Increased Plasma Epinephrine Research Articles

Subdiaphragmatic vagotomy enhances stress-induced epinephrine release in rats.

Neuroendocrine stress response is regulated by several feedback loops. Since it has been suggested that afferent vagal pathways contribute to these feedback loops, we examined the effect of surgical subdiaphragmatic vagotomy on both baseline and stress-induced increases in plasma epinephrine, norepinephrine, and corticosterone levels in vagotomized and sham-operated Sprague Dawley rats. On either the 3rd or 14th day following vagotomy, the animals were exposed to acute immobilization stress and blood from the jugular vein was collected both before and during stress exposure. We found that vagotomy significantly enhanced immobilization-induced increases of plasma epinephrine, norepinephrine, and corticosterone levels on the 3rd day following surgery. However, on the 14th day following surgery, vagotomy enhanced only increase of plasma epinephrine levels in stressed rats. Our data indicate that afferent pathways of the vagus nerve are involved in negative feedback regulation of epinephrine secretion from the adrenal medulla during stressful conditions. We hypothesize that this feedback mechanism might be mediated by the binding of circulating epinephrine on β2-adrenergic receptors localized on sensory endings of the vagus nerve.

The effects of exercise training programs on plasma concentrations of proenkephalin Peptide F and catecholamines

To determine if exercise training alters the pattern and magnitude of plasma concentrations of proenkephalin Peptide F and epinephrine, plasma proenkephalin [107–140] Peptide Fir and catecholamines were examined pre-training (T-1), and after 4- (T-2), 8- (T-3), and 12-weeks (T-4) of training. 26 healthy men were matched and randomly assigned to one of three groups: heavy resistance strength training (Strength, n=9), high intensity endurance training (Endurance, n=8), or both training modalities combined (Combined, n=9). Blood was collected using a syringe with a cannula inserted into a superficial arm vein with samples collected at rest, after each 7min stage and 5 and 15min into recovery. With training, all groups observed shifted plasma Peptide F responses to graded exercise, where significant increases were observed at lower exercise intensities. Increases in plasma epinephrine with exercise were observed in all groups. The Combined group saw increases at 25% at T-3 and for 50% at T-2, T-3, and T-4 which was higher than T-1. The Endurance group demonstrated increases for 50% at T-1, T-2, T-3 but not at T-4. The plasma epinephrine response to graded exercise was reduced in the Strength group. Increases in plasma norepinephrine above rest were observed starting at 50% ▪. The Strength group demonstrated a significant reduction in norepinephrine observed at 100% at T-3 and T-4. Peptide F and catecholamines responses to graded exercise can be altered by different types of physical exercise training. Simultaneous high intensity training may produce adrenal medulla exhaustion when compared to single mode training.

Body composition and plasma lipid and stress hormone levels during 3 weeks of feed restriction and refeeding in low birth weight female pigs.

Compensatory growth in response to feed restriction (FR) affects deposition rates of lean and adipose tissues. It is, however, unclear whether pigs with low birth weight differ from their counterparts with normal birth weight with regard to compensatory growth. Female littermate pigs with low (UW; 1.1 kg) and normal (NW; 1.5 kg) birth weight were fed to appetite (control, CON) or feed restricted (RES) at 60% of DMI of the CON group between 78 and 98 d of age and subsequently refed at the level of the CON group until 131 d of age. Subgroups of pigs were slaughtered at 75, 98, 104, and 131 d of age to compare BW and body composition. Blood samples were taken at 98 and 119 d of age to analyze plasma metabolites and hormones. At birth UW pigs were shorter and had lower BW until 131 d of age than NW pigs ( < 0.05). Feed intake per kilogram of BW was greater in UW than in NW pigs ( < 0.01). The UW and NW pigs differed in carcass composition as indicated by greater relative subcutaneous fat at 75 d ( < 0.1), greater shoulder back fat ( < 0.05) at 98 d, and lower carcass weight at 131 d with greater abdominal and subcutaneous neck back fat in UW compared with NW pigs ( < 0.05). During FR, BW gain of RES pigs was lower than in NW pigs. The RES pigs showed greater feed intake after termination of FR until 131 d than CON pigs ( < 0.01). At 98 d RES pigs were leaner than CON pigs ( < 0.05). After 6 d of refeeding (104 d) relative fat depot weights were still smaller ( < 0.03) in RES pigs than in CON pigs. After 5 wk of refeeding, RES pigs had lower abdominal fat weights and greater plasma cortisol levels than CON pigs ( < 0.05). Regarding the plasma metabolite and hormone response, at 98-d fasting levels of plasma NEFA and glycerol were greater in RES than in CON pigs ( < 0.05), and after the drop in their levels after morning feeding ( < 0.001), plasma NEFA and glycerol and also triacylglycerol increased until the next meal in RES vs. CON pigs ( < 0.01). Plasma cortisol was greater in RES pigs after 3-wk FR ( < 0.05), whereas only a trend for increased plasma adrenalin concentrations in RES pigs at the end of the FR period and after 5 wk of refeeding was found ( < 0.1). In conclusion, UW pigs at 75 d of age (20 to 23 kg BW) had greater subcutaneous fat, whereas at 131 d (61 to 68 kg BW) they showed greater abdominal fat than NW pigs, suggesting that subcutaneous fat is deposited earlier than abdominal fat. The FR caused similar changes in body composition, plasma lipids, and stress hormones in UW and NW pigs.

Abstract 18368: Evidence for Activation of Cerebral Autonomic Center in Response to Cardiac Electrical Stimulation in Humans -A New Finding of Cardio-Cerebral Connection

Introduction: Anterior cingulate cortex (ACC) is one of the cortical receptive fields of afferent nerves innervating the visceral organs and modulates autonomic nervous system in collaboration with hypothalamus and brainstem. Cardiac afferent nerves are associated with not only chest pain but also sympathetic arousal in heart failure, in which ACC could be involved. However, the cortical receptive fields of cardiac afferent nerves still remain to be elucidated. Hypothesis: We thus investigated whether ACC is activated in response to cardiac electrical stimulation in humans. Methods: We studied 10 patients (74.7±1.9 yrs, M/F 9/1) with cardiac pacemaker implantation. Before the measurement, mode of cardiac pacemaker was changed to VVI 80-90 bpm with 1.5V intensity. Cerebral blood flow (CBF) was measured using [15O]H2O positron emission tomography (PET) during sham stimulation (1.5V) and intense stimulation (7.5-8V). The CBF images of intense stimulation were compared with those of sham stimulation using SPM8, a common analysis tool for neuroimages. Cardiac sensation was evaluated with an ordinate scale after CBF measurements. Blood samples were obtained from the cubital vein before and after CBF measurements for plasma catecholamine levels (one patient was excluded for the analysis due to urination before the last blood sampling). Results: Intense stimulation did not induce cardiac sensation but significantly increased plasma adrenaline levels as compared with sham stimulation (intense, 6.1±1.8 vs. sham, 0.1±3.0 pg/ml, P=0.031, n=9 each). CBF in ACC was significantly increased in response to intense stimulation as compared with sham stimulation (intense, 64.6±0.7 vs. sham, 61.0±1.3 ml/100g/min, P=0.008, n=10 each) ( Figure, yellow arrowhead ). Conclusions: This study demonstrates for the first time that ACC could be the cortical receptive field of cardiac afferent nerves associated with sympathetic arousal in humans.

The effect of adrenal medullectomy on metabolic responses to chronic intermittent hypoxia

Obstructive sleep apnea causes intermittent hypoxia (IH) and is associated with insulin resistance and type 2 diabetes. IH increases plasma catecholamine levels, which may increase insulin resistance and suppress insulin secretion. The objective of this study was to determine if adrenal medullectomy (MED) prevents metabolic dysfunction in IH. MED or sham surgery was performed in 60 male C57BL/6J mice, which were then exposed to IH or control conditions (intermittent air) for 6 weeks. IH increased plasma epinephrine and norepinephrine levels, increased fasting blood glucose and lowered basal and glucose-stimulated insulin secretion. MED decreased baseline epinephrine and prevented the IH induced increase in epinephrine, whereas the norepinephrine response remained intact. MED improved glucose tolerance in mice exposed to IH, attenuated the impairment in basal and glucose-stimulated insulin secretion, but did not prevent IH-induced fasting hyperglycemia or insulin resistance. We conclude that the epinephrine release from the adrenal medulla during IH suppresses insulin secretion causing hyperglycemia.

A tale of two mechanisms: a meta-analytic approach toward understanding the autonomic basis of cardiovascular reactivity to acute psychological stress.

A series of meta-analyses was undertaken to determine the contributions of sympathetic and parasympathetic activation to cardiovascular stress reactivity. A literature search yielded 186 studies of sufficient quality that measured indices of sympathetic (n = 113) and/or parasympathetic activity (n = 73). A range of psychological stressors perturbed blood pressure and heart rate. There were comparable aggregate effects for sympathetic activation, as indexed by increased plasma epinephrine and norepinephrine, and shortened pre-ejection period and parasympathetic deactivation, as indexed by heart rate variability measures. Effect sizes varied with stress task, sex, and age. In contrast to alpha-adrenergic blockade, beta-blockade attenuated cardiovascular reactivity. Cardiovascular reactivity to acute psychological stress would appear to reflect both beta-adrenergic activation and vagal withdrawal to a largely equal extent.

PMM.37 Undiagnosed Pheochromocytoma in Labour – Would you suspect it?

Aims/ObjectivesThis is a case presentation aiming to draw attention to the clinical suspicious of pheochromocytoma as a differential of severe hypertension in labour.BackgroundPheochromocytoma in a pregnant woman is extremely rare...

Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans.

Excessive or persistent proinflammatory cytokine production plays a central role in autoimmune diseases. Acute activation of the sympathetic nervous system attenuates the innate immune response. However, both the autonomic nervous system and innate immune system are regarded as systems that cannot be voluntarily influenced. Herein, we evaluated the effects of a training program on the autonomic nervous system and innate immune response. Healthy volunteers were randomized to either the intervention (n = 12) or control group (n = 12). Subjects in the intervention group were trained for 10 d in meditation (third eye meditation), breathing techniques (i.a., cyclic hyperventilation followed by breath retention), and exposure to cold (i.a., immersions in ice cold water). The control group was not trained. Subsequently, all subjects underwent experimental endotoxemia (i.v. administration of 2 ng/kg Escherichia coli endotoxin). In the intervention group, practicing the learned techniques resulted in intermittent respiratory alkalosis and hypoxia resulting in profoundly increased plasma epinephrine levels. In the intervention group, plasma levels of the anti-inflammatory cytokine IL-10 increased more rapidly after endotoxin administration, correlated strongly with preceding epinephrine levels, and were higher. Levels of proinflammatory mediators TNF-α, IL-6, and IL-8 were lower in the intervention group and correlated negatively with IL-10 levels. Finally, flu-like symptoms were lower in the intervention group. In conclusion, we demonstrate that voluntary activation of the sympathetic nervous system results in epinephrine release and subsequent suppression of the innate immune response in humans in vivo. These results could have important implications for the treatment of conditions associated with excessive or persistent inflammation, such as autoimmune diseases.

Nocturnal light exposure alters hepatic Pai-1 expression by stimulating the adrenal pathway in C3H mice.

Recent studies have suggested the possibility that nocturnal light exposure affects many biological processes in rodents, especially the circadian rhythm, an endogenous oscillation of approximately 24 h. However, there is still insufficient information about the physiological effects of nocturnal light exposure. In this study, we examined the changes in gene expression and serum levels of plasminogen activator inhibitor-1 (PAI-1), a major component of the fibrinolytic system that shows typical circadian rhythmicity, in C3H/He mice. Zeitgeber time (ZT) was assessed with reference to the onset of light period (ZT0). Exposure to fluorescent light (70 lux) for 1 h in the dark period (ZT14) caused a significant increase in hepatic Pai-1 gene expression at ZT16. Serum PAI-1 levels also tended to increase, albeit not significantly. Expression levels of the typical clock genes Bmal1, Clock, and Per1 were significantly increased at ZT21, ZT16, and ZT18, respectively. Exposure to nocturnal light significantly increased plasma adrenalin levels. The effects of nocturnal light exposure on Pai-1 expression disappeared in adrenalectomized mice, although the changes in clock genes were still apparent. In conclusion, our results suggest that nocturnal light exposure, even for 1 h, alters hepatic Pai-1 gene expression by stimulating the adrenal pathway. Adrenalin secreted from the adrenal gland may be an important signaling mediator of the change in Pai-1 expression in response to nocturnal light exposure.

Mild Transient Hypercapnia as a Novel Fear Conditioning Stimulus Allowing Re-Exposure during Sleep

IntroductionStudies suggest that sleep plays a role in traumatic memories and that treatment of sleep disorders may help alleviate symptoms of posttraumatic stress disorder. Fear-conditioning paradigms in rodents are used to investigate causal mechanisms of fear acquisition and the relationship between sleep and posttraumatic behaviors. We developed a novel conditioning stimulus (CS) that evoked fear and was subsequently used to study re-exposure to the CS during sleep.MethodsExperiment 1 assessed physiological responses to a conditioned stimulus (mild transient hypercapnia, mtHC; 3.0% CO2; n = 17)+footshock for the purpose of establishing a novel CS in male FVB/J mice. Responses to the novel CS were compared to tone+footshock (n = 18) and control groups of tone alone (n = 17) and mild transient hypercapnia alone (n = 10). A second proof of principle experiment re-exposed animals during sleep to mild transient hypercapnia or air (control) to study sleep processes related to the CS.ResultsFootshock elicited a response of acute tachycardia (30–40 bpm) and increased plasma epinephrine. When tone predicted footshock it elicited mild hypertension (1–2 mmHg) and a three-fold increase in plasma epinephrine. When mtHC predicted footshock it also induced mild hypertension, but additionally elicited a conditioned bradycardia and a smaller increase in plasma epinephrine. The overall mean 24 hour sleep–wake profile was unaffected immediately after fear conditioning.DiscussionOur study demonstrates the efficacy of mtHC as a conditioning stimulus that is perceptible but innocuous (relative to tone) and applicable during sleep. This novel model will allow future studies to explore sleep-dependent mechanisms underlying maladaptive fear responses, as well as elucidate the moderators of the relationship between fear responses and sleep.

Choline Supplementation Promotes Hepatic Insulin Resistance in Phosphatidylethanolamine N-Methyltransferase-deficient Mice via Increased Glucagon Action

Biosynthesis of hepatic choline via phosphatidylethanolamine N-methyltransferase (PEMT) plays an important role in the development of type 2 diabetes and obesity. We investigated the mechanism(s) by which choline modulates insulin sensitivity. PEMT wild-type (Pemt(+/+)) and knock-out (Pemt(-/-)) mice received either a high fat diet (HF; 60% kcal of fat) or a high fat, high choline diet (HFHC; 4 g of choline/kg of HF diet) for 1 week. Hepatic insulin signaling and glucose and lipid homeostasis were investigated. Glucose and insulin intolerance occurred in Pemt(-/-) mice fed the HFHC diet, but not in their Pemt(-/-) littermates fed the HF diet. Plasma glucagon was elevated in Pemt(-/-) mice fed the HFHC diet compared with Pemt(-/-) mice fed the HF diet, concomitant with increased hepatic expression of glucagon receptor, phosphorylated AMP-activated protein kinase (AMPK), and phosphorylated insulin receptor substrate 1 at serine 307 (IRS1-s307). Gluconeogenesis and mitochondrial oxidative stress were markedly enhanced, whereas glucose oxidation and triacylglycerol biosynthesis were diminished in Pemt(-/-) mice fed the HFHC diet. A glucagon receptor antagonist (2-aminobenzimidazole) attenuated choline-induced hyperglycemia and insulin intolerance and blunted up-regulation of phosphorylated AMPK and IRS1-s307. Choline induces glucose and insulin intolerance in Pemt(-/-) mice through modulating plasma glucagon and its action in liver.

Hypoxaemia‐induced catecholamine secretion from adrenal chromaffin cells inhibits glucose‐stimulated hyperinsulinaemia in fetal sheep

Abstract Hypoxaemia elicits adrenergic suppression of fetal glucose-stimulated hyperinsulinaemia. We postulate that this effect is mediated by catecholamines, exclusively, from fetal adrenal chromaffin cells. To investigate this hypothesis, square-wave hyperglycaemic clamp studies were performed under normoxaemic (26 ± 0.9 mmHg) and hypoxaemic (14 ± 0.3 mmHg) steady-state conditions in near-term fetal sheep that had undergone either surgical sham or bilateral adrenal demedullation (AD), values mentioned are ± SEM. Under normoxaemic conditions plasma noradrenaline concentrations were lower in AD fetuses than in sham-operated fetuses (457 ± 122 versus 1073 ± 103 pg ml(-1), P < 0.05). Plasma insulin concentrations were not different at euglycaemia between shams (0.46 ± 0.07 ng ml(-1)) and AD fetuses (0.44 ± 0.04 ng ml(-1)) and increased (P < 0.05) with hyperglycaemia in both groups although to a lesser extent in AD fetuses (0.94 ± 0.19 ng ml(-1)) compared to shams (1.31 ± 0.15 ng ml(-1); P < 0.05). Hypoxaemia increased plasma adrenaline (26-fold) and noradrenaline (5-fold) in shams but elicited no change in AD fetuses. Under hypoxaemic conditions, euglycaemic plasma insulin concentrations were reduced (P < 0.05) in both sham and AD fetuses to 0.30 ± 0.05 ng ml(-1) and 0.27 ± 0.01 ng ml(-1) respectively, and the insulin response to hyperglycaemia was abolished in shams but not affected in AD fetuses (0.33 ± 0.06 versus 0.73 ± 0.02 ng ml(-1), P < 0.05). Hypoxaemia also induced hyperlactacaemia and hypocarbia to a greater extent in shams than in AD fetuses, indicating that catecholamines potentiate reductions in oxidative metabolism independently of insulin. These findings demonstrate that the fetal adrenal chromaffin cells are the source for acute hypoxaemia-induced elevations in fetal plasma catecholamines and suppression of glucose-stimulated hyperinsulinaemia, but other factors reduce plasma insulin at euglycaemia.

Palm vitamin E reduces catecholamines, xanthine oxidase activity and gastric lesions in rats exposed to water-immersion restraint stress

BackgroundThis study examined the effects of Palm vitamin E (PVE) and α-tocopherol (α-TF) supplementations on adrenalin, noradrenalin, xanthine oxidase plus dehydrogenase (XO + XD) activities and gastric lesions in rats exposed to water-immersion restraint stress (WIRS).MethodsSixty male Sprague–Dawley rats (200-250 g) were randomly divided into three equal sized groups. The control group was given a normal diet, while the treated groups received the same diet with oral supplementation of PVE or α-TF at 60 mg/kg body weight. After the treatment period of 28 days, each group was further subdivided into two groups with 10 rats without exposing them to stress and the other 10 rats were subjected to WIRS for 3.5 hours. Blood samples were taken to measure the adrenalin and noradrenalin levels. The rats were then sacrificed following which the stomach was excised and opened along the greater curvature and examined for lesions and XO + XD activities.ResultsThe rats exposed to WIRS had lesions in their stomach mucosa. Our findings showed that dietary supplementations of PVE and α-TF were able to reduce gastric lesions significantly in comparison to the stressed control group. WIRS increased plasma adrenalin and noradrenalin significantly. PVE and α-TF treatments reduced these parameters significantly compared to the stressed control.ConclusionsSupplementations with either PVE or α-TF reduce the formation of gastric lesions. Their protective effect was related to their abilities to inhibit stress induced elevation of adrenalin and noradrenalin levels as well as through reduction in xanthine oxidase and dehydrogenase activities.

Exercise Significantly Increases Plasma Adrenaline and Oxidized Low-Density Lipoprotein in Normal Healthy Subjects But Not in Persons With Spinal Cord Injury

Mitsui T, Nakamura T, Ito T, Umemoto Y, Sakamoto K, Kinoshita T, Nakagawa M, Tajima F. Exercise significantly increases plasma adrenaline and oxidized low-density lipoprotein in normal healthy subjects but not in persons with spinal cord injury. ObjectivesTo compare plasma concentrations of oxidized low-density lipoprotein (oxLDL) and adrenaline during exercise between persons with spinal cord injury (SCI) and able-bodied (AB) individuals. DesignRandomized controlled study. SettingHuman laboratory at a medical university. ParticipantsPersons with SCI (n=7) and AB individuals (n=9). InterventionTwo-hour arm crank ergometer exercise at 60% maximum oxygen consumption. Main Outcome MeasuresPlasma oxLDL and adrenaline levels. ResultsExercise significantly increased plasma adrenaline levels in AB persons (mean ± SD: rest, 45.4±32.2pg/mL; exercise, 200.9±113.7pg/mL; P<.05) and persons with SCI; however; the magnitude of the increase in those with SCI was attenuated (mean ± SD: rest, 45.4±14.0pg/mL; exercise, 83.0±55.8pg/mL; P<.05). Exercise also significantly increased plasma oxLDL levels in AB persons (mean ± SD: rest, 102.2±30.2U/L; exercise, 179.7±60.0U/L; P<.05), but not in persons with SCI (mean ± SD: rest, 124.3±66.0U/L; exercise, 138.9±59.5U/L). ConclusionsThe results suggest that increases in plasma adrenaline levels during exercise contribute to the increase in plasma oxLDL levels.

Insights into the mechanisms mediating hyperglycemic and stressogenic outcomes in rats treated with monocrotophos, an organophosphorus insecticide

The present investigation provides mechanistic insights into the hyperglycemic and stressogenic effects of monocrotophos, an organophosphorus insecticide. Pre-treatment of rats with mifepristone (glucocorticoid receptor antagonist) prevented induction of liver tyrosine aminotransferase activity (TAT), but was ineffective in attenuating hyperglycemia induced by monocrotophos. Pre-treatment with propranolol (β-adrenergic receptor antagonist) and phentolamine (α-adrenergic receptor antagonist) were effective in abrogating monocrotophos-induced hyperglycemia. Interestingly, while propranolol offered partial protection against hyperglycemia, phentolamine completely abolished the same. However, monocrotophos-induced hyperlactacidemia was completely abolished by propranolol. Both the adrenoreceptor antagonists, however, failed to attenuate the stressogenic potential of monocrotophos. Hyperglycemia and hyperlactacidemia induced by monocrotophos were abolished by pre-treatment with atropine. Exogenous epinephrine was associated with hyperglycemia and hyperlactacidemia. The impact of adrenergic antagonists on epinephrine-induced hyperglycemia and hyperlactacidemia were remarkably similar to that of monocrotophos-induced hyperglycemia and hyperlactacidemia. Further, hydrazine sulfate (a gluconeogenesis inhibitor) abolished hyperglycemia in monocrotophos-treated rats. From our data, it can be hypothesized that excessive stimulation of adrenoreceptors, probably elicited by increased plasma epinephrine, mediates hyperglycemic outcomes induced by monocrotophos. Pattern of changes in plasma lactate suggests that β-adrenergic activation mediates monocrotophos-induced hyperlactacidemia, while α-adrenergic receptor mediates lactate utilization, leading to hyperglycemia. Induction of liver TAT activity is attributable to glucocorticoid receptor activation as a result of hypercorticosteronemia.

Wheelchair half-marathon race increases natural killer cell activity in persons with cervical spinal cord injury

Non-randomized study. We reported that individuals with cervical spinal cord injury (CSCI) showed no increase in natural killer cell activity (NKCA) in response to 20-min arm exercise. It could be argued that this lack of response was owing to the short duration and intensity of the exercise. The 29th Oita International wheelchair marathon race. The present study compared the effects of wheelchair half-marathon race on natural killer (NK) cell count, NKCA and other hematological and hormonal parameters in six subjects with CSCI and seven control subjects with spinal cord injury between T4 and L1 (SCI), before, immediately after and 2 h after recovery. NK cell counts increased at both time points after the race in SCI, but not in CSCI, compared with before the race. NKCA increased immediately in both groups of subjects after the race, and then returned to the pre-race level at 2 h after the race. Plasma cortisol did not change in both groups throughout the study. Plasma adrenaline increased sharply in SCI after the race, then returned to the pre-race level at 2 h after the race, whereas no change was observed in CSCI throughout the study. The present study demonstrated that wheelchair half-marathon race increases NKCA despite the lack of increase in plasma adrenaline in CSCI, suggesting the activation of NKCA by mechanisms other than circulating adrenaline level.

Effects of body temperature maintenance on glucose, insulin, and corticosterone responses to acute hypoxia in the neonatal rat

One of the biggest challenges of premature birth is acute hypoxia. Hypothermia during acute hypoxic periods may be beneficial. We hypothesized that prevention of hypothermia during neonatal hypoxia disrupts glucose homeostasis and places additional metabolic challenges on the neonate. Pups at PD2 and PD8 were exposed to 8% O2 for 3 h, during which they were allowed to either spontaneously cool or were kept isothermic. There was also a time control group that was subjected to normoxia and kept isothermic. Plasma glucose, insulin, C-peptide, corticosterone, and catecholamines were measured from samples collected at baseline, 1 h, 2 h, and 3 h. In postnatal day 2 (PD2) rats, hypoxia alone resulted in no change in plasma glucose by 1 h, an increase by 2 h, and a subsequent decrease below baseline values by 3 h. Hypoxia with isothermia in PD2 rats elicited a large increase in plasma insulin at 1 h. In PD8 rats, hypoxia with isothermia resulted in an initial increase in plasma glucose, but by 3 h, glucose had decreased significantly to below baseline levels. Hypoxia with and without isothermia elicited an increase in plasma corticosterone at both ages and an increase in plasma epinephrine in PD8 rats. We conclude that the insulin response to hypoxia in PD8 rats is associated with an increase in glucose similar to an adult; however, insulin responses to hypoxia in PD2 rats were driven by something other than glucose. Prevention of hypothermia during hypoxia further disrupts glucose homeostasis and increases metabolic challenges.

Rate of fall in blood glucose and recurrent hypoglycemia affect glucose dynamics and noradrenergic activation in the ventromedial hypothalamus

Noradrenergic activity in the ventromedial hypothalamus (VMH) is increased and activates a sympathoadrenal response during hypoglycemia. How the rate at which hypoglycemia develops affects local glucose concentrations and norepinephrine (NE) release was evaluated by placing microdialysis probes into the VMH of male Sprague-Dawley rats receiving insulin (20 mU·kg(-1)·min(-1)) and variable glucose infusions. During a first episode of hypoglycemia, interstitial glucose concentrations in the VMH generally declined at the same rate as plasma glucose; however, the faster hypoglycemia developed, the greater the magnitude of the initial NE release in the VMH (r(2) = 0.72, P < 0.001). Following recurrent episodes of hypoglycemia, VMH glucose decreased at a slower rate than plasma glucose, and the initial NE release was attenuated at the same rates of blood glucose decline. The plasma glucose threshold for the initial NE release in VMH was similar for all groups (∼3.23 mM); however, the VMH glucose threshold was stimulated and was lower when blood glucose declined more slowly (0.86 ± 0.06 vs. 1.06 ± 0.04 mmol/l, P < 0.01). The timing of the initial increase in NE release in VMH corresponded with an increase in plasma epinephrine during the first episode of hypoglycemia but not following recurrent hypoglycemia. Although a decrease in VMH glucose concentration is required for noradrenergic activation in VMH, there does not appear to be a set glucose threshold within the VMH for activation of this response.

Renal function and endocrine responses to arm exercise in euhydrated individuals with spinal cord injury

This study investigated the renal and endocrine responses to arm exercise in persons with spinal cord injury (SCI) under euhydration conditions (ad libitum drinking of water) and determined the physiological effects of exercise on renal function in these subjects. Eleven SCI (spinal lesions between T6 and L1, American Spinal Injury Association impairment scale A) and 14 able-bodied (AB) persons first rested for 1h in a sitting position, before undergoing 2-h arm-crank ergometer exercise at 60% of maximum oxygen consumption followed by a 2-h recovery period. On another day, all subjects participated in a time control study (5h of rest condition in sitting position). Urine and blood samples were collected hourly. There were no differences in mean blood pressure between the two groups. SCI patients showed attenuated increase in plasma adrenaline and increase in plasma aldosterone compared with AB controls, but similar changes in human atrial natriuretic polypeptide, plasma renin activity and plasma antidiuretic hormone following the exercise. Creatinine clearance, osmolal clearance, free water clearance and fractional excretion of Na(+) did not change during exercise in any of the subjects. These findings suggested that activated aldosterone and attenuated adrenaline responses during exercise in SCI could be due to adaptation to disordered sympathetic nervous system triggered to maintain renal function. The results showed no exercise-related adverse effects on renal function in hydrated subjects with SCI.

Abstract 10: Effect of behavioral stress on therapeutic sensitivity of prostate cancer

Abstract Behavioral stress has been long implicated in cancer pathogenesis, yet mechanistic aspects of stress/tumor interactions are understudied. Several publications described effects of stress hormone epinephrine on tumor stroma components: vasculature and immune cells; however it was not clear whether epinephrine could influence cancer cells directly and if increase of epinephrine induced by behavioral stress could activate anti-apoptotic signaling in tumors and diminish efficacy of anti-cancer therapies. Here, we studied whether subjecting mice to behavioral stress increases resistance of PTEN-deficient prostate cancer to treatments with PI3K inhibitors. We examined effects of behavioral stress on C4-2Luc prostate cancer xenografts that express firefly luciferase and could be non-invasively monitored by luminescent imaging. In these tumor xenografts PI3K pathway is constitutively active due to the loss of PTEN expression. Injection of PI3K inhibitors into C4-2Luc xenografts induced apoptosis and substantially reduced luminescence. Subjecting mice to immobilization stress for 1 hour increased plasma epinephrine levels up to 10-15 nM, inhibited apoptosis and prevented reduction of luminescence in C4-2Luc xenografts treated with PI3K inhibitors. Injections of epinephrine had similar to stress effects. Conversely, the effect of either stress or epinephrine was completely blocked by beta2-adrenergic receptor (ADRB2) selective antagonist ICI118,551, implying that effects of stress/epinephrine are mediated via ADRB2. Elevated phosphorylation of BAD and CREB and inhibition of apoptosis was observed in xenograft tumors of mice subjected to immobilization stress. Effects of stress on BAD and CREB phosphorylation were completely blocked by ADRB2 selective antagonist ICI118,551. To test the role of protein kinase A (PKA) in anti-apoptotic signaling by stress/epinephrine in vivo we generated C4-2Luc cells that inducibly express chimera of PKA inhibitor peptide PKI and GFP (PKI-GFP). Induction of PKI-GFP expression in prostate cancer xenografts blocked stress/epinephrine-induced activation of PKA as judged by lack of CREB phosphorylation. It also prevented stress/epinephrine-induced activation of anti-apoptotic signals that phosphorylated BAD. Furthermore, C4-2Luc xenografts that inducibly express GFP-PKI were not protected from apoptosis by epinephrine or stress. In summary, we found that subjecting mice to behavioral stress resulted in increase of serum epinephrine level leading to activation of the ADRB2 and PKA pathway in prostate tumors. This ADRB2/PKA activation is necessary for in vivo BAD phosphorylation and protection of prostate tumors from apoptosis induced by PI3K inhibitors. Thus, elevated epinephrine levels could contribute to therapy resistance of prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 10. doi:10.1158/1538-7445.AM2011-10