Norepinephrine Excretion Research Articles

Effect of the cannabinoid receptor-1 antagonist rimonabant on lipolysis in rats

The cannabinoid receptor 1 antagonist, rimonabant, reduces food intake and body weight, but contradictory findings have been reported as to whether the weight-reducing effect is fully accounted for by the reduced food intake or if rimonabant also mediates a lipolytic effect. In the present study, the effect on weight loss was studied in diet-induced obese rats after 3 days and 3 weeks of exposure to rimonabant, respectively. Induction of lipolysis was examined following acute administration and following 3 weeks of repeated dosing. Rimonabant-treated rats lost significantly more weight than their food-restricted controls. This effect was most pronounced in the beginning of the treatment period. No increase in lipolytic activity was found after 3 weeks of repeated dosing as measured by microdialysis in adipose tissue whereas acute administration of 10 mg/kg produced a significant increase in microdialysate levels of glycerol illustrating an acute stimulation of lipolysis. No equivalent increase in glycerol was, however, observed in vitro following incubation of isolated rat adipocytes with rimonabant. This finding excludes a direct lipolytic action of rimonabant on tissue level. Instead, administration of 10 mg/kg produced a significant increase in noradrenaline excretion in diet-induced obese rats, suggesting an increase in sympathoadrenal activity. In conclusion, the present study suggests an acute lipolytic effect of rimonabant mediated through activation of the sympathoadrenal system.

Correlations between urinary excretion of catecholamines and electrocardiographic parameters of vagal hyperreactivity in infants with fainting spells. Implication of sympathetic hypotonia?

Vagal hyperreactivity (VHR) is a frequent etiology of infant fainting spells; but it is sometimes difficult to diagnose. A biochemical test would therefore be useful, especially as the oculocardiac reflex (OCR) test innocuity is not absolute. To evaluate urinary excretions of norepinephrine, epinephrine and dopamine as markers for vagal hyperreactivity. During check-up of 55 infants from 0.5 to 11 months of age, for discomfort episodes, including OCR and Holter recording, 24h urinary assays of total norepinephrine, epinephrine and dopamine were carried out to evaluate sympathetic activity. Epinephrine and norepinephrine urinary excretions were negatively correlated with VHR intensity, as measured by the OCR ECG parameters: RRmax, % cardiac deceleration and minimal frequency; dopamine excretion was not. When RRmax(OCR) was greater or equal to 800 ms, epinephrine urinary excretion tended to be less or equal to 9 nmol/mmol creatinine and norepinephrine excretion less or equal to 190 nmol/mmol creatinine. A delay in maturation of the sympathetic system and/or adrenomedullary glands with low secretion of norepinephrine and epinephrine inducing a desequilibrium of the sympathetic/parasympathetic balance may contribute to the fainting spells observed with VHR. Epinephrine and norepinephrine urinary excretions may provide informative complementary noninvasive markers for VHR.

Nitric oxide(NO)合成慢性阻害時の血圧上昇機序に関する検討

Although the inhibition of nitric oxide (NO) synthesis is known to induce systemic hypertension, the underlying mechanisms mediating this type of hypertension are incompletely understood. In the present study we investigated the influence of sodium intake on the pressor effect of long-term administration of the NO synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 16 mg/dl in drinking fluid for 8 weeks), in conscious Sprague-Dawley rats. Urinary excretion rates of catecholamine during NO synthesis inhibition were also examined. Long-term administration of L-NAME produced a sustained elevation in tail-cuff pressure without altering urine flow, or sodium excretion rate. L-NAME-induced hypertension was accompanied by a decreased urinary excretion of the stable NO metabolites, NO2- and NO3-, and was aggravated when rats drank 0.9% saline in place of tap water. Thus, inhibition of NO synthesis resulted in a rightward shift of the pressure natriuresis relationship and a significant decrease in the slope of this relationship. Urinary excretion of epinephrine and norepinephrine, but not that of dopamine, in L-NAME-treated rats significantly increased within the first week of the study when compared with those observed in control rats. A natriuretic index of the sympathetic nervous system, the ratio of dopamine to norepinephrine excretion, was significantly less in L-NAME-treated rats than in control rats. After 8-week treatment with L-NAME, renal morphologic evaluation revealed significant narrowing and obliteration of the arterioles. L-arginine (2 g/dl in drinking fluid) completely reversed the elevation of blood pressure as well as the decrease in urinary NO2- and NO3- excretion and the increased urinary excretion of catecholamines associated with L-NAME treatment after 3 weeks of concomitant administration. These results suggest that the inhibition of chronic NO synthesis produces sodium-sensitive hypertension and that changes in sympathetic nerve activity may, at least in part, contribute to the sodium sensitivity in this type of hypertension.

Salt sensitivity is associated with insulin resistance, sympathetic overactivity, and decreased suppression of circulating renin activity in lean patients with essential hypertension

The mechanisms by which a derangement of glucose metabolism causes high blood pressure are not fully understood. This study aimed to clarify the relation between salt sensitivity of blood pressure and insulin resistance, which are important subcharacteristics of hypertension and impaired glucose metabolism, respectively. Effects on the renin-angiotensin and sympathetic nervous systems were also studied. The state of glucose metabolism was assessed by a hyperinsulinemic euglycemic glucose clamp technique and a 75-g oral-glucose-tolerance test in 24 essential hypertensive patients who were lean and without diabetes or chronic kidney disease. The subjects were classified as salt-sensitive or salt-resistant on the basis of the difference (Delta mean blood pressure > or =5%) between 24-h ambulatory blood pressure monitoring results on the seventh day of low-salt (34 mmol/d) and high-salt (252 mmol/d) diets. Urine and blood samples were collected for analyses. There was a robust inverse relation between the glucose infusion rate (GIR) and the salt sensitivity index. The GIR correlated directly with the change in urinary sodium excretion and was inversely related to the change in hematocrit when the salt diet was changed from low to high, which is indicative of salt and fluid retention in salt-sensitive subjects. The GIR also showed an inverse correlation compared with the changes in urinary norepinephrine excretion, plasma renin activity, and plasma aldosterone concentration. Salt sensitivity of blood pressure is strongly associated with insulin resistance in lean, essential hypertensive patients. Hyperinsulinemia, sympathetic overactivation, and reduced suppression of the renin-angiotensin system may play a role in this relation.

Pediatric endocrine screening for von Hippel-Lindau disease: Benefits and the challenge of compliance

Fifteen children and adolescents (4 male) with a median age of 5.4 yr (range 1.2 -13.6 yr) were entered into a screening protocol to identify lesions of von Hippel-Lindau (VHL) disease. Fourteen had an affected first-degree relative and one had a previous VHL lesion. Screening during the period of 2000 to 2008 followed published guidelines and consisted of measurement of urinary catecholamines, adrenal and renal imaging and ophthalmological and central nervous system examinations and imaging. Screening identified 8 VHL lesions in 6 asymptomatic patients with confirmed genetic mutations. Five patients had elevated urinary noradrenaline excretion and in each case the presence of a pheochromocytoma was identified on adrenal magnetic resonance imagin scan. In one patient a left-sided tumor was identified 1 yr after a right-sided tumor had been removed. In a sixth patient a retinal capillary hemangioma and a cerebellar hemangioblastoma were identified. Patient compliance with the screening protocol was variable reflecting its time-intensive nature. A formal screening programme for this at-risk population of pediatric patients, despite being intensive, can identify VHL lesions during a pre-morbid phase and may thus have a beneficial impact on prognosis in this serious disorder.

C-Type Natriuretic Peptide as a New Regulator of Food Intake and Energy Expenditure

The physiological implication of C-type natriuretic peptide (CNP) including energy metabolism has not been elucidated, because of markedly short stature in CNP-null mice. In the present study we analyzed food intake and energy expenditure of CNP-null mice with chondrocyte-targeted CNP expression (CNP-Tg/Nppc(-/-) mice), in which marked skeletal dysplasia was rescued, to investigate the significance of CNP under minimal influences of skeletal phenotypes. In CNP-Tg/Nppc(-/-) mice, body weight and body fat ratio were reduced by 24% and 32%, respectively, at 20 wk of age, and decreases of blood glucose levels during insulin tolerance tests were 2-fold exaggerated at 17 wk of age, as compared with CNP-Tg/Nppc(+/+) mice. Urinary noradrenalin excretion of CNP-Tg/Nppc(-/-) mice was greater than that of CNP-Tg/Nppc(+/+) mice by 28%. In CNP-Tg/Nppc(-/-) mice, rectal temperature at 1600 h was higher by 1.1 C, and uncoupling protein-1 mRNA expression in the brown adipose tissue was 2-fold increased, which was canceled by propranolol administration, as compared with CNP-Tg/Nppc(+/+) mice. Oxygen consumption was significantly increased in CNP-Tg/Nppc(-/-) mice compared with that in CNP-Tg/Nppc(+/+) mice. Food intake of CNP-Tg/Nppc(-/-) mice upon ad libitum feeding and refeeding after 48 h starvation were reduced by 21% and 61%, respectively, as compared with CNP-Tg/Nppc(+/+) mice. This study unveiled a new aspect of CNP as a molecule regulating food intake and energy expenditure. Further analyses on precise mechanisms of CNP actions would lead to the better understanding of the significance of the CNP/guanylyl cyclase-B system in food intake and energy expenditure.

Elevated Urinary Free and Deconjugated Catecholamines after Consumption of a Catecholamine-Rich Diet

The biochemical diagnosis of pheochromocytoma depends on the demonstration of elevated levels of catecholamines (i.e. epinephrine, norepinephrine, and dopamine) and their metabolites. The aim of the study was to determine the preanalytical influence of a catecholamine-rich diet on urinary free and deconjugated catecholamines in healthy volunteers with a highly specific and sensitive analytical technique. We conducted a crossover study involving 27 healthy adults in a specialist medical center. Subjects consumed catecholamine-rich nuts and fruits at fixed times on one day (about 35 micromol dopamine and 1 micromol norepinephrine) and catecholamine-poor products on another day. Urine samples were collected at timed intervals before, during, and after experimental and control interventions. We performed automated online sample preparation coupled to isotope-dilution mass spectrometry measurements of urinary concentrations of free and deconjugated catecholamines. The catecholamine-rich diet had substantial effects on urinary excretions of deconjugated dopamine (up to 20-fold increases) and norepinephrine (up to 10-fold). Dietary catecholamines had less but significant effects on urinary excretion of free dopamine and norepinephrine (up to 1.5-fold increases). Outputs of urinary free and deconjugated epinephrine remained unaffected. Urinary excretion of deconjugated norepinephrine and dopamine is strongly affected by consumption of catecholamine-rich food products, thereby increasing the likelihood of a false-positive test result during hormonal evaluation for pheochromocytoma. Measurement of deconjugated catecholamines should therefore preferably be avoided, in favor of measurement of urinary free catecholamines. In case of demonstrating increased urinary excretion of deconjugated norepinephrine and dopamine, repeated measurements are warranted with dietary restrictions prior to sample collection.

Central angiotensin type 2 receptor stimulation reduces blood pressure and norepinephrine excretion in conscious normal rats

In previous studies, we found a significant down regulation of Angiotensin II Type 2 receptors (AT2R) in the rostral ventrolateral medulla (RVLM) and a critical role of the AT2R in sympatho‐excitation in rats with chronic heart failure. In this experiment, we determined the effects of intracerebroventricular (icv) infusion of Compound 21 (C21), the first selective non‐peptide AT2R agonist, on the mean blood pressure (MAP), heart rate (HR), and norepinephrine (NE) excretion in conscious normal rats. C21 was infused by a Micro‐osmotic pump at a rate of 0.5μg/μl/2hrs for 7 days. On day 7 the rats were euthanized and the RVLM was punched out to measure AT1R and nNOS protein expression by western blot. We found that: (1) C21 treatment significantly decreased MAP (81.5 ± 6.2 vs 93.2 ± 5.9 mmHg, P < 0.05), but did not change HR; (2) both NE concentration in urine (104 ± 12.6 vs 366 ± 9.7 ng/ml, P < 0.05) and NE excretion (1.9 ± 0.3 vs 8.7 ± 1.2 μg/day, P < 0.05) were decreased in the C21 treated rats; (3) C21 down‐regulated AT1R protein expression (0.5 ± 0.1 vs 1.2 ± 0.3 AT1R/GAPDH, P < 0.05) and up‐regulated nNOS (0.7 ± 0.1 vs 0.3 ± 0.1 nNOS/GAPDH, P < 0.05) protein expression in the RVLM. These results suggest that activation of central AT2R evoked hypotension through a sympatho‐inhibitory mechanism, in part, by decreasing AT1R expression and activating nNOS signaling.

GPER‐1 activation reduces oxidative stress and alters renin‐angiotensin system components in the kidneys of salt‐sensitive mRen2.Lewis females

Female mRen2.Lewis (mRen2) rats fed a high salt diet (HS) exhibit increased blood pressure and end organ injury, as well as enhanced renal expression of the novel estrogen receptor GPER‐1 (GPR30). We reported that in vivo activation of GPER‐1 by the agonist G‐1 did not alter blood pressure in HS females; however, renal hypertrophy and proteinuria were reduced and creatinine clearance was increased. The current study examined the mechanisms that may contribute to the protective actions of G‐1 in the HS fed female mRen2. Urinary excretion of norepinephrine, epinephrine, sodium, and potassium were not altered by G‐1. However, urinary excretion of 8‐isoprostane was decreased by G‐1 (4.8 ± 0.3 vs. 2.8 ± 0.4 ng/mg creatinine, N=9 per group, P<0.01). In addition, 4‐hydroxy‐2‐nonenal (4‐HNE) staining, another marker of oxidative stress, was decreased with G‐1 (P<0.05, N=4 per group). While renal ACE activity was unchanged, G‐1 increased ACE2 activity (18 ± 1 vs. 23 ± 1 fmol/mg/min, N=4 per group, P<0.05) and decreased neprilysin activity (1526±74 vs. 1223±56 fmol/mg/min, N=4 per group, P<0.05). Finally, G‐1 treatment reduced mRNA levels of cortical angiotensinogen by 70% (N=7–8, P<0.01). We conclude that the renoprotective actions of GPER‐1 activation may involve attenuation of oxidative stress and differential regulation of the renin‐angiotensin system within the kidney. Funding: HL‐56973, HL‐51952, AHA 0825515.

Toll‐like receptor expression is increased via activation of AT1 receptor in the brain associated with sympathoexcitation in mice with heart failure

BackgroundPrevious studies suggest that heart failure (HF) is associated with sympathoexcitation due to oxidative stress in the brain induced by AT1 receptor (AT1R) and NAD (P) H oxidase. They are also known as an upstream of inflammatory signaling pathway mediated by Toll‐like receptor 4 (TLR4) in the brain. The aim of the present study was to determine whether AT1R‐induced sympatho‐excitation is mediated by TLR4 in the brain of heart failure model or not.Methods and ResultsAs a HF model, ligation of the left coronary artery was performed to make large myocardial infarction (MI) and subsequent HF in ICR mice. On day 10 after left coronary artery ligation, mice received either intracerebroventricular (icv) losartan (10μg/h, CHF‐Los) or vehicle (CHF‐Veh) by osmotic minipumps for 14 days. Urinary norepinephrine excretion as a parameter of sympathetic nervous system activity was significantly higher in HF than in sham mice and was significantly lower in CHF‐Los than in CHF‐Veh(0.34±0.04 vs 0.62±0.06, n=3, P<0.05). The expression of TLR4 in the whole brain determined by Western blot analysis was significantly higher in HF than in sham mice, and was significantly lower in CHF‐Los than in CHF‐Veh.ConclusionToll‐like receptor expression is increased via activation of AT1 receptor in the brain associated with sympathoexcitation in mice with heart failure.

Cardiac dysfunction in HgCl2-induced nephrotic syndrome

The experimental model of HgCl(2) injection is characterized by a systemic autoimmune disease which leads to the development of nephrotic syndrome (NS). NS seems to be accompanied by cardiovascular alterations, since patients with NS present an increased incidence in cardiac disease. The aim of our work was to study the effects of HgCl(2)-induced NS on myocardial function and morphometry. Normotensive Brown-Norway rats were injected with HgCl(2) (1 mg/kg, HgCl(2) group; n = 6, subcutaneous) or the vehicle (control group; n = 6, subcutaneous) on days 0, 2, 4, 7, 9 and 11. The animals were placed in metabolic cages for evaluation of urinary excretion of noradrenaline, sodium, total proteins, albumin and creatinine. Fourteen and 21 days after the first HgCl(2) injection, left ventricle (LV) hemodynamics was evaluated through pressure micromanometers in basal and isovolumetric heartbeats. The heart and gastrocnemius muscle weights and tibial length were also examined. In an additional group of animals cardiac dimensions and ejection fraction were assessed by echocardiography and LV apoptosis and fibrosis were studied. HgCl(2)-injected rats presented proteinuria, albuminuria, hyperlipidemia, anemia, sodium retention and ascites at day 14. These alterations were accompanied by LV hemodynamic changes only in isovolumetric heartbeats. Similarly, on day 21, HgCl(2)-injected rats presented proteinuria, albuminuria, hyperlipidemia, anemia, but no sodium retention or ascites. These animals presented LV systolic and diastolic dysfunction in both basal and isovolumetric heartbeats, as well as cardiac atrophy, LV fibrosis and an increase in myocyte apoptosis. In conclusion, HgCl(2)-induced NS is accompanied by LV dysfunction and can be a promising model for studying the link between NS and cardiac disease.

Effect of enalapril (Reniteс) on the renin-angiotensin-aldosterone and sympathoadrenal system in hypertensive patients

Objective. To study the infl uence of enalapril 20 mg/day on the sympathoadrenal (SAS) and renin-angiotensinaldosterone systems (RAAS). Design and methods. 149 subjects (102 patients with essential arterial hypertension (EAH) and 47 patients with primary hyperaldosteronism, PHA) were included. Mean systolic blood pressure (BP) (M  m) was 194,6  7,4 mmHg, diastolic BP - 116, 2  5,4 mmHg. Plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were estimated by radio-immune method in active patients. PRA was rated as normal if ranged 1,0-3,0 ng/ml/h, PAC - 0,18-0,83 nmol/l (5-23 ng/dl or 50-230 pg/ml). Normal PAC/PRA ratio was 5-23. The daily urine excretion of adrenaline (normal - 18-33 mmol/l) and noradrenaline (normal - 150-256 mmol/l) were determined by fl uorometric method. Conclusions. 1) Effects of angiotensin-converting enzyme (ACE) inhibitors on the synthesis of aldosterone and catecholamines in EAH patients are associated with the changes of circulating angiotensin II concentration, and in PHA patients - with the decrease of tissue angiotensin II concentration in cortical layers of the adrenal gland and central nervous system. 2) Reactive increase PRA in EAH patients treated with enalapril is rather related to the blockade of renal tissue angiotensin-converting enzyme than to the circulating angiotensin II. 3) PHA patients are characterized by the phenomenon of up regulation of aldosterone receptors and of tissue renin-angiotensin system that is defi ned by optimum reduction of PAC, the lack of normalization of PRA and blood pressure in response to the application of enalapril 20 mg/day.

EVOLUTION STAGES OF LOW RENIN HYPERTENSION

Aim. To find out similarities and differences between various evolutionary stages of low rennin hypertension (LRHT), and to develop its diagnostic criteria. Material and methods. Patients (n=190) with LRHT and the high cardiovascular risk were included into the study. All patients received ACE inhibitor, enalapril 10 mg twice a day, during 4 weeks. Before and after enalapril treatment plasma renin activity (PRA) and plasma aldosterone level (PAL) were determined by radioimmunoassay method in active patients. 24-hour urinary excretion of epinephrine (UEE) and norepinephrine (UENE) was also determined by laser flowmetry. Results. Three forms of LRHT were defined among all patients: 1) patients (n=144) with essential LRHT had stimulated renin, eu- or hyperaldosteronism without adrenal hyperplasia; 2) patients (n=14) with transient LRHT had nonstimulated renin, eualdosteronism, presence or absence of adrenal hyperplasia; 3) patients (n=32) with the primary idiopathic hyperaldosteronism had nonstimulated renin, hyperaldosteronism and adrenal hyperplasia. Conclusion. Three stages of LRHT evolution are found out. They have similar pathogenesis and different expression of morphofunctional changes in the juxtaglomerular complex and in the adrenal cortex as well as different respond to enalapril test (20 mg/daily).

10.1007/s11174-008-2005-1

A complex study of the functional state of the sympathoadrenal system and adrenal cortex in 10–15-year-old children of both sexes was carried out using the indices of daily excretion of adrenaline, noradrenaline, 17-ketosteroids, and 17-hydroxycorticosteroids. A synchronism in the functional activity of the mediator component of the sympathoadrenal system as well as of the androgenic and glucocorticoid functions of the adrenal cortex was observed with age and during pubertal development of children. At the same time, heterochronic maturation was observed in the sex groups: in girls at the age of 10 and 12 years and in boys at the age of 14–15 years. The changes of different direction and intensity in the excretion of the studied hormones and hormonal metabolites were observed in the sex and age groups. A sharp increase in the daily excretion of glucocorticoid metabolites accompanied by a considerable decrease in the age index of noradrenaline secretion was observed in 14-and 15-year-old boys from beginning to end of school year; in addition, an increase in the daily excretion of sex hormones was observed at the age of 15 years. In girls, these indices varied within the age range, which points to a more sophisticated neuroendocrine control of physiological functions in girls during puberty.

Lose Sleep, Gain Weight: Another Piece of the Obesity Puzzle

It’s 11 p.m., and you sit in front of a glowing computer screen, writing e-mails and eating a sandwich. You’ll work until after midnight, when you’ll fall asleep in front of the light and blare of a TV before rising again at 6 a.m. What’s wrong with this picture? Because of modern conveniences and pressures, many of us keep our bodies exposed to light, food, and activity at times when our organs and cells expect dark, quiet, and sleep. In epidemiologic studies, shorter sleep has been correlated with incidence of obesity, hypertension, and other metabolic disorders. Experimental sleep studies find a similar connection. Increasingly, studies of the possible mechanisms behind these associations suggest that lack of sleep is part of a bigger problem with the 24/7 lifestyle many people today lead. Increasingly, scientists are finding that many physiologic activities related to metabolism don’t happen continuously but oscillate on a regular schedule. Studies in mice as well as humans suggest that when our internal clock is disrupted, it may throw off many bodily functions, especially metabolism. Many environmental factors have been shown to contribute to circadian disruption. Noise in busy hospitals, street noise, and airport noise have all been reported to disrupt sleep or reduce its quality. Research in animals and humans shows that exposure to light during early biological night resets the main circadian clock by producing a phase delay (the biological urge to go to sleep and wake up later than usual), and exposure during late biological night results in a phase advance (going to sleep and waking up earlier than usual). We live in a world where air passengers can see the glow of major cities 200 miles away. So the fact that human circadian systems appear sensitive even to low-level artificial light exposure raises significant concerns for the health effects of our electrified modern society. For instance, exposure to a few hours of ordinary room light of about 100 lux brightness (which most people get every night before they go to bed) can significantly reset the human circadian pacemaker, Jamie Zeitzer and colleagues reported in the September 2005 American Journal of Physiology—Regulatory, Integrative and Comparative Physiology. However, it’s not certain what the effects of very brief light exposures may be. The duration of light exposure needed to cause shifts hasn’t been well studied, according to a review by Charles Czeisler and Joshua Gooley in volume 27 (2007) of Cold Spring Harbor Symposia on Quantitative Biology. [For more information about the health effects of too much artificial light, see “Missing the Dark: Health Effects of Light Pollution,” EHP 117:A20–A27 (2009).] Epidemiologic studies suggest that lack of sleep or sleeping on an altered schedule is an independent risk factor for gaining weight. But it’s still not certain whether short sleep actually causes obesity and its associated health effects. For instance, some scientists have suggested that the association between obesity and lack of sleep may be due to the fact that people who are obese may be more likely to have a sleep disorder such as sleep apnea, or that the reported lack of sleep is a symptom of psychosocial stress. But a body of studies have shown a connection between short sleep and obesity, other health effects associated with obesity, and increased appetite or food intake.

Oral l‐histidine exerts antihypertensive effects via central histamine H3 receptors and decreases nitric oxide content in the rostral ventrolateral medulla in spontaneously hypertensive rats

1. L-histidine is generally found in meat, poultry and fish. To investigate its effects on blood pressure, L-histidine was administered to 9-week-old spontaneously hypertensive rats (SHR). 2. Oral administration of L-histidine (100 mg / kg) increased histamine content in cerebrospinal fluid and reduced mean arterial pressure (MAP) in SHR. Intracerebroventricular injection of L-histidine (0.01 microg / 5 microL) also caused a decrease in MAP, which was reversed by cotreatment with the histamine H3 receptor antagonist thioperamide (20.4 microg / 5 microL, i.c.v.). There was a significant, time-dependent increase (over 6 h) in the NOx (NO2- + NO3-) content of the dialysate from the rostral ventrolateral medulla (RVLM), a major vasomotor centre, after oral administration of L-histidine. 3. In another experiment, SHR were treated with l-histidine (100 mg / kg) twice a day for 4 weeks. Chronic treatment with L-histidine inhibited the age-dependent increases in systolic blood pressure and urinary noradrenaline excretion seen in vehicle-treated SHR. Conversely, intracerebroventricular injection of thioperamide (20.4 microg / 5 microL, i.c.v.) reversed the decrease in MAP in response to L-histidine in SHR. 4. Reverse transcription-polymerase chain reaction analysis revealed that the aortic expression of angiotensin-converting enzyme mRNA was suppressed by chronic treatment with L-histidine. 5. These results suggest that L-histidine decreases blood pressure by attenuating sympathetic output via the central histamine H3 receptor in SHR. In addition, the antihypertensive effects of L-histidine appear to be associated with an increase in nitric oxide in the RVLM.

Atorvastatin Improves the Impaired Baroreflex Sensitivity via Anti-Oxidant Effect in the Rostral Ventrolateral Medulla of SHRSP

We have demonstrated that oxidative stress in the rostral ventrolateral medulla (RVLM), a vasomotor center in brainstem, increases sympathetic nerve activity (SNA) and that oral administration of atorvastatin inhibited SNA via anti-oxidant effect in the RVLM of stroke-prone spontaneously hypertensive rats (SHRSPs). The impairment of baroreflex sensitivity (BRS) is known as the predictive factor of mortality in the hypertension and BRS is impaired in SHRSP. The aim of the present study was to determine whether oral administration of atorvastatin improved the impaired BRS via anti-oxidant effect in the RVLM in SHRSP. Atorvastatin (20 mg/kg/day) or vehicle was orally administered for 28 days in SHRSPs. Systolic blood pressure (SBP), heart rate, and 24-h urinary norepinephrine excretion as an indicator of SNA were comparable between atorvastatin- and control-SHRSP. Thiobarbituric acid-reactive substance (TBARS) levels as a marker of oxidative stress was significantly lower in atorvastatin-SHRSP than in control-SHRSP. Baroreflex sensitivity measured by the spontaneous sequence method was significantly higher in atorvastatin-SHRSP than in control-SHRSP. These results suggest that atorvastatin improves the impaired BRS in SHRSP via its anti-oxidant effect in the RVLM of SHRSP.

Abstract 4891: Angiotensin II-activated Caspase 3-dependent Apoptosis in the RVLM Contributes to Sympathoexcitaion Through the Activation of Ras/MAPK/ERK Pathway

Background: The rostal ventrolateral medulla (RVLM) regulates sympathetic nerve activity (SNA). Angiotensin II-derived superoxide anion in the RVLM induces the pressor response via the activation of p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase (ERK). Small G protein Ras mediates caspase 3-dependent apoptosis through the activation of p38 MAPK and ERK. We hypothesized that angiotensin II/angiotensin II type 1 receptor (AT 1 R)-activated caspase 3-dependent apoptosis in the RVLM contributes to sympathoexcitation through the activation of Ras/p38 MAPK/ERK pathway in stroke-prone spontaneously hypertensive rats (SHRSP). Methods and Results: Telemetrically measured mean blood pressure (MBP) and heart rate (HR) under a conscious state, and SNA assessed by urinary norepinephrine excretion, were significantly higher in SHRSP than in Wistar-Kyoto (WKY) rats. Activities of Ras, p38 MAPK, ERK, and caspase 3 in the RVLM were significantly higher in SHRSP than in WKY (Ras; 1.7 ± 0.2 U vs 1.3 ± 0.2 U, p38 MAPK; 1.8 ± 0.1 U vs 1.2 ± 0.3 U, ERK; 2.1 ± 0.3 U vs 1.4 ± 0.3 U, caspase 3; 1.7 ± 0.1 U vs 1.1 ± 0.2 U, n = 5 for each, P < 0.01). Mitochondrial apoptotic proteins Bax and Bad in the RVLM were also significantly increased in SHRSP (Bax; + 38 ± 2%, Bad; + 43 ± 3%, n = 5 for each, P < 0.01). In SHRSP, intracerebroventricular (ICV) infusion of Ras inhibitor, Z-DEVD-FMK, significantly reduced MBP, HR, and SNA (MBP; −38 ± 4mmHg, HR; −44 ± 18bpm, SNA; −0.8 ± 0.2 μ g/day, n = 5 for each, P < 0.01) and inhibited activities of Ras/p38 MAPK/ERK, Bax, Bad, and caspase 3 in the RVLM (Ras; −36 ± 3%, p38 MAPK; −27 ± 3%, ERK; −24 ± 2%, Bax; −21 ± 3%, Bad; −28 ± 5%, caspase 3; −39 ± 6%, n = 5 for each, P < 0.01). ICV of caspase 3 inhibitor also decreased MBP, HR, and SNA in SHRSP. ICV of AT 1 R blocker, candesartan, in SHRSP decreased MBP, HR, and SNA (MBP; −34 ± 5mmHg, HR; −52 ± 14bpm, SNA; −0.9 ± 0.2 μ g/day, n = 5 for each, P < 0.01) and reduced activities of Ras/p38 MAPK/ERK, Bax, Bad, and caspase 3 in the RVLM. Conclusion: Angiotensin II/AT 1 R-activated caspase 3-dependent apoptosis in the RVLM increases SNA through the activation of Ras/p38 MAPK/ERK pathway in SHRSP. This mechanism of sympathoexcitation may play a crucial role in the pathogenesis of hypertension.

Abstract 4890: Telmisartan Decreases Sympathetic Nerve Activity via Reduction in Oxidative Stress Through the Blockade of AT1 Receptor in the Vasomotor Center in Dietary-induced Obesity Rat

Background: Activation of sympathetic nerve activity (SNA) is critically involved in the occurrence of hypertension in metabolic syndrome (MetS). However, the mechanism(s) involved remains unknown. Reactive oxygen species (ROS) generation in the brain may elicit sympathoexcitation in MetS. The rostral ventrolateral medulla (RVLM) is the vasomotor center that determines basal central sympathetic outflow. ROS in the RVLM is produced mainly by NAD (P) H oxidase via angiotensin II type 1 receptor stimulation (AT 1 R). The present study aimed to determine whether telmisartan decreases SNA via a reduction in ROS through the blockade of AT 1 R in the RVLM of MetS model rats. Methods and Results: Male Sprague-Dawley rats were fed a high-fat diet and segregated into obesity-prone (OP, n = 5) and obesity-resistant (OR, n = 5) groups based on their body weight (BW) after 13 weeks. The OP group was then divided into 2 groups, OP with telmisartan (5mg/kg/day for 12 weeks, TLM-OP, n = 3) and OP without telmisartan (VEH-OP, n = 3). At 13 weeks, body weight (BW), systolic blood pressure (SBP), heart rate (HR), and urinary norepinephrine excretion (uNE) as a parameter of SNA were significantly higher in OP than in OR (BW; 760 ± 46g vs 548 ± 13g, SBP; 151 ± 5mmHg vs 123 ± 7mmHg, HR; 375 ± 11bpm vs 333 ± 5bpm, uNE; 0.35 ± 0.05 μ g/day/kg vs 0.25 ± 0.04 μ g/day/kg, n = 5 for each, P < 0.05 for each). ROS in the RVLM, measured by the thiobarbituric acid-reactive substances (TBARS) method, was significantly higher in OP than in OR (7.2 ± 0.8 μ mol/g vs 2.2 ± 1.9 μ mol/g wet wt, n = 4 each, P < 0.05). Microinjection of AT 1 R blocker (ARB), candesartan, into the RVLM induced a significantly greater mean SBP reduction in OP than in OR. The expression of angiotensinogen, angiotensin-converting enzyme (ACE), and AT 1 R in the RVLM assessed by Affymetrix microarray was significantly higher in OP than in OR. TLM-OP had significantly lower BW, SBP, HR, uNE, and TBARS than VEH-OP. Microinjection of angiotensin II into the RVLM resulted in significantly lower pressor responses in TLM-OP than in VEH-OP. Conclusion: In MetS, increased ROS in the RVLM produced by upregulation of the local renin-angiotensin system increases SNA. Telmisartan inhibits SNA via a reduction of ROS through the blockade of AT 1 R in the RVLM.

Age- and sex-related characteristics and mechanisms of adaptations during the prepubertal and pubertal periods of development

Integrated study of the functional state of the sympathoadrenal system and the adrenal cortex in children of both sexes aged 10–15 years. The study was conducted on the basis of the daily adrenaline, noradrenaline, 17-ketosteroid, and 17-oxycorticosteroid excretion values, which allowed certain synchrony to be established in the manifestation of the activity of the transmitter link of the sympathoadrenal system and the adrenal cortex androgenic and glucocorticoid functions with age, during sexual maturation. The heterogeneous character of maturation was found in the sex groups: in girls at an age of 10 and 12 years and in the boys at an age of 14–15 years. Changes in the excretion of the hormones and hormone metabolites with different directions and rates in the age-sex groups were observed throughout the academic year. In 14- to 15-year-old boys, a sharp increase in the daily excretion of the glucocorticoid metabolites accompanied by a substantial decrease in the age-related noradrenaline excretion values and the sex hormone metabolite values at an age of 15 years was observed. In the girls, these values varied within the age range, which indicates a more perfect character of the neuroendocrine regulation of their physiological functions in the period of sexual maturation.