Elevated Plasma Epinephrine Research Articles

Severe mesenteric traction syndrome is associated with increased systemic inflammatory response, endothelial dysfunction, and major postoperative morbidity.

To determine whether mesenteric traction syndrome (MTS) leads to increased systemic inflammation and dysfunction of the glycocalyx and endothelial cell and whether this correlates with the degree of postoperative morbidity. Severe MTS is associated with increased postoperative morbidity following major gastrointestinal surgery, but the pathophysiological mechanism has not been previously explored. Systemic inflammatory response and impaired glycocalyx and endothelial cells may be responsible for the development of symptoms. The study analyzed prospectively collected data from two cohorts (n = 67). The severity of the MTS response was graded intraoperatively and blood samples for PGI2, catecholamines, IL6, and endothelial biomarkers obtained at predefined time points. Patients undergoing either esophagectomy (n = 45) or gastrectomy (n = 22) were included. Surgery led to significantly increased plasma concentrations of all biomarkers. Yet, patients who developed severe MTS had higher baseline epinephrine levels (p < 0.05) and higher levels of PGI2 (p < 0.05), Syndecan-1 (p < 0.001), and sVEGFR1 (p < 0.001). Peak values of IL6, Syndecan-1, sVEGFR1, and sTM all correlated to peak PGI2. Lastly, patients with high postoperative morbidity had higher baseline epinephrine (p = 0.009) and developed higher plasma IL6 (p = 0.007) and sTM (p = 0.022). The development of severe MTS during upper gastrointestinal surgery is associated with preoperative elevated plasma epinephrine and further a more pronounced proinflammatory response and damage to the vascular endothelium. The increased postoperative morbidity seen in patients with severe MTS may thus, in part, be explained by an inherent susceptibility towards an inappropriate secretion of PGI2, which leads to an increased surgical stress response and endothelial damage. These findings must be confirmed in a new prospective cohort.

Whole transcriptome analysis of adrenal glands from prenatal glucocorticoid programmed hypertensive rodents

Prenatal glucocorticoid exposure is associated with the development of hypertension in adults. We have previously demonstrated that antenatal dexamethosone (DEX) administration in Wistar-Kyoto dams results in offspring with increased blood pressure coupled with elevated plasma epinephrine levels. In order to elucidate the molecular mechanisms responsible for prenatal DEX-mediated programming of hypertension, a whole-transcriptome analysis was performed on DEX programmed WKY male adrenal glands using the Rat Gene 2.0 microarray. Differential gene expression (DEG) analysis of DEX-exposed offspring compared with saline-treated controls revealed 142 significant DEGs (109 upregulated and 33 downregulated genes). DEG pathway enrichment analysis demonstrated that genes involved in circadian rhythm signaling were most robustly dysregulated. RT-qPCR analysis confirmed the increased expression of circadian genes Bmal1 and Npas2, while Per2, Per3, Cry2 and Bhlhe41 were significantly downregulated. In contrast, gene expression profiling of Spontaneously Hypertensive (SHR) rats, a genetic model of hypertension, demonstrated decreased expression of Bmal1 and Npas2, while Per1, Per2, Per3, Cry1, Cry2, Bhlhe41 and Csnk1D were all upregulated compared to naïve WKY controls. Taken together, this study establishes that glucocorticoid programmed adrenals have impaired circadian signaling and that changes in adrenal circadian rhythm may be an underlying molecular mechanism responsible for the development of hypertension.

Brain nitric oxide induces facilitation of the micturition reflex through brain glutamatergic receptors in rats.

Brain nitric oxide (NO) have been reported in regulation of the sympatho-adrenomedullary system, which can affect voiding and storage functions. Therefore, we investigated effects of intracerebroventricularly (icv) administered 3-(4-morpholinyl)sydnonimine, hydrochloride (SIN-1) (NO donor) on the micturition reflex, focusing on their dependence on the sympatho-adrenomedullary system and on brain N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in urethane-anesthetized (0.8 g/kg, ip) male Wistar rats. Plasma noradrenaline and adrenaline were measured just before and 5 minutes after SIN-1 administration. Evaluation of urodynamic parameters was started 1 hour before SIN-1 administration or intracerebroventricular pretreatment with other drugs. SIN-1 (100 and 250 µg/animal) elevated plasma adrenaline and reduced intercontraction interval([ICI]values; 110.5% [SIN-1, 0 µg]and 54.9% [SIN-1, 250 µg]during 15 minutes after SIN-1 administration [P < .05;η2 = 0.59]) without affecting plasma noradrenaline or maximal voiding pressure. SIN-1 (250 µg/animal) reduced single-voided volume and bladder capacity without affecting post-voiding residual volume. The SIN-1 (250 µg/animal)-induced adrenaline elevation and ICI reduction were attenuated by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, sodium salt (carboxy-PTIO) (NO scavenger, icv) (ICI values; 44.7% [vehicle + SIN-1]and 77.5% [carboxy-PTIO + SIN-1]during 15 minutes after SIN-1 administration [P < .05;η2 = 0.51]). Acute bilateral adrenalectomyabolished SIN-1-induced adrenaline elevation, while showed no effect on the SIN-1-induced ICI reduction. The ICI reduction was attenuated by MK-801 (NMDA receptor antagonist, icv) (ICI values; 47.0% [vehicle + SIN-1]and 87.6% [MK-801 + SIN-1]during 15 minutes after SIN-1 administration [P < .05;η2 = 0.61]), but not by DNQX (AMPA receptor antagonist, icv). Brain NO is involved in facilitation of the rat micturition reflex through brain NMDA receptors, independently of the sympatho-adrenomedullary outflow modulation.

A 3-day dietary manipulation affects muscle glycogen and results in modifications of carbohydrate and fat metabolism during exercise when hyperglycaemic

The effect of hyperglycaemia on exercise with low and elevated muscle glycogen on glucose utilization (GUR), carbohydrate and fat oxidation, hormonal and metabolite responses, as well as rating of perceived exertion (RPE) were explored. Five healthy trained males were exercised for 90min at 70% V̇O2max in two trials, while glucose was infused intravenously at rates to "clamp" blood glucose at 12mM. On one occasion, participants were 'loaded' with carbohydrate (CHO-L), whilst on a separate occasion, participants were glycogen depleted (CHO-D). Prior exercise and dietary manipulations produced the 'loaded' and 'depleted' states. The CHO-L and CHO-D conditions resulted in muscle glycogen concentrations of 377 and 159mmol/g dw, respectively. Hyperglycaemia elevated plasma insulin concentrations with higher levels for CHO-L than for CHO-D (P < 0.01). Conversely, CHO-D elevated plasma adrenaline and noradrenaline higher than CHO-L (P < 0.05). Plasma fat metabolites (NEFA, β-hydroxybutyrate, and glycerol) were higher under CHO-D than CHO-L (P < 0.01). The resultant was that the rates of total carbohydrate and fat oxidation were elevated and depressed for loaded CHO-L vs CHO-D respectively (P < 0.01), although no difference was found for GUR (P > 0.05). The RPE over the exercise period was higher for CHO-D than CHO-L (P < 0.05). Hyperglycaemia during exercise, when muscle glycogen is reduced, attenuates insulin but promotes catecholamines and fat metabolites. The effect is a subsequent elevation of fat oxidation, a reduction in CHO oxidation without a concomitant increase in GUR, and an increase in RPE.

Sympathectomy-induced blood pressure reduction in adult normotensive and hypertensive rats is counteracted by enhanced cardiovascular sensitivity to vasoconstrictors.

The effect of chemical sympathectomy on cardiovascular parameters and the compensatory role of adrenal hormones, the renin-angiotensin system, and cardiovascular sensitivity to vasoconstrictors were studied in spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats. Sympathectomy was induced in 20-week-old rats by daily intraperitoneal guanethidine administration (30 mg/kg b.w.) for 2 weeks. Basal blood pressure (BP), heart rate (HR), and restraint stress-induced cardiovascular changes were measured by radiotelemetry. The BP response to catecholamines was determined in rats with implanted catheters. Sympathectomy decreased BP only transiently, and after 14-day guanethidine treatment, BP returned to basal values in both strains. Sympathectomy permanently lowered HR, improved baroreflex sensitivity, and decreased the low-frequency domain of systolic blood pressure variability (a marker of vascular sympathetic activity). Guanethidine also attenuated the BP and HR responses to restraint stress. On the other hand, the BP response to catecholamines was augmented in sympathectomized rats, and this was not due to the de novo synthesis of vascular adrenergic receptors. Sympathectomy caused adrenal enlargement, enhanced the expression of adrenal catecholamine biosynthetic enzymes, and elevated plasma adrenaline levels in both strains, especially in WKY rats. Guanethidine also increased the plasma levels of aldosterone and corticosterone in WKY rats only. In conclusion, sympathectomy produced a transient decrease in BP, a chronic decrease in HR and improvement in baroreflex sensitivity. The effect of sympathectomy on BP was counteracted by increased vascular sensitivity to catecholamines in WKY rats and SHRs and/or by the enhanced secretion of adrenal hormones, which was more pronounced in WKY rats.

MON-386 Finding Truth from Two False-Positives

Certain medications can interfere with catecholamines levels and result in a misleading diagnosis of pheochromocytoma. Tricyclic antidepressants, alpha-blockers, beta-blockers, and acetaminophens are the most common cause of falsely elevated levels of catecholamines. To confirm and localize pheochromocytoma, 123I-Metaiodobenzylguanidine (123I-MIBG) scintigraphy scan is usually performed following a biochemical test if CT or MRI has failed to detect the tumor. Here we describe a 48-year-old African-American male who was found to have a medication-related elevation in catecholamines with positive 123I-MIBG adrenal uptake. He was referred to the endocrinology clinic for elevated plasma epinephrine, norepinephrine, and dopamine levels. His primary care physician obtained catecholamines levels for recurrent episodes of anxiety, sweating, and dizziness. No history of hypertension was noted. His medications include alprazolam for anxiety, hydrocodone/acetaminophen for chronic back pain, valproic acid for mood-stablilizing, and escitalopram for depression. At the first visit, his blood pressure was 162/110. Otherwise, an unremarkable physical exam was noted. Initial blood work at an outside facility showed plasma dopamine > 3000 pg/mL (Ref 0-20 pg/mL), epinephrine 6827 pg/mL (Ref 0-62 pg/mL), and norepinephrine 51919 pg/mL (Ref 80-520 pg/mL). The patient underwent MRI of the abdomen and pelvis before the referral, which was unremarkable, and had an 123I-MIBG scan that showed increased accumulation over the left adrenal gland; none was seen over the right adrenal gland. We withheld his medications except for alprazolam. Catecholamine levels were retested after four weeks and showed normal plasma epinephrine, norepinephrine, metanephrine, and normetanephrine levels. The 123I-MIBG scan is highly sensitive and specific for the detection of pheochromocytoma. However, 123I-MIBG uptake can also be seen in normal adrenal medulla (16% of scans after 48 h). The pattern of 123I-MIBG uptake may be asymmetrical between the left and right adrenals, and therefore, caution should be applied in interpreting the images obtained, particularly to avoid unnecessary or misguided surgery. This case demonstrates a unilateral 123I-MIBG adrenal uptake possibly associated with medications. It is expected that the uptake would be bilateral, given the systemic effect of the medications. Nonetheless, in this case, unilateral adrenal uptake was found. Medication-induced catecholamine elevation has to be ruled out before further investigation for pheochromocytoma. This step is crucial given the non-specific symptoms of pheochromocytoma and the possibility of having false catecholamines elevation and false 123I-MIBG uptake, both of which further challenge the diagnosis of pheochromocytoma.

Molecular Pathogenesis of Chewable Tobacco.

In Pakistan, extensive use of several precarious chewable tobacco formulations has made oral cancer the second leading malignancy. Selection of literature was done by a survey of studies published from 1990 to 2017 mainly, from PUBMED and few from other search engines, on naswar, gutka, areca nut and betel quid, which included published reviews, original articles and other data sources on chewable tobacco, its epidemiology, pathological implications, and psychological effects. These studies have revealed that the chemicals in these formulations bind and mutate DNA of oral mucosa through down regulating cellular repair pathways and upregulating genetic networks associated with pathogenesis. Areca nut, having aercoline (the major alkaloid) causes carcinogenicity, mutagenicity, and genotoxicity of oral mucosa through increased production of growth factors and corticotrophin-releasing hormone, and genetic alteration in expression of CASP8, APAF-1, BAX, BAD, and upregulation of caspas-3. Gutka addiction leads to precancerous lesions resulting in characteristic facial abnormalities, following trismus. Naswar, in addition to oral cancer, causes adverse cardiovascular events by reducing glutathione per oxidase (GPx) and super-oxide dismutase (SOD), serum levels of HDL, whereas, increasing the ratio of cholesterol, LDL, triglycerides and LDL-C/HDL-C. Betel quid (Paan), causes psychoactivity affecting central and autonomic nervous systems leading to dependence with decreased cognition, euphoria, sweating, salivation, palpitation, heightened alertness and zest to work. Metabolically, cardio-acceleration, cortical desynchronisation of EEG, elevated plasma noradrenaline and adrenaline were found. This review highlights the corrosive effects of various most popular chewable tobacco formulations; and damage done by their cocktail of carcinogenic substances and added ingredients, leading to oropharangeal cancer.

Impact of adrenaline and metabolic stress on exercise‐induced intracellular signaling and PGC‐1α mRNA response in human skeletal muscle

This study tested the hypothesis that elevated plasma adrenaline or metabolic stress enhances exercise‐induced PGC‐1α mRNA and intracellular signaling in human muscle. Trained (VO 2‐max: 53.8 ± 1.8 mL min−1 kg−1) male subjects completed four different exercise protocols (work load of the legs was matched): C – cycling at 171 ± 6 W for 60 min (control); A – cycling at 171 ± 6 W for 60 min, with addition of intermittent arm exercise (98 ± 4 W). DS – cycling at 171 ± 6 W interspersed by 30 sec sprints (513 ± 19 W) every 10 min (distributed sprints); and CS – cycling at 171 ± 6 W for 40 min followed by 20 min of six 30 sec sprints (clustered sprints). Sprints were followed by 3:24 min:sec at 111 ± 4 W. A biopsy was obtained from m. vastus lateralis at rest and immediately, and 2 and 5 h after exercise. Muscle PGC‐1α mRNA content was elevated (P < 0.05) three‐ to sixfold 2 h after exercise relative to rest in C, A, and DS, with no differences between protocols. AMPK and p38 phosphorylation was higher (P < 0.05) immediately after exercise than at rest in all protocols, and 1.3‐ to 2‐fold higher (P < 0.05) in CS than in the other protocols. CREB phosphorylation was higher (P < 0.05) 2 and 5 h after exercise than at rest in all protocols, and higher (P < 0.05) in DS than CS 2 h after exercise. This suggests that neither plasma adrenaline nor muscle metabolic stress determines the magnitude of PGC‐1α mRNA response in human muscle. Furthermore, higher exercise‐induced changes in AMPK, p38, and CREB phosphorylation are not associated with differences in the PGC‐1α mRNA response.

The combined effect of green tea and acute interval sprinting exercise on fat oxidation of trained and untrained males.

[Purpose]This study investigated the combined effect of green tea and acute interval sprinting exercise on fat oxidation of trained and untrained males.[Methods]Fourteen trained and 14 untrained males ingested one capsule containing either green tea or cellulose with breakfast, lunch, and dinner, 24 hours before two exercise sessions. A fourth capsule was consumed 90 minutes before exercise after overnight NPO (nil per os). Participants performed a 20-minute interval sprinting cycling protocol, consisting of repeated bouts of 8-seconds of sprint cycling (at 65% of maximum power output) and 12-seconds of recovery (at 25% of maximum power output), followed by 75 minutes of post-exercise recovery.[Results]Fat oxidation was significantly greater in the resting condition after green tea ingestion (p < 0.05) compared with the placebo. Fat oxidation was also significantly increased post-exercise in the green tea, compared with the placebo condition (p < 0.01). During and after exercise the plasma glycerol levels significantly increased in both groups after green tea consumption and were significantly higher in the untrained group compared with the trained group (p < 0.05). Compared with the placebo, the plasma epinephrine levels were significantly higher for both groups in the green tea condition during and after exercise, however, norepinephrine levels were only significantly greater, p < 0.05, during and after exercise in the untrained group.[Conclusion]Green tea significantly increased resting and post-exercise fat oxidation and also elevated plasma glycerol and epinephrine levels during and after interval sprinting. Glycerol and norepinephrine levels during interval sprinting were significantly higher in the untrained group compared with the trained group.

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.

Direct effects of recurrent hypoglycaemia on adrenal catecholamine release.

In Type 1 and advanced Type 2 diabetes mellitus, elevation of plasma epinephrine plays a key role in normalizing plasma glucose during hypoglycaemia. However, recurrent hypoglycaemia blunts this elevation of plasma epinephrine. To determine whether recurrent hypoglycaemia affects peripheral components of the sympatho-adrenal system responsible for epinephrine release, male rats were administered subcutaneous insulin daily for 3 days. These recurrent hypoglycaemic animals showed a smaller elevation of plasma epinephrine than saline-injected controls when subjected to insulin-induced hypoglycaemia. Electrical stimulation of an adrenal branch of the splanchnic nerve in recurrent hypoglycaemic animals elicited less release of epinephrine and norepinephrine than in controls, without a change in adrenal catecholamine content. Responsiveness of isolated, perfused adrenal glands to acetylcholine and other acetylcholine receptor agonists was also unchanged. These results indicate that recurrent hypoglycaemia compromised the efficacy with which peripheral neuronal activity stimulates adrenal catecholamine release and demonstrate that peripheral components of the sympatho-adrenal system were directly affected by recurrent hypoglycaemia.

Possible involvement of brain prostaglandin E2 and prostanoid EP3 receptors in prostaglandin E2 glycerol ester-induced activation of central sympathetic outflow in the rat

We recently reported that intracerebroventricularly administered 2-arachidonoylglycerol elevated plasma noradrenaline and adrenaline by brain monoacylglycerol lipase- (MGL) and cyclooxygenase-mediated mechanisms in the rat. These results suggest that 2-arachidonoylglycerol is hydrolyzed by MGL to free arachidonic acid, which is further metabolized to prostaglandins (PGs) by cyclooxygenase in the brain, thereby elevating plasma noradrenaline and adrenaline. On the other hand, 2-arachidonoylglycerol can be also metabolized by cyclooxygenase to PG glycerol esters (PG-Gs), which seems to be hydrolyzed by MGL to free PGs. Here, we examined the involvement of brain PG-Gs in the elevation of plasma noradrenaline and adrenaline regarding PGE2-G and prostanoid EP receptors using anesthetized male Wistar rats. Intracerebroventricularly administered PGE2-G (1.5 and 3 nmol/animal) dose-dependently elevated plasma noradrenaline but not adrenaline. PGE2-G also elevated systolic, mean and diastolic blood pressure and heart rate. The PGE2-G-induced elevation of plasma noradrenaline was attenuated by JZL184 (MGL inhibitor). Intracerebroventricularly administered PGE2 (0.3 and 1.5 nmol/animal) and sulprostone (0.1 and 0.3 nmol/animal) (EP1/EP3 agonist) also elevated plasma noradrenaline but not adrenaline in a dose-dependent manner. The sulprostone-induced elevation was attenuated by L-798,106 (EP3 antagonist), but not by SC-51322 (EP1 antagonist). L-798,106 also attenuated the PGE2-G- and PGE2-induced elevation of plasma noradrenaline, while PF-04418948 (EP2 antagonist) and L-161,982 (EP4 antagonist) had no effect on the PGE2-G-induced response. These results suggest a possibility that brain PGE2-G produced from 2-arachidonoylglycerol can be hydrolyzed to free PGE2, thereby activating central sympathetic outflow by brain prostanoid EP3 receptor-mediated mechanisms in the rat.

Adreno-medullary sympathetic nerves and ascending baroreceptor pathways are not affected in Parkinson's disease patients with orthostatic hypotension

s from the Japanese Journal: The autonomic nervous system #1 Adreno-medullary sympathetic nerves and ascending baroreceptor pathways are not affected in Parkinson's disease patients with orthostatic hypotension Toshimasa Yamamoto, Akifumi Miyake, Toshinori Kimura, Yasuko Ohe, Naotoshi Tamura, Nobuo Araki Department of Neurology, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan We investigated whether the activity in adreno-medullary nerves and in ascending baroreceptor pathways in Parkinson's disease with orthostatic hypotension differs from that in multiple system atrophy. We examined noradrenergic, adreno-medullary, and ascending baroreceptor pathway abnormalities, by measuring plasma noradrenaline, adrenaline and arginine-vasopressin in Parkinson's disease patients with and without orthostatic hypotension, in multiple system atrophy patients with orthostatic hypotension and in healthy controls, before and during a 70° passive head-up tilt lasting 10 min. We found that elevation of plasma noradrenaline to tilt was significantly smaller in both sets of patients with orthostatic hypotension (compared to controls), but there was no difference between the two groups of patients. Elevation of plasma adrenaline to tilt was significantly higher in Parkinson's disease patients with orthostatic hypotension compared to the other two groups of patients. Elevation of plasma vasopressin to tilt was significantly higher in Parkinson's disease patients with orthostatic hypotension than in the other three groups. We conclude that noraderenergic pathways are functionally disturbed in patientswith Parkinson's diseasewith orthostatic hypotension. The functions of adreno-medullary nerves and of the ascending baroreceptor pathways are well preserved in Parkinson's disease with orthostatic hypotension, but are adversely affected in patients with multiple system atrophy. (The Autonomic Nervous System, 48: 251-257, 2011) doi:10.1016/j.autneu.2012.08.006 #2 Chrono-medical impact on morning hypertension therapy and home blood pressure measurement: The Val-HOPE study Kuniaki Otsuka, Kim Gwang U., Tatsushi Sugiura, Yoshiaki Harada, Keiko Mochizuki, Hamyuki Nakagawa, Hideaki Sudo and Val-HOPE study group Department of Medicine, Tokyo Women's Medical University Medical Center East Department of Internal Medicine, Nishi-Arai Hospital Department of Internal Medicine, Seiwa Clinic, Nishi-Arai Hospital Department of Internal Medicine, Harada Clinic Department of Internal Medicine, Nishikawa Clinic Department of Internal Medicine, Nakagawa Clinic Department of Internal Medicine, Johoku Clinic, Tokyo 116-8567, Japan We evaluated chrono-medically the effect of valsartan's therapy on home-measured blood pressure (BP) in patients, whose blood pressure was inadequately controlled with or without anti-hypertensive agents. The subjects were 42 men and 63 women, of average age of 63.4 years. Administration of valsartan significantly reduced blood pressure both at the clinic and at home, i.e., from 158.6±13.7/90.9±11.6 to 139.3±12.9/82.5±10.2 mmHg, and from 150.0±11.6/89.4±10.9 to 136.6±11.9/82.5±10.2 mm Hg (pb0.001), respectively. Morning and evening blood pressure levels were both significantly decreased (pb0.001), and the difference morning/evening dropped from 9.9/5.6 (systolic/diastolic) mmHg to 6.6/4.0 mmHg (pb0.05). In 34 subjects who suffered from amorning blood pressure surge and had a morning/ evening difference of more than 15 mmHg, the morning/evening difference decreased from 24.2±7.6 to 14.3±10.2 mmHg (pb0.001) after the valsartan treatment. Among 81 subjects whose systolic blood pressure levels in both morning and evening exceeded 135 mm Hg, 62 subjects showed a reduction of the evening blood pressure of over 5 mm Hg after administration of valsartan. In these 62 subjects, the ratio of the fall in pressure in the morning over that in the evening (M/E ratio, index of continuousness of antihypertensive action) was 1.13+0.62 when calculated in the individual patients and was 1.02 when calculated from mean values of the patient group. Depression symptoms were significantly alleviated (pb0.05), and no adverse events were seen. In conclusion the chrono-medical assessment of this study has shown that valsartan is a potential, well-tolerated antihypertensive agent. (The Autonomic Nervous System, 48: 258-265, 2011) doi:10.1016/j.autneu.2012.08.007 #3 Evaluation of chilly constitution in young women with a postural change test Shunji Sakaguchi, Yoshihisa Kojima, Junji Miyazaki, Hiroshi Kuge, Hidetoshi Mori Autonomic Neuroscience: Basic and Clinical 171 (2012) 89–91

Effect of lesions of A5 or A7 noradrenergic cell group or surgical transection of brainstem catecholamine pathways on plasma catecholamine levels in rats injected subcutaneously by formalin

The pain-induced activation of the sympatho-adrenal system is modulated by several brain areas, including brainstem catecholamine cell groups. In the present study, we evaluated the effect of bilateral lesions of the A5 or A7 cell groups or bilateral transections of brainstem catecholaminergic pathways on plasma catecholamine levels in Sprague-Dawley rats injected subcutaneously by formalin or saline. Plasma levels of both epinephrine and norepinephrine were slightly elevated after formalin injections within 15-30 min in rats with or without lesions of the A7 catecholamine cell group. However, saline but not formalin elicited a significant increase in plasma epinephrine level in both sham-operated and A5-lesioned groups. It is more likely, that formalin blocks the effect of the handling and the painful injection procedure. In rats with bilateral partial transections of the lower brainstem, formalin was more effective than saline in the elevation of plasma epinephrine and norepinephrine levels at several time-points through the investigation period. Our data indicate the involvement of A5 and A7 norepinephrine neurons and brainstem catecholaminergic pathways in the regulation of the activity of the sympatho-adrenal system during acute painful situations. Their modulatory effect, however, seems to be a very rapid one, short and moderate.

Role of brainstem thyrotropin-releasing hormone-triggered sympathetic overactivation in cardiovascular mortality in type 2 diabetic Goto–Kakizaki rats

Sympathetic hyperactivity has an important role in cardiovascular mortality in patients with type 2 diabetes (T2D). Thyrotropin-releasing hormone (TRH)-containing fibers innervate autonomic motor and premotor nuclei of the brainstem and spinal cord that regulate cardiovascular functions. We compared cardiovascular responses to application of TRH-analog in the brainstem of Wistar and T2D Goto-Kakizaki (GK) rats. GK rats exhibited basal systolic hypertension (152±2 mm Hg) and had a significantly potentiated, dose-related hypertensive response to intracisternal (i.c.) injection of the TRH-analog RX77368 (10-60 ng). In GK rats only, i.c. RX77368 (30-60 ng) markedly increased heart rate (HR; +88 b.p.m.) and induced acute cardiac mortality (100%), concurrent with extreme hyperglycemia (>26 mmol l(-1)), increased plasma H(2)O(2) and 8-isoprostane, and enhanced heart expression of NADPH oxidase 4 and vascular cell adhesion molecule-1 mRNAs. GK rats also had elevated basal plasma epinephrine, higher adrenal gene expression of tyrosine hydroxylase and dopamine β-hydroxylase (DβH), and greater plasma catecholamine and adrenal DβH responses to i.c. TRH-analog, compared with Wistar rats. In GK rats, hexamethonium blocked i.c. RX77368-induced hypertensive and tachycardic responses, and reduced mortality by 86%, whereas phentolamine abolished the hypertensive response but enhanced tachycardia (+160 b.p.m.), and reduced mortality by 50%. The angiotensin II type 1 receptor antagonist irbesartan prevented i.c. RX77368-induced increases in blood pressure, HR and mortality. In conclusion, sympathetic overactivation triggered by brainstem TRH contributes to the mechanism of cardiovascular morbidity and mortality in T2D, which involves heightened cardiac inflammation and peripheral oxidative stress responses to sympathetic drive, and a mediating role of the renin-angiotensin system.

Therapeutic inhibition of fatty acid oxidation in right ventricular hypertrophy: exploiting Randle’s cycle

Right ventricular hypertrophy (RVH) and RV failure are major determinants of prognosis in pulmonary hypertension and congenital heart disease. In RVH, there is a metabolic shift from glucose oxidation (GO) to glycolysis. Directly increasing GO improves RV function, demonstrating the susceptibility of RVH to metabolic intervention. However, the effects of RVH on fatty acid oxidation (FAO), the main energy source in adult myocardium, are unknown. We hypothesized that partial inhibitors of FAO (pFOXi) would indirectly increase GO and improve RV function by exploiting the reciprocal relationship between FAO and GO (Randle's cycle). RVH was induced in adult Sprague-Dawley rats by pulmonary artery banding (PAB). pFOXi were administered orally to prevent (trimetazidine, 0.7 g/L for 8 weeks) or regress (ranolazine 20 mg/day or trimetazidine for 1 week, beginning 3 weeks post-PAB) RVH. Metabolic, hemodynamic, molecular, electrophysiologic, and functional comparisons with sham rats were performed 4 or 8 weeks post-PAB. Metabolism was quantified in RV working hearts, using a dual-isotope technique, and in isolated RV myocytes, using a Seahorse Analyzer. PAB-induced RVH did not cause death but reduced cardiac output and treadmill walking distance and elevated plasma epinephrine levels. Increased RV FAO in PAB was accompanied by increased carnitine palmitoyltransferase expression; conversely, GO and pyruvate dehydrogenase (PDH) activity were decreased. pFOXi decreased FAO and restored PDH activity and GO in PAB, thereby increasing ATP levels. pFOXi reduced the elevated RV glycogen levels in RVH. Trimetazidine and ranolazine increased cardiac output and exercise capacity and attenuated exertional lactic acidemia in PAB. RV monophasic action potential duration and QTc interval prolongation in RVH normalized with trimetazidine. pFOXi also decreased the mild RV fibrosis seen in PAB. Maladaptive increases in FAO reduce RV function in PAB-induced RVH. pFOXi inhibit FAO, which increases GO and enhances RV function. Trimetazidine and ranolazine have therapeutic potential in RVH.

Brain α4β2 nicotinic acetylcholine receptors are involved in the secretion of noradrenaline and adrenaline from adrenal medulla in rats

Recently, we reported that intracerebroventricularly (i.c.v.) administered (±)-epibatidine (a non-selective agonist of nicotinic acetylcholine receptors) elevates plasma noradrenaline and adrenaline through brain nicotinic acetylcholine receptor-mediated mechanisms in rats. In the present study, we characterized the receptors involved in these responses using selective agonists and antagonists of nicotinic acetylcholine receptor subtypes in anesthetized rats. (±)-Epibatidine (5 and 10 nmol/animal, i.c.v.) and (−)-nicotine (250 and 500 nmol/animal, i.c.v.) both elevated plasma noradrenaline and adrenaline (adrenaline > noradrenaline) but the former was more efficient than the latter. The (±)-epibatidine (5 nmol/animal, i.c.v.)-induced elevation of plasma catecholamines was reduced by dihydro-β-erythroidine (a selective antagonist of α4β2 nicotinic acetylcholine receptors) (100 and 300 nmol/animal, i.c.v.), while methyllycaconitine (a selective antagonist of α7 nicotinic acetylcholine receptors) (100 and 300 nmol/animal, i.c.v.) had no effect on the (±)-epibatidine-induced responses. RJR-2403 (a selective agonist of α4β2 nicotinic acetylcholine receptors) (2.5 and 5 μmol/animal, i.c.v.) elevated plasma noradrenaline and adrenaline (adrenaline > noradrenaline), while PNU-282987 (a selective agonist of α7 nicotinic acetylcholine receptors) (2.5 and 5 μmol/animal, i.c.v.) had no effect. Furthermore, the RJR-2403 (5 μmol/animal, i.c.v.)-induced responses were abolished by acute bilateral adrenalectomy. Immunohistochemical procedures demonstrated the expression of α4 and β2 nicotinic acetylcholine receptor subunits on the spinally projecting hypothalamic paraventricular neurons. Taken together, brain α4β2 nicotinic acetylcholine receptors seem to be involved in the secretion of noradrenaline and adrenaline from adrenal medulla in rats.

Chronic exposure to elevated norepinephrine suppresses insulin secretion in fetal sheep with placental insufficiency and intrauterine growth restriction

In this study, we examined chronic norepinephrine suppression of insulin secretion in sheep fetuses with placental insufficiency-induced intrauterine growth restriction (IUGR). Glucose-stimulated insulin secretion (GSIS) was measured with a square-wave hyperglycemic clamp in the presence or absence of adrenergic receptor antagonists phentolamine (alpha) and propranolol (beta). IUGR fetuses were hypoglycemic and hypoxemic and had lower GSIS responsiveness (P < or = 0.05) than control fetuses. IUGR fetuses also had elevated plasma norepinephrine (3,264 +/- 614 vs. 570 +/- 86 pg/ml; P < or = 0.05) and epinephrine (164 +/- 32 vs. 60 +/- 12 pg/ml; P < or = 0.05) concentrations. In control fetuses, adrenergic inhibition increased baseline plasma insulin concentrations (1.7-fold, P < or = 0.05), whereas during hyperglycemia insulin was not different. A greater (P < or = 0.05) response to adrenergic inhibition was found in IUGR fetuses, and the average plasma insulin concentrations increased 4.9-fold at baseline and 7.1-fold with hyperglycemia. Unlike controls, basal plasma glucose concentrations fell (P < or = 0.05) with adrenergic antagonists. GSIS responsiveness, measured by the change in insulin, was higher (8.9-fold, P < or = 0.05) in IUGR fetuses with adrenergic inhibition than controls (1.8-fold, not significant), showing that norepinephrine suppresses insulin secretion in IUGR fetuses. Strikingly, in IUGR fetuses, adrenergic inhibition resulted in a greater GSIS responsiveness, because beta-cell mass was 56% lower and the maximal stimulatory insulin response tended (P < 0.1) to be higher than controls. This persistent norepinephrine suppression appears to be partially explained by higher mRNA concentrations of adrenergic receptors alpha(1D), alpha(2A), and alpha(2B) in a cohort of fetuses that were naïve to the antagonists. Therefore, norepinephrine suppression of insulin secretion was maintained, in part, by upregulating adrenergic receptor expression, but the beta-cells also appeared to compensate with enhanced GSIS. These findings may begin to explain why IUGR infants have a propensity for increased glucose requirements if norepinephrine is suddenly decreased after birth.

Acute altitude-induced hypoxia suppresses plasma glucose and leptin in healthy humans

To examine the effects of acute altitude-induced hypoxia on the hormonal and metabolic response to ingested glucose, 8 young, healthy subjects (5 men and 3 women; age, 26 ± 2 years; body mass index, 23.1 ± 1.0 kg/m 2) performed 2 randomized trials in a hypobaric chamber where a 75-g glucose solution was ingested under simulated altitude (ALT, 4300 m) or ambient (AMB, 362 m) conditions. Plasma glucose, insulin, C-peptide, epinephrine, leptin, and lactate concentrations were measured at baseline and 30, 60, 90, and 120 minutes after glucose ingestion during both trials. Compared with AMB, the plasma glucose response to glucose ingestion was reduced during the ALT trial ( P = .04). There were no differences in the insulin and C-peptide responses between trials or in insulin sensitivity based on the homeostasis model assessment of insulin resistance. Epinephrine and lactate were both elevated during the ALT trial ( P < .05), whereas the plasma leptin response was reduced compared with AMB ( P < .05). The data suggest that the plasma glucose response is suppressed at ALT, but this is not due to insulin per se because insulin and C-peptide levels were similar for both trials. Elevated plasma epinephrine and lactate during ALT are indicative of increased glycogenolysis, which may have masked the magnitude of the reduced glucose response. We conclude that, during acute altitude exposure, there is a rapid metabolic response that is accompanied by a shift in the hormonal milieu that appears to favor increased glucose utilization.

Sound Stress–Induced Long-Term Enhancement of Mechanical Hyperalgesia in Rats Is Maintained by Sympathoadrenal Catecholamines

Although stress plays an important role in chronic widespread pain syndromes, such as fibromyalgia, the underlying mechanism has remained elusive. We have recently demonstrated, in a model of chronic widespread pain, that prolonged enhancement of immune mediator hyperalgesia, induced by unpredictable sound stress, requires a contribution of both the sympathoadrenal (epinephrine) and the hypothalamic-pituitary adrenal (corticosterone) neuroendocrine stress axes. Because this stress protocol produced sustained elevation of plasma epinephrine, in the current study we tested the hypothesis that the sympathoadrenal axis also plays a role in maintenance of symptoms in this model of chronic widespread pain. After establishment, adrenal medullectomy abolished the enhancement of epinephrine-induced cutaneous and muscle hyperalgesia. Administration of stress levels of epinephrine to adrenal medullectomized rats reconstituted the pain phenotype. These observations suggest that the sympathoadrenal stress axis plays a major role in the induction as well as maintenance of stress-induced enhancement of mechanical hyperalgesia, mediated by prolonged elevation of circulating epinephrine. We present data showing mechanical hyperalgesia persisting for up to 28 days after exposure to sound stress, with evidence that the sympathoadrenal axis mediator epinephrine plays a major role. These findings could have clinical implications with regard to novel potential treatments for chronic widespread pain syndromes, such as fibromyalgia.