additional rationale for applying baroreflex activation therapy in patients with chronic heart failure.

Influence of Apnea-induced Hypoxia on Catecholamine Release and Cardiovascular Dynamics.

Prolonged breath-hold causes complex compensatory mechanisms such as increase in blood pressure, redistribution of blood flow, and bradycardia. We tested whether apnea induces an elevation of catecholamine-concentrations in well-trained apneic divers.11 apneic divers performed maximal dry apnea in a horizontal position. Parameters measured during apnea included blood pressure, ECG, and central, in addition to peripheral hemoglobin oxygenation. Peripheral arterial hemoglobin oxygenation was detected by pulse oximetry, whereas peripheral (abdominal) and central (cerebral) tissue oxygenation was measured by Near Infrared Spectroscopy (NIRS). Exhaled O2 and CO2, plasma norepinephrine and epinephrine concentrations were measured before and after apnea.Averaged apnea time was 247±76 s. Systolic blood pressure increased from 135±13 to 185±25 mmHg. End-expiratory CO2 increased from 29±4 mmHg to 49±6 mmHg. Norepinephrine increased from 623±307 to 1 826±984 pg ml-1 and epinephrine from 78±22 to 143±65 pg ml-1 during apnea. Heart rate reduction was inversely correlated with increased norepinephrine (correlation coefficient -0.844, p=0.001). Central (cerebral) O2 desaturation was time-delayed compared to peripheral O2 desaturation as measured by NIRSabdominal and SpO2.Increased norepinephrine caused by apnea may contribute to blood shift from peripheral tissues to the CNS and thus help to preserve cerebral tissue O2 saturation longer than that of peripheral tissue.

Low epinephrine levels and selective deficiency of β2-adrenoceptor vasodilation at birth

AimsEpinephrine is unique among biogenic catecholamines as a potent agonist of β2-adrenoceptors. The β2-adrenoceptor mediated effects during development might be linked to the increase of epinephrine synthesis. Our purpose was to characterize β-adrenoceptor-mediated relaxation in the aorta of newborn and young rabbits (3 to 4months old), and to relate those responses with the epinephrine content of the adrenal gland. Main methodsThe epinephrine levels and the tyrosine hydroxylase activity were determined in adrenal glands of newborn and young rabbits. Also, concentration–response curves to phenylephrine (selective α1-adrenoceptor agonist), dobutamine (selective β1-adrenoceptor agonist), terbutaline (selective β2-adrenoceptor agonist), and CL 316243 (selective β3-adrenoceptor agonist) were determined in isolated aortic rings obtained from both groups. Key findingsThe adrenal gland content and the plasma concentrations of epinephrine were lower in newborn than in young rabbits. In contrast, the tyrosine hydroxylase activity was higher in newborn than in young rabbits. On the other hand, the maximal response to phenylephrine was lower in newborn than in young rabbits. Terbutaline at concentrations selective for β2-adrenoceptors had no relaxing effects in neonates, in contrast to young rabbits. The potency and the maximal response of neither dobutamine nor CL 316243 were significantly different between the two groups. SignificanceIn rabbits, as well as in humans, β2-adrenoceptor-mediated responses and epinephrine synthesis are both immature at birth. On the other hand, the β1 and β3-adrenoceptor-mediated responses are fully developed. We conclude that epinephrine may influence the development of the β2-adrenoceptor-mediated responses at birth and the rabbit is an excellent model to study these issues.

Adrenal Demedullation and Oxygen Supplementation Independently Increase Glucose-Stimulated Insulin Concentrations in Fetal Sheep With Intrauterine Growth Restriction

In pregnancies complicated by placental insufficiency and intrauterine growth restriction (IUGR), fetal glucose and oxygen concentrations are reduced, whereas plasma norepinephrine and epinephrine concentrations are elevated throughout the final third of gestation. Here we study the effects of chronic hypoxemia and hypercatecholaminemia on β-cell function in fetal sheep with placental insufficiency-induced IUGR that is produced by maternal hyperthermia. IUGR and control fetuses underwent a sham (intact) or bilateral adrenal demedullation (AD) surgical procedure at 0.65 gestation. As expected, AD-IUGR fetuses had lower norepinephrine concentrations than intact-IUGR fetuses despite being hypoxemic and hypoglycemic. Placental insufficiency reduced fetal weights, but the severity of IUGR was less with AD. Although basal plasma insulin concentrations were lower in intact-IUGR and AD-IUGR fetuses compared with intact-controls, glucose-stimulated insulin concentrations were greater in AD-IUGR fetuses compared with intact-IUGR fetuses. Interestingly, AD-controls had lower glucose- and arginine-stimulated insulin concentrations than intact-controls, but AD-IUGR and AD-control insulin responses were not different. To investigate chronic hypoxemia in the IUGR fetus, arterial oxygen tension was increased to normal levels by increasing the maternal inspired oxygen fraction. Oxygenation of IUGR fetuses enhanced glucose-stimulated insulin concentrations 3.3-fold in intact-IUGR and 1.7-fold in AD-IUGR fetuses but did not lower norepinephrine and epinephrine concentrations. Together these findings show that chronic hypoxemia and hypercatecholaminemia have distinct but complementary roles in the suppression of β-cell responsiveness in IUGR fetuses.

The Effects of Insulin-Induced Hypoglycaemia on Tyrosine Hydroxylase Phosphorylation in Rat Brain and Adrenal Gland.

In this study we investigated the effects of insulin-induced hypoglycaemia on tyrosine hydroxylase (TH) protein and TH phosphorylation in the adrenal gland, C1 cell group, locus coeruleus (LC) and midbrain dopaminergic cell groups that are thought to play a role in response to hypoglycaemia and compared the effects of different concentrations of insulin in rats. Insulin (1 and 10U/kg) treatment caused similar reductions in blood glucose concentration (from 7.5-9 to 2-3mmol/L); however, plasma adrenaline concentration was increased 20-30 fold in response to 10 U/kg insulin and only 14 fold following 1U/kg. Time course studies (at 10U/kg insulin) revealed that in the adrenal gland, Ser31 phosphorylation was increased between 30 and 90min (4-5 fold), implying that TH was activated to increase catecholamine synthesis in adrenal medulla to replenish the stores. In the brain, Ser19 phosphorylation was limited to certain dopaminergic groups in the midbrain, while Ser31 phosphorylation was increased in most catecholaminergic regions at 60min (1.3-2 fold), suggesting that Ser31 phosphorylation may be an important mechanism to maintain catecholamine synthesis in the brain. Comparing the effects of 1 and 10U/kg insulin revealed that Ser31 phosphorylation was increased to similar extent in the adrenal gland and C1 cell group in response to both doses whereas Ser31 and Ser19 phosphorylation were only increased in response to 1U/kg insulin in LC and in response to 10U/kg insulin in most midbrain regions. Thus, the adrenal gland and some catecholaminergic brain regions become activated in response to insulin administration and brain catecholamines may be important for initiation of physiological defences against insulin-induced hypoglycaemia.

Epinephrine increases contextual learning through activation of peripheral β2-adrenoceptors.

Phenylethanolamine-N-methyltransferase knockout (Pnmt-KO) mice are unable to synthesize epinephrine and display reduced contextual fear. However, the precise mechanism responsible for impaired contextual fear learning in these mice is unknown. Our aim was to study the mechanism of epinephrine-dependent contextual learning. Wild-type (WT) or Pnmt-KO (129x1/SvJ) mice were submitted to a fear conditioning test either in the absence or in the presence of epinephrine, isoprenaline (non-selective β-adrenoceptor agonist), fenoterol (selective β2-adrenoceptor agonist), epinephrine plus sotalol (non-selective β-adrenoceptor antagonist), and dobutamine (selective β1-adrenoceptor agonist). Catecholamines were separated by reverse-phase HPLC and quantified by electrochemical detection. Blood glucose was measured by coulometry. Re-exposure to shock context induced higher freezing in WT and Pnmt-KO mice treated with epinephrine and fenoterol than in mice treated with vehicle. In addition, freezing response in Pnmt-KO mice was much lower than in WT mice. Freezing induced by epinephrine was blocked by sotalol in Pnmt-KO mice. Epinephrine and fenoterol treatment restored glycemic response in Pnmt-KO mice. Re-exposure to shock context did not induce a significant difference in freezing in Pnmt-KO mice treated with dobutamine and vehicle. Aversive memories are best retained if moderately high plasma epinephrine concentrations occur at the same moment as the aversive stimulus. In addition, epinephrine increases context fear learning by acting on peripheral β2-adrenoceptors, which may induce high levels of blood glucose. Since glucose crosses the blood-brain barrier, it may enhance hippocampal-dependent contextual learning.

Angiotensin II centrally induces frequent detrusor contractility of the bladder by acting on brain angiotensin II type 1 receptors in rats.

Angiotensin (Ang) II plays an important role in the brain as a neurotransmitter and is involved in psychological stress reactions, for example through activation of the sympatho-adrenomedullary system. We investigated the effects of centrally administered Ang II on the micturition reflex, which is potentially affected by the sympatho-adrenomedullary system, and brain Ang II receptors in urethane-anesthetized (1.0 g/kg, intraperitoneally) male rats. Central administration of Ang II (0.01, 0.02, and 0.07 nmol per rat, intracerebroventricularly, icv) but not vehicle rapidly and dose-dependently decreased the urinary bladder intercontraction interval, without altering the bladder detrusor pressure. Central administration of antagonists of Ang II type 1 but not type 2 receptors inhibited the Ang II-induced shortening of intercontraction intervals. Administration of the highest dose of Ang II (0.07 nmol per rat, icv) but not lower doses (0.01 and 0.02 nmol per rat, icv) elevated the plasma concentration of adrenaline. Bilateral adrenalectomy reduced Ang II-induced elevation in adrenaline, but had no effect on the Ang II-induced shortening of the intercontraction interval. These data suggest that central administration of Ang II increases urinary frequency by acting on brain Ang II type 1 receptors, independent of activation of the sympatho-adrenomedullary system.

Gintonin enhances performance of mice in rotarod test: Involvement of lysophosphatidic acid receptors and catecholamine release

Ginseng has a long history of use as a tonic for restoration of vigor. One example of ginseng-derived tonic effect is that it can improve physical stamina under conditions of stress. However, the active ingredient and the underlying molecular mechanism responsible for the ergogenic effect are unknown. Recent studies show that ginseng contains a novel ingredient, gintonin, which consists of a unique class of herbal-medicine lysophosphatidic acids (LPAs). Gintonin activates G protein-coupled LPA receptors to produce a transient [Ca2+]i signal, which is coupled to diverse intra- and inter-cellular signal transduction pathways that stimulate hormone or neurotransmitter release. However, relatively little is known about how gintonin-mediated cellular modulation is linked to physical endurance. In the present study, systemic administration of gintonin, but not ginsenosides, in fasted mice increased blood glucose concentrations in a dose-dependent manner. Gintonin treatment elevated blood glucose to a maximum level after 30min. This elevation in blood glucose level could be abrogated by the LPA1/3 receptor antagonist, Ki16425, or the β-adrenergic receptor antagonist, propranolol. Furthermore, gintonin-dependent enhanced performance of fasted mice in rotarod test was likewise abrogated by Ki16425. Gintonin also elevated plasma epinephrine and norepinephrine concentrations. The present study shows that gintonin mediates catecholamine release through activation of the LPA receptor and that activation of the β-adrenergic receptor is coupled to liver glycogenolysis, thereby increasing the supply of glucose and enhancing performance in the rotarod test. Thus, gintonin acts via the LPA-catecholamine-glycogenolysis axis, representing a candidate mechanism that can explain how ginseng treatment enhances physical stamina.

Vesicovascular reflexes in the spontaneously hypertensive rat.

We investigated the effects of hypertension and acute blood pressure changes on rats' vesicovascular reflexes (VVRs). Twelve-week-old male Wistar rats and spontaneously hypertensive rats (SHRs) were anesthetized with urethane, and underwent real-time cystometry and blood pressure monitoring. The SHRs were administered nifedipine or valsartan intravenously. The Wistar rats were administered intravenous noradrenaline continuously. The intercontraction intervals, maximum detrusor pressures, blood pressure during the voiding and the urine storage phases, blood pressure elevations associated with the VVRs, and arterial pulses were assessed. Plasma adrenaline and noradrenaline concentrations were measured using HPLC. The degree of atherosclerosis was assessed histologically based on the aortic wall thickness. Blood pressure elevations associated with the voiding reflexes were significantly lower and intercontraction intervals were significantly shorter in the SHRs compared with the Wistar rats. Although nifedipine and valsartan reduced the systolic blood pressure and noradrenaline increased the systolic blood pressure, they failed to alter the blood pressure elevations associated with the VVRs and the intercontraction intervals. No significant differences occurred with respect to the maximum detrusor pressures among the experimental groups. The reflected waves' shapes were normal in the Wistar rats, but they almost disappeared in the SHRs. The aortic walls were significantly thicker in SHRs compared with those in Wistar rats. The blood pressure elevations associated with the VVRs were lower in the SHRs than in the Wistar rats. Acute blood pressure reductions failed to ameliorate the blood pressure elevations associated with VVRs in the SHRs.

Influence of Endurance Exercise Overloading Patterns on the Levels of Left Ventricular Catechoamines After a Bout of Lactate Threshold Test in Male Wistar Rat.

Background:It is well known that exercise training has positive effect on catecholamine response to a given work load. But in this regard, the effective method of training needs to be studied.Objectives:The aim of this study was to compare the effects of 8 weeks endurance exercise with two overloading patterns on the left ventricular catecholamine levels.Materials and Methods:29 male Wistar rats were randomly assigned to control (n = 9), daily sinusoidal overloading (n = 10) and weekly sinusoidal overloading (n = 10) groups. After the last exercise session, left ventricular blood samples were obtained immediately after lactate threshold test. Plasma concentrations of adrenaline and noradrenaline were measured by ELISA method. One way analysis of variance was used for analysis of the data.Results:Immediately after lactate threshold test, adrenaline level was significantly (P < 0.05) lower in weekly loading group than in control and daily loading groups. Adrenaline was higher in the daily loading group compared with control group but did not reach the significant level. Noradrenaline levels were not significantly (P > 0.05) different between three study groups.Conclusions:The results showed 8 weeks of endurance exercise with weekly sinusoidal overloading pattern could induce a lower adrenal medulla activity (reflection of physical and physiological improvement) than daily sinusoidal loading pattern in response to the same absolute work load.

The effects of moderate energy restriction on apnoea severity and CVD risk factors in obese patients with obstructive sleep apnoea

Nutritional intervention for weight loss is one of the treatment options for obstructive sleep apnoea (OSA) in patients with overweight or obesity. However, the effects of moderate energy restriction on OSA severity are not yet known. The present study aimed to evaluate the effects of moderate energy restriction on OSA severity and CVD risk factors in obese patients with OSA. In this 16-week randomised clinical trial, twenty-one obese subjects aged 20-55 years and presenting an apnoea/hypopnoea index (AHI)≥5 events/h were randomised into two groups: the energy restriction group (ERG) and the control group (CG). The ERG was instructed to follow an energy-restricted diet -3347·2 kJ/d (-800 kcal/d) and the CG was advised not to change their food intake. At the beginning and at the end of the study, participants underwent evaluation of the following: OSA (Watch-PAT200®), nutritional parameters, blood pressure, sympathetic activity, inflammatory biomarkers, metabolic profile and endothelial function. The ERG (n 11), compared with the CG (n 10), had a significantly greater reduction in body weight (Cohen's d=-1·19; P<0·001), in AHI (Cohen's d=-0·95; P=0·04) and in plasma concentrations of adrenaline (Cohen's d=-1·02; P=0·04) as well as a significantly greater increase in minimum O2 saturation (Cohen's d=1·08; P=0·03). Although energy restriction was not associated with significant improvements in CVD risk factors, medium-to-large effect sizes were observed, suggesting that the statistically non-significant difference between groups may be due to the small sample size. This study suggests that in obese patients with OSA, moderate energy restriction is able to reduce the parameters of OSA severity and sympathetic activity.

Impaired hepatic counterregulatory response to insulin-induced hypoglycemia in hepatic denervated pigs

ObjectiveThe liver reacts to hypoglycemia by increasing its glucose output. This response is assumed to depend both on glucose sensing at the liver and the brain, as well as efferent impulses from the brain to the liver. We tested the importance of this signaling pathway by studying the hepatic response to insulin-induced hypoglycemia in hepatic complete denervated pigs. Materials/methodsTwo weeks prior to the metabolic study, 36-kg pigs underwent either total hepatic denervation (DN; n = 12) or sham operation (sham; n = 12). On the metabolic study day, measurements were performed at baseline conditions and during a hypoglycemic hyperinsulinemic (5 mU/kg/min) clamp. Endogenous insulin and glucagon secretions were inhibited by somatostatin, and glucagon was replaced at baseline levels. Endogenous glucose production (EGP) and glucose utilization (Rd) were determined by [3-3H] glucose infusion. ResultsBaseline plasma concentrations of glucose, insulin, EGP and Rd did not differ significantly between the two groups of animals. During insulin infusion, the plasma glucose concentration was clamped at ~3 mmol/L in both groups of animals resulting in an increase in plasma concentrations of epinephrine and norepinephrine in sham pigs (both P < 0.05), while this effect was abolished in DN pigs. While insulin action (P = 0.09) and glucose utilization (P = 0.44) were similar, EGP was markedly decreased in the DN pigs (P < 0.05). ConclusionThe findings indicate a blunted hepatic counterregulatory response to hypoglycemia following complete hepatic denervation. This implies that intact neural impulses to and from the liver are necessary to maintain the increase in EGP that protects the organism against hypoglycemia.

Effects of Acute Endurance Exercise Performed in the Morning and Evening on Inflammatory Cytokine and Metabolic Hormone Responses.

PurposeTo compare the effects of endurance exercise performed in the morning and evening on inflammatory cytokine responses in young men.MethodsFourteen healthy male participants aged 24.3 ± 0.8 years (mean ± standard error) performed endurance exercise in the morning (0900–1000 h) on one day and then in the evening (1700–1800 h) on another day with an interval of at least 1 week between each trial. In both the morning and evening trials, the participants walked for 60 minutes at approximately 60% of the maximal oxygen uptake () on a treadmill. Blood samples were collected to determine hormones and inflammatory cytokines at pre-exercise, immediately post exercise, and 2 h post exercise.ResultsPlasma interleukin (IL)-6 and adrenaline concentrations were significantly higher immediately after exercise in the evening trial than in the morning trial (P < 0.01, both). Serum free fatty acids concentrations were significantly higher in the evening trial than in the morning trial at 2 h after exercise (P < 0.05). Furthermore, a significant correlation was observed between the levels of IL-6 immediately post-exercise and free fatty acids 2 h post-exercise in the evening (r = 0.68, P < 0.01).ConclusionsThese findings suggest that the effect of acute endurance exercise in the evening enhances the plasma IL-6 and adrenaline concentrations compared to that in the morning. In addition, IL-6 was involved in increasing free fatty acids, suggesting that the evening is more effective for exercise-induced lipolysis compared with the morning.

Population pharmacokinetic and pharmacodynamic modeling of epinephrine administered using a mobile inhaler

Inhaled epinephrine is a potential alternative to self-administered intramuscular epinephrine in imminent anaphylactic reactions. The objective was to develop a pharmacokinetic-pharmacodynamic model describing exposure and effects on heart rate of inhaled epinephrine. Data from a 4-phase cross-over clinical trial in 9 healthy volunteers including 0.3 mg intramuscular epinephrine, two doses of inhaled epinephrine (4 mg/mL solution administered during [mean] 18 and 25 min, respectively) using a mobile pocket inhaler, and an inhaled placebo were analyzed using mixed-effects modeling. Inhaled epinephrine was available almost immediately and more rapidly than via the intramuscular route (absorption half-live 29 min). Epinephrine plasma concentrations declined rapidly after terminating inhalation (elimination half-life 4.1 min) offering the option to stop exposure in case of adverse events. While the expected maximum concentration was higher for inhaled epinephrine, this was not associated with safety concerns due to only moderate additional hemodynamic effects compared to intramuscular administration. Bioavailability after inhalation (4.7%) was subject to high interindividual and interoccasional variability highlighting that training of inhalation would be essential for patients. The proposed model suggests that the use of a highly concentrated epinephrine solution via inhalation may offer an effective treatment option in anaphylaxis, while efficacy in patients remains to be shown.

Chronic stress promotes oral cancer growth and angiogenesis with increased circulating catecholamine and glucocorticoid levels in a mouse model

Chronic stress was previously reported to play a role in the development of oral cancer, yet the correlation between stressors and oral cancer progression is not well understood. We implanted human oral cancer cell line CAL 27 in nude mice to investigate the effects of chronic stress on tumor growth, and designed a physical restraint system to create an experimentally stressed animal model, in which periodic immobilization induced characteristic chronic stress. Tumor burdened animal were randomly assigned into four groups: (a) control group, (b) daily stress for 2h with light, (c) daily stress for 2h in dark, and (d) daily stress for 6h with light. Animals were sacrificed after three weeks. Various analyses were performed on parameters including body weight, tumor weight, in situ expression of MMP-2 and VEGF, and the plasma concentrations of epinephrine, norepinephrine and glucocorticoid. Our data showed that chronic stress resulted in greater tumor size, more expression of MMP-2 and VEGF, higher level of plasma catecholamines, and more invasive growth of oral carcinoma cells in a mice model. We have successfully set up an animal model, which studied the effect of chronic stress on oral carcinoma growth rate and progression. These data further suggested that catecholamine and glucocorticoid might stimulate tumor progression under chronic stress.

Mimicking disruption of brain-immune system-joint communication results in collagen type II-induced arthritis in non-susceptible PVG rats

The brain–immune system–joint communication is disrupted during collagen type II (CII) arthritis in DA rats. Since PVG rats are not susceptible to arthritis induction, comparison of hypothalamic and peripheral neuro-endocrine and immune responses between immunized DA and PVG rats might help to explain their different susceptibility to develop the disease. PVG and DA rats were immunized with CII. Corticosterone, neurotransmitters, anti-CII antibodies, and cytokine concentrations in plasma, and hypothalamic neurotransmitters and cytokines were determined by ELISA, Luminex, HPLC and RT-qPCR. Adrenalectomy or sham-operation was performed in PVG and DA rats 14 days before immunization. Basal plasma corticosterone and adrenaline concentrations were significantly higher, and plasma cytokines and hypothalamic noradrenaline were lower in PVG rats than in DA rats. While DA rats developed severe arthritis upon immunization (maximum score 16), only 12 out of 28 PVG rats showed minimal symptoms (score 1–2). The density of sympathetic nerve fibers in arthritic joints of DA rats markedly decreased, but it remained stable in immunized PVG rats. The ratio corticosterone to IL-1β levels in plasma was markedly higher in immunized PVG rats than in arthritic DA rats. Adrenalectomy resulted in severe arthritis in PVG rats upon immunization with CII. While DA rats show an altered immune-brain communication that favors the development of arthritis, PVG rats express a protective neuro-endocrine milieu, particularly linked to the basal tone of the HPA axis. Mimicking disruption of this axis elicits arthritis in non-susceptible PVG rats.

Mechanism-based population pharmacokinetic and pharmacodynamic modeling of intravenous and intranasal dexmedetomidine in healthy subjects.

Dexmedetomidine is an α2-adrenoceptor agonist used for perioperative and intensive care sedation. This study develops mechanism-based population pharmacokinetic-pharmacodynamic models for the cardiovascular and central nervous system (CNS) effects of intravenously (IV) and intranasally (IN) administered dexmedetomidine in healthy subjects. Single doses of 84 μg of dexmedetomidine were given once IV and once IN to six healthy men. Plasma dexmedetomidine concentrations were measured for 10 h along with plasma concentrations of norepinephrine (NE) and epinephrine (E). Blood pressure, heart rate, and CNS drug effects (three visual analog scales and bispectral index) were monitored to assess the pharmacological effects of dexmedetomidine. PK-PD modeling was performed for recently published data (Eur J Clin Pharmacol 67: 825, 2011). Pharmacokinetic profiles for both IV and IN doses of dexmedetomidine were well fitted using a two-compartment PK model. Intranasal bioavailability was 82%. Dexmedetomidine inhibited the release of NE and E to induce their decline in blood. This decrease in NE was captured with an indirect response model. The concentrations of the mediator NE served via a biophase/transduction step and nonlinear pharmacologic functions to produce reductions in blood pressure and heart rate, while a direct effect model was used for the CNS effects. The comprehensive panel of two biomarkers and seven response measures were well captured by the population PK/PD models. The subjects were more sensitive to the CNS (lower EC 50 values) than cardiovascular effects of dexmedetomidine.

CSACI position statement: epinephrine auto-injectors and children < 15kg.

Epinephrine (adrenaline) is the treatment of choice for anaphylaxis. While other medications, including H1-antihistamines, H2-antihistamines, corticosteroids, and inhaled beta-2 agonists are often used to treat anaphylaxis in the emergency setting, none of these medications has been shown to reverse anaphylaxis. Fatal anaphylaxis is related to the delayed use of epinephrine. In community settings, epinephrine is available as an auto-injector in two doses, 0.15 mg and 0.3 mg. The recommended dose for children is 0.01 mg per kilogram. For infants at risk of anaphylaxis in the community, there are few options with regard to providing an optimal epinephrine dose for first-aid treatment. The Canadian Society of Allergy and Immunology (CSACI) therefore recommends, for the child weighing less than 15 kg, given the lack of a suitable alternative, prescribing the 0.15 mg epinephrine autoinjector. Adverse effects of an epinephrine dose of 0.15 mg given intramuscularly in infants or children weighing less than 15 kg are expected to be mild and transient at the plasma epinephrine concentrations achieved; therefore, these effects need to be measured against the consequences of not receiving epinephrine at all, which can include fatality.