Higher Plasma Norepinephrine Research Articles

BETA1 (ARG389GLY, SER49GLY)- AND BETA2 (ARG16GLY)-ADRENOCEPTOR POLYMORPHISMS ARE RELATED TO LEFT VENTRICULAR HYPERTROPHY USING ECG IN MIDDLE-AGED, NORMOTENSIVE SUBJECTS: PP.22.358

Objective: Left ventricular hypertrophy (LVH) accompanying elevated sympathetic nervous activity (SNA) is more common in hypertensive and obese people. Elevated SNA is an important mechanism in cardiovascular complications and cardiac morbidity and mortality. β2-adrenoceptor (ADRB2) polymorphisms are closely linked to hypertension and obesity, and β1-adrenoceptor (ADRB1) play roles directly with the heart. We evaluated the relationships between ADRB1 polymorphisms, ADRB2 polymorphisms and LVH. Methods: In 215 nonobese, normotensive Japanese men, ADRB1 polymorphisms (Arg389Gly, Ser49Gly), ADRB2 polymorphisms (Arg16Gly, Gln27Glu), BMI, BP, heart rates (HR), total body fat-mass, waist-to-hip ratio (W/H), plasma norepinephrine (NE), insulin, leptin and ECG were measured. LVH was determined by the Sokolow-Lyon voltage criteria. Results: Twenty-four subjects (11.2%) showed LVH on ECG. Subjects with LVH had higher NE, BP levels and HR compared to those without LVH (all P < 0.05), but BMI, fat-mass, W/H, insulin and leptin were similar. Subjects with LVH had higher frequencies of Gly389 or Gly49 alleles of ADRB1 polymorphisms (χ2 = 49.94, P = 0.002; χ2 = 11.43, P = 0.001, respectively), and Gly16 or Glu27 alleles of ADRB2 polymorphisms (χ2 = 9.59, P = 0.002; χ2 = 3.12, P = 0.059, respectively). Distributions of Gly389 and Gly49 alleles of ADRB1 polymorphisms and Gly16 and Glu27 alleles of ADRB2 were 39.5%, 27.9%, 74.4% and 11.2%, respectively. Subjects with Gly389 or Gly49 had higher frequencies of LVH, higher NE and HR (all P < 0.05), whereas BMI, fat-mass, W/H, BP, insulin and leptin were similar. Subjects with Gly16 had higher frequencies of LVH and greater BMI, fat-mass, systolic BP, NE and insulin compared to those without Gly16 allele (all P < .05). In multiple regression analysis, plasma NE was a significant determinant for systolic BP and LVH in all subjects. Conclusions: Subjects carrying Gly389 and Gly49 alleles of ADRB1 polymorphisms and Gly16 allele of ADRB2 polymorphisms had higher frequency of LVH accompanying high plasma NE. ADRB1 polymorphisms might relate to LVH directly through elevated SNA, but ADRB2 polymorphisms might relate to LVH through obesity and hypertension associated with elevated SNA and insulin resistance.

Norepinephrine-induced nerve growth factor depletion causes cardiac sympathetic denervation in severe heart failure

In severe congestive heart failure (CHF), sympathetic overactivity correlates with the exacerbation of cardiac performance. To test the hypothesis that the cardiac sympathetic nerve density dramatically changes with the acceleration of circulating norepinephrine (NE) concentration, we investigated the temporal association of nerve growth factor (NGF) expression in the heart and cardiac sympathetic nerve density during the development of CHF in the continuous NE-infused rats. The animals were analyzed at 0-, 1-, 3-, 7-, 14-, and 28-day after implantation of osmotic pump at a rate of 0.05 mg/kg/hr. The cardiac performance was temporally facilitated in NE-exposed rats at 3-day in accordance with the sympathetic hyper-innervation induced by the augmentation of NGF mRNA expression in the heart. In NE-treated rats, left ventricular end-diastolic pressure was significantly increased after 7-day and marked left ventricular hypertrophy and systemic fluid retention were observed at 28-day. CHF-induced sympathetic overactivity further increased plasma NE concentration in NE-treated rats and finally reached to 16.1 ± 5.6 ng/ml at 28-day (control level was 0.39 ± 0.1 ng/ml, p < 0.01). In the decompensated CHF rats at 28-day, the NGF mRNA expression was conspicuously reduced concomitant with the obvious nerve fiber loss confirmed by the immunostaining of nerve axonal marker, PGP9.5 and sympathetic neuron marker, tyrosine hydroxylase. This resulted in the attenuated tissue NE contents and the exacerbating cardiac performance. The cardiac sympathetic fiber loss was also confirmed in NE-exposed DBH (dopamine β-hydroxylase)-Cre/Floxed-EGFP (enhanced green fluorescent protein) mice with severe CHF, in which sympathetic nerve could be traced by EGFP. Our results suggest that the cardiac sympathetic nerve density is strictly regulated by the NGF expression in the heart and long-exposure of high plasma NE concentration caused myocardial NGF reduction, following sympathetic fiber loss in severe CHF animals.

Evidence of vasopressinergic-noradrenergic mechanisms in depression with above-normal plasma vasopressin concentration with and without psychotic features

Previous studies in the field of melancholic or endogenous depression have resulted in support for a subcategory of depression with above-normal plasma vasopressin (AVP) concentration (ANA). Since an analogous animal model with increased release of above-normal plasma vasopressin exhibits reduced Sympathetic-Nervous-System activity, the present study investigated the plasma norepinephrine concentration and the correlation between plasma norepinephrine and AVP in this ANA depression. As psychotic-melancholic patients may have increased plasma norepinephrine concentration, and noradrenergic activation may stimulate AVP release, potentially confounding effects of psychotic features were also investigated. The data set of the same depressed patient sample that was used before, but limited to those with complete hormonal data (n = 75), was re-analysed. ANA depression (n = 14) had negatively correlating AVP and norepinephrine concentrations. A very small subcategory of ANA depression with psychotic features (n = 3) had high plasma norepinephrine concentration, suggesting that this could be an independent subcategory. This was supported by the combination of relatively low above-normal plasma AVP concentrations with the highest severity scores for depression in this subcategory, which does not correspond with the positive correlation between AVP concentration and severity in non-psychotic ANA depression. The results further support the validity of ANA depression and the analogy with the High Anxiety Behaviour animal model of depression. Further investigations are needed to replicate these findings and to search for genetic and traumatic factors involved.

Are Electrocardiographic Changes in Patients with Acute Subarachnoid Hemorrhage Associated with Takotsubo Cardiomyopathy?

Background: Subarachnoid hemorrhage (SAH) has been associated with electrocardiographic (ECG) changes, arrhythmias, and release of cardiac enzymes. Recently, Takotsubo cardiomyopathies, presenting typical ECG changes and left ventricular (LV) regional wall-motion abnormalities (RWMAs), have been reported and considered to be a result of high norepinephrine (NE) levels. We hypothesized that ST-T-wave changes in patients with SAH may be manifestations of Takotsubo cardiomyopathy and associated with RWMAs. Methods: We instituted consecutive echocardiographic screening of all patients with acute aneurysmal SAH. A standard 12-lead ECG and blood samples for creatine kinase (CK) MB isoenzyme and troponin-T (Tn-T) were obtained. To evaluate sympathetic nervous activity, we obtained blood samples and urine samples for NE. Results: Of 42 patients with acute aneurysmal SAH, 26 had abnormal ECG including rhythm abnormalities. Ten of 12 patients with ST-T-wave changes had severe neurologic deficits, but 1 patient had RWMAs on echocardiography. Another patient with LV dysfunction showed a normal ST-T wave. In patients with ST-T-wave changes, elevated Tn-T (8.3 vs. 3.3%), CK-MB (8.3 vs. 10.0%), plasma and urine NE (16.7 and 33.3% vs. 16.7 and 50.0%), and mortality (8.3 vs. 13.3%) were not significantly higher. All 5 deaths resulted from noncardiac causes. High plasma and urine NE levels were not related to neurologic severity or mortality. Conclusions: Although ECG abnormalities are frequently seen in SAH patients, the incidence of RWMAs is very low. Electrocardiographic manifestations in patients with SAH and Takotsubo cardiomyopathy are similar, but ECG abnormalities in patients with SAH are mostly not related to LV dysfunction.

S9.4 Parkinson disease with orthostatic hypotension: Distinctions from Parkinson disease without orthostatic hypotension and from pure autonomic failure

About 40% of patients with Parkinson disease (PD) have orthostatic hypotension (OH). This study reviewed clinical and laboratory data from PD+OH patients compared to PD patients without OH or patients with pure autonomic failure (PAF), a rare Lewy body disease in which OH occurs without parkinsonism. Laboratory assessments used physiologic measures (e.g., baroreflex-cardiovagal gain), neurochemical assays (e.g., concentrations of norepinephrine and its deaminated metabolite, dihydroxyphenylglycol (DHPG), in plasma and skeletal muscle microdialysate), tissue noradrenergic innervation examined by 6-[18F]fluorodopamine positron emission tomographic scanning (PET) of the head, thorax, and abdomen, and striatal dopaminergic innervation by brain 6-[18F]fluorodopa PET. PD+OH patients were older than PD patients without OH, both at the time of testing and at the time of onset of the movement disorder; had worse olfactory dysfunction; and were more likely to have constipation, erectile failure, decreased sweating, dementia, and magnetic resonance imaging evidence of cerebral cortical atrophy. PD+OH patients had higher supine systolic blood pressures, lower baroreflex–cardiovagal slopes, and higher prevalances of abnormal systolic pressure responses to the Valsalva maneuver and of atrial ectopy and sinus bradycardia. Among patients off levodopa, plasma norepinephrine concentrations were lower and increased by less during orthostasis in PD+OH than in PD without OH. Plasma and skeletal muscle microdialysate concentrations of DHPG were lower in PD+OH. PD+OH was associated with lower organ:liver ratios of 6-[18F]fluorodopamine-derived radioactivity, for the interventricular septum and free wall, renal cortex, thyroid, and spleen. Compared to PAF patients, PD+OH patients had higher plasma norepinephrine, DHPG, and epinephrine levels, lower putamen:occipital cortex and caudate:occipital cortex ratios of 6-[18F]fluorodopa-derived radioactivity, and similar substantia nigra:occipital cortex ratios. Taken together, the results indicate that PD+OH differs from PD without OH in terms of age, severity of olfactory dysfunction, baroreflex–cardiovagal failure, supine hypertension, evidence of cortical atrophy, and cardiac and extracardiac noradrenergic denervation. PD+OH differs from PAF in terms of striatal but not nigral dopaminergic deficiency. PAF, PD+OH, and PD without OH therefore seem to be characterized by different relative extents of central and peripheral catecholaminergic denervation.

Abstract 5161:β 1 (Arg389Gly, Ser49Gly)- and β2 (Arg16Gly) -adrenoceptor Polymorphisms are Related to Left Ventricular Hypertrophy in Middle-aged, Nonobese, Normotensive Men, but Through Different Mechanisms

Objective: β2-adrenoceptor (ADRB2) polymorphisms are closely linked to hypertension and obesity, and both of them are major cardiac risk. Left ventricular hypertrophy (LVH) is more common in people who have hypertension or obesity. We examined the relationships between ADRB1 and ADRB2 polymorphisms and LVH in nonobese, normotensive subjects. Methods: In 447 middle-aged, normotensive, nonobese men, ADRB1 (Arg389Gly, Ser49Gly) and ADRB2 (Arg16Gly, Gln27Glu) polymorphisms, BMI, BP, heart rates (HR), total body fat-mass, waist-to-hip ratio (W/H), plasma norepinephrine (NE) and ECG were measured after overnight fasting in the supine position. LVH was determined by ECG. Results: Thirty-nine subjects (8.7%) showed LVH on ECG. Subjects with LVH had higher plasma NE and HR compared to those without LVH (both P&lt;.05). Distributions of Gly389 and Gly49 alleles of ADRB1 polymorphisms were 23.5% (Arg/Arg:Arg/Gly:Gly/Gly=270:144:33) and 14.1% (Ser/Ser:Ser/ Gly:Gly/Gly=327:114:6). Thirty-seven subjects with LVH (94.9%) carried Gly389 and Gly49 alleles, especially homozygous for Gly389 or Gly49. Subjects with Gly389 or Gly49 alleles had higher frequencies of LVH (20.9% vs. 0.7%, 30.8% vs. 0.6%). Subjects carrying Gly389 or Gly49 alleles had higher plasma NE and HR (both P&lt;.05), whereas BMI, fat mass, W/H and BP were similar. The Gly16 and Glu27 alleles of ADRB2 polymorphisms were noted in 42.8% (Arg/Arg :Arg/Gly:Gly/Gly=69:245:133) and 36.6% of the subjects (Gln/Gln:Gln/Glu:Glu/ Glu=176:215:56). Twenty-nine subjects with LVH (74.4%) carried Gly16 allele, especially Gly16 homozygous. Subjects with Gly16 allele had higher frequencies of LVH (P&lt;.05), and they had greater BMI, fat mass, W/H, BP, HR and NE compared to those without Gly16 allele (all P&lt;.05). Conclusions: Subjects carrying Gly389 and Gly49 alleles of ADRB1 polymorphisms and Gly16 allele of ADRB2 polymorphism had higher frequency of LVH accompanying high plasma NE. ADRB1 and ADRB2 polymorphisms play important roles in LVH even in nonobese, normotensive subjects. ADRB1 polymorphisms might relate to LVH through heightened sympathetic nerve activity, but ADRB2 polymorphisms might relate to LVH through obesity, hypertension and heightened sympathetic nerve activity.

Cardiovascular dynamics in healthy subjects with differing heart rate responses to tilt

Orthostatic stress such as head-up tilt (HUT) elicits a wide range of heart rate (HR) and arterial pressure (AP) responses among healthy individuals. In this study, we evaluated cardiovascular dynamics in healthy subjects with different HR responses to HUT, but without autonomic dysfunction. We measured AP (brachial artery) and HR (ECG) during 5 min of 60 degrees HUT in 76 healthy normotensive individuals. We then chose individuals on the basis of the extremes of HR responses to HUT (high = DeltaHR > or = 20 beats/min, and low = DeltaHR < or = 10 beats/min; n = 15 per group). Peak HR during HUT was 87 +/- 10 beats/min in the high and 69 +/- 14 beats/min in the low group (P < 0.05). High HR responders had lower systolic pressure at baseline (121 +/- 9 vs. 129 +/- 11 mmHg, P < 0.05) and during HUT (120 +/- 10 vs. 131 +/- 13 mmHg, P < 0.05), and higher plasma norepinephrine (NE) response to HUT (DeltaNE: 156.9 +/- 17.8 vs. 89.0 +/- 17.2 pg/ml; P < 0.05). DeltaNE during HUT was also significantly correlated with DeltaHR when all 76 subjects were included in a regression analysis (r = 0.39; P < 0.001). Pulse pressure was lower during HUT in high HR responders compared with low HR responders (45 +/- 1 vs. 55 +/- 2 mmHg, P < 0.05). High HR responders also had larger fluctuations in systolic and pulse pressure during HUT (coefficient of variation = 10.7 +/- 0.7 vs. 5.7 +/- 0.3%; 7.9 +/- 0.5 vs. 4.1 +/- 0.4%, respectively, P < 0.05). Sex distribution was different between groups (high: 5 women, 10 men; low: 10 women, 5 men). Higher HR with lower AP during HUT is consistent with normal baroreflex mechanisms of integration. Although interindividual variability appears to be a fundamental part of cardiovascular regulation, the mechanisms of these differences and the sex discrepancy requires further investigation.

A Case of Malignant Pheochromocytoma with Holt-Oram Syndrome

A 23-year-old female patient with malignant pheochromocytoma was admitted to the Tokyo Women's Medical University. The patient had been clinically diagnosed with Holt-Oram syndrome at birth. Since she had complex congenital heart disease, chronic heart failure, and severe hypoxia, the risk surrounding surgery to remove the primary tumor was predicted to be very high, and subsequently, chemotherapy was performed. The patient was not able to continue chemotherapy due to adverse effects. However, for one year, both her hypertension and catecholamine-dependent symptoms were well controlled by an alpha-adrenergic and beta-adrenergic receptor blockade, although the patient did experience high plasma norepinephrine levels. To our knowledge, this is the first report of a patient with the combination of malignant pheochromocytoma and Holt-Oram syndrome. A correlation between chronic hypoxia and pheochromocytoma has been reported. This instructive case reminds us to consider the possibility of pheochromocytoma with congenital heart disease when these types of unexpected or unusual symptoms are encountered.

Arginine 16 Glycine β 2-Adrenoceptor Polymorphism and Cardiovascular Structure and Function in Patients with Heart Failure

The beta2/beta1 adrenoceptor ratio increases in congestive heart failure (CHF), making the heart relatively more dependent on inotropic, lusitropic, and chronotropic stimulation by the beta2-adrenergic receptor (ADRB2). In healthy human beings, those who are homozygous for arginine (Arg) at amino acid 16 of the ADRB2 have reduced receptor function when compared with individuals homozygous for glycine (Gly) at this position. The cardiovascular effects of the Arg16Gly polymorphism of the ADRB2 in CHF are not well understood. The aim of this study was to examine the influence of common polymorphisms of the ADRB2 on cardiovascular structure and function in patients with CHF. Echocardiography, neurohormonal assays, and exercise tests were performed in 68 healthy individuals and 95 patients with CHF. All of the patients with CHF were stable, New York Heart Association class II to III, of ischemic or nonischemic cause, with an ejection fraction of 40% or less. Of the patients with CHF, 16 were Arg/Arg, 36 were Arg/Gly, and 43 were Gly/Gly at amino acid 16. In those without CHF, the Arg16Gly polymorphism of the ADRB2 had no effect on cardiovascular function. In contrast, in CHF, Arg/Arg homozygotes had higher plasma norepinephrine and atrial natriuretic peptide levels, greater left atrial diastolic dimension, higher peak velocity of early/late diastolic filling ratio, and shorter deceleration time compared with Gly16 homozygotes. Furthermore, Arg16 homozygotes had reduced exercise tolerance compared with Gly16 homozygotes (evidenced by shorter exercise duration and lower peak oxygen consumption per unit time), and a lesser chronotropic response to exercise. In patients with CHF, but not in demographically matched healthy persons, the Arg16Gly polymorphism of the ADRB2 exerts important effects on cardiovascular structure and function, neurohormonal activation, and exercise tolerance.

High Plasma Norepinephrine Levels Associated with .BETA.2-Adrenoceptor Polymorphisms Predict Future Renal Damage in Nonobese Normotensive Individuals

Renal injury is common in obesity and hypertension. In the present study, we examined relationships between renal function alterations, plasma norepinephrine (NE), and beta2-adrenoceptor polymorphisms in a longitudinal design over 5 years. In 219 nonobese, normotensive men with entry-normal renal function, we measured serum blood urea nitrogen (BUN), creatinine, creatinine clearance, plasma NE, homeostasis model assessment of insulin resistance (HOMA-IR), body mass index (BMI), total body fat mass, and blood pressure (BP) annually for 5 years. beta2 (Arg16Gly, Gln27Glu)-adrenoceptor polymorphisms were determined. The subjects were stable in body weight and BP (<10%) for 5 years. High plasma NE was defined as > or =mean+1 SD at entry. Thirty-seven subjects had entry-high plasma NE and 182 were entry-normal. Entry-high plasma NE subjects had significantly greater total body fat mass and plasma NE and significantly lower creatinine clearance at entry and throughout the study. Increases in BMI, fat mass, BP, plasma NE, BUN, and creatinine, as well as the reduction in creatinine clearance in the 5 years, were significantly greater in entry-high NE subjects. These subjects had significantly higher frequencies of the Gly16 allele of beta2-adrenoceptor polymorphisms. Throughout the study, subjects carrying the Gly16 allele had higher plasma NE, HOMA-IR, and fat mass, and significantly greater reductions in creatinine clearance. Plasma NE at entry was a determinant variable for changes in BUN, creatinine, and creatinine clearance over the 5-year period in multiple regression analysis. In conclusion, high plasma NE at entry, associated with the Gly16 allele of the beta2-adrenoceptor polymorphisms, predict renal function deterioration (seen in elevations of BUN and creatinine and reduction of creatinine clearance) over a 5-year period accompanying further heightened sympathetic nerve activity and deterioration of insulin resistance.

β 2-Adrenoceptor Polymorphisms Relate to Obesity Through Blunted Leptin-Mediated Sympathetic Activation

Obesity is a growing public health problem. It has been reported that beta2-adrenoceptor polymorphisms are associated with obesity. This study examines the associations of beta2-adrenoceptor polymorphism with relationships between plasma norepinephrine (NE) and leptin to evaluate further the mechanisms of obesity. In 329 normotensive (BP <140/90 mm Hg) men with a wide range of BMI (17.0 to 36.5 kg/m2), we measured BMI, total body fat mass, waist-to-hip ratio (W/H), BP, plasma NE, leptin, and the beta2-(Arg16Gly, Gln27Glu) adrenoceptor polymorphisms. The subjects consisted of 206 nonobese (BMI <25 kg/m2) and 123 overweight or obese (BMI >or=25 kg/m2) men. Overweight or obese subjects had a significantly higher frequency of Gly16 and Glu27 alleles compared with nonobese subjects. The subjects carrying Gly16 or Glu27 alleles regardless of BMI had greater total fat mass, W/H and plasma leptin compared with those without the Gly16 or Glu27 alleles, indicating that Gly16 and Glu27 alleles of the beta2-adrenoceptor gene are related to obesity and fat mass. Only in the nonobese subjects who carried the Gly16 and Glu27 alleles was there a high plasma NE level, but similar in overweight or obese subjects. To evaluate leptin-mediated sympathetic activation, we performed linear regression analyses between plasma leptin and NE. In groups with and without the Gly16 or Glu27 alleles, plasma leptin correlated with NE, but the slope in the group carrying the Gly16 or Glu27 allele was significantly lower than that without the Gly16 or Glu27. The findings demonstrate a strong and significant association of the Gly16 and Glu27 alleles with obesity. Lower slopes between leptin and NE in the subjects carrying these beta2-adrenoceptor polymorphisms indirectly indicate a blunted leptin-mediated sympathetic nerve activity. We propose that the beta2-adrenoceptor polymorphisms related to blunted leptin-mediated sympathetic activation offers further proof for the mechanisms of obesity.

Plasma catecholamines and blood volume in native Andeans during hypoxia and normoxia

Plasma catechols and blood volume were measured in 20 male, native high-altitude residents of Cerro de Pasco, Peru (4338 m), while hypoxic and subsequently while normoxic at sea level. Ten subjects were healthy controls,with hematocrits lower than 61%, and ten had chronic mountain sickness (CMS), a syndrome of maladaptation to altitude, characterized by polycythemia (hematocrit > 61%), profound hypoxemia, and neurologic symptoms. The main aim of the study was to evaluate the chronic effects of hypoxia on plasma catechols and on blood volume, by studying these parameters during hypoxia at high altitude (HA) and shortly after exposure to normoxia at sea level (SL). Subjects were first studied at HA in their habitual hypoxic environment, and measurements were repeated within 4 hours of arrival at SL (Lima, Peru, 150 m). All subjects had higher plasma norepinephrine (NE), dopamine (DA), and dihydroxyphenylglycol (DHPG) levels in HA (NE in controls and CMS: 414+/-47 and 514+/-35 pg/mL; DA: 9+/-1 and 13+/-1 pg/mL, DHPG: 817+/-48 and 972+/-77 pg/mL) than at SL (NE: 164+/-9 and 243+/-28 pg/mL; DA: 4+/-0.5 and 5+/-1 pg/mL DHPG: 502+/-23 and 649+/-39 pg/mL). Group differences were statistically significant only for NE in the CMS group. Plasma volume was higher in HA in both groups (p<0.05); red cell volume was higher in HA only in the CMS group. The results indicate sympathetic nervous stimulation by chronic ambient hypoxia at altitude in Andean natives, independent of maladaptation to their native environment.

Sympathetic Neural Regulation of Heart Rate Is Robust against High Plasma Catecholamines

The sympathetic regulation of heart rate (HR) may be attained by neural and humoral factors. With respect to the humoral factor, plasma noradrenaline (NA) and adrenaline (Adr) can reportedly increase to levels approximately 10 times higher than resting level during severe exercise. Whether such high plasma NA or Adr interfered with the sympathetic neural regulation of HR remained unknown. We estimated the transfer function from cardiac sympathetic nerve stimulation (SNS) to HR in anesthetized and vagotomized rabbits. An intravenous administration of NA (n = 6) at 1 and 10 microg.kg(-1).h(-1) increased plasma NA concentration (pg/ml) from a baseline level of 438 +/- 117 (mean +/- SE) to 974 +/- 106 and 6,830 +/- 917 (P < 0.01), respectively. The dynamic gain (bpm/Hz) of the transfer function did not change significantly (from 7.6 +/- 1.2 to 7.5 +/- 1.1 and 8.1 +/- 1.1), whereas mean HR (in bpm) during SNS slightly increased from 280 +/- 24 to 289 +/- 22 (P < 0.01) and 288 +/- 22 (P < 0.01). The intravenous administration of Adr (n = 6) at 1 and 10 microg.kg(-1).h(-1) increased plasma Adr concentration (pg/ml) from a baseline level of 257 +/- 86 to 659 +/- 172 and 2,760 +/- 590 (P < 0.01), respectively. Neither the dynamic gain (from 8.0 +/- 0.6 to 8.4 +/- 0.8 and 8.2 +/- 1.0) nor the mean HR during SNS (from 274 +/- 13 to 275 +/- 13 and 274 +/- 13) changed significantly. In contrast, the intravenous administration of isoproterenol (n = 6) at 10 microg.kg(-1).h(-1) significantly increased mean HR during SNS (from 278 +/- 11 to 293 +/- 9, P < 0.01) and blunted the transfer gain value at 0.0078 Hz (from 5.9 +/- 1.0 to 1.0 +/- 0.4, P < 0.01). In conclusion, high plasma NA or Adr hardly affected the dynamic sympathetic neural regulation of HR.

Norepinephrine-induced diastolic dysfunction with aortic valve opening under calcium-loading in rats

Heart failure associated with a high plasma level of norepinephrine (NE) has an extremely poor prognosis with NE being the most powerful predictor of all-cause mortality. An increase in the diastolic intracellular calcium level (Ca2+) occurs in left ventricular dysfunction; however, the cause-and-effect relationships among Ca2+loading, high plasma NE, and an increase in diastolic ventricular pressure is unclear. Here, we examined the relationship between diastolic dysfunction and NE with and without Ca2+loading in rats. Animals were studied in four groups: Ca2+loading for 45 min (Ca2+group), NE alone for 25 min (30 µg/kg/min NE for 25 min; NE group), Ca2+loading and NE for 25 min after Ca2+loading (Ca2+-NE group), and a vehicle group. Hemodynamics were examined using a micromanometer-tipped pressure catheter, and diastolic function was studied using Doppler echocardiography. Significantly increased left ventricular end-diastolic pressure (LVEDP) and decreased E and Ea waves and deceleration time (DCT) were found in the Ca2+-NE group, compared with the Ca2+and NE groups. There were no changes in left ventricular pressure (LVP) and LV ejection fraction (EF) among the four groups. NE-induced diastolic contracture (NEIDC) with aortic valve opening occurred in the diastole when LVP overshot the aortic pressure after co-administration of NE and Ca2+after Ca2+loading, and pulmonary hemorrhage was observed in all animals of the Ca2+-NE group. The results support the suggestion that NE may be an important factor in the development of diastolic dysfunction in ischemic heart disease. Drug Dev. Res. 67:511–518, 2006. © 2006 Wiley-Liss, Inc.

.BETA.2- and .BETA.3-Adrenoceptor Polymorphisms Relate to Subsequent Weight Gain and Blood Pressure Elevation in Obese Normotensive Individuals

High blood pressure (BP) is a major determinant of cardiovascular events in obesity. The beta2- and beta3-adrenoceptor polymorphisms are associated with obesity and hypertension. In the present study, we examine the relationships of beta2- and beta3-adrenoceptor polymorphisms with further weight gain-induced BP elevation in obese subjects. Changes in BP, body weight, total body fat-mass, waist-to-hip ratio, plasma norepinephrine (NE) and leptin levels, and beta2(Arg16Gly)- and beta3(Trp64Arg)-adrenoceptor polymorphisms were measured periodically over a 5-year period in 55 entry obese (body mass index [BMI]> or =25.0 kg/m(2)) normotensive (BP<140/90 mmHg) men. BP elevation and weight gain were defined as > or =10% increases from entry levels over 5 years in mean BP or BMI. Obese subjects with weight gain, BP elevation or weight gain-induced BP elevation had higher frequencies of the Gly16 allele of Arg16GIy and Arg64 allele of Trp64Arg. Subjects carrying the Gly16 or Arg64 alleles had significantly greater total fat-mass and waist-to-hip ratio at entry and over a 5-year period compared to the subjects who did not carry these polymorphisms. Subjects carrying the Gly16 allele had similar levels of plasma NE, higher levels of plasma leptin and a lower slope of the regression lines between plasma leptin and NE levels. Those carrying the Arg64 allele had higher plasma NE levels at entry and over a 5-year period compared to the subjects without the Arg64 allele, but plasma leptin levels and slopes were similar. The findings demonstrate that the Arg64 allele of the beta3-adrenoceptor polymorphisms relates to weight gain-induced BP elevation accompanying high plasma NE (heightened sympathetic activity) in obese men. The Gly16 allele of the beta2-adrenoceptor polymorphisms links to weight gain-induced BP elevation associated with leptin resistance. beta2- and beta3-adrenoceptor polymorphisms could predict the future BP elevation and further weight gain-induced BP elevation in originally obese subjects.

Reduced Adiposity in Bitter Melon (Momordica charantia)–Fed Rats Is Associated with Increased Lipid Oxidative Enzyme Activities and Uncoupling Protein Expression

To further explore the antiobesity effect of freeze-dried bitter melon (BM) juice, activities of mitochondrial lipid oxidative enzymes as well as the expression of uncoupling proteins and their transcription coactivator peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1alpha) were determined in diet-induced obese (DIO) rats. Rats were fed high-fat (HF) diets to induce obesity, and the effect of BM was assessed at doses of 0.75, 1.0, or 1.25% (wt:wt). In a dose-response experiment, BM-supplemented rats had lower energy efficiency (g weight gained/kJ consumed), visceral fat mass, serum glucose, and insulin resistance index, but higher plasma norepinephrine than unsupplemented rats (P < 0.05). Hepatic and skeletal muscle triglyceride concentrations were lower in supplemented HF diet-fed rats than in unsupplemented HF diet-fed rats (P < 0.05). An HF diet supplemented with BM elevated activities of hepatic and muscle mitochondrial carnitine palmitoyl transferase-I (CPT-I) and acyl-CoA dehydrogenase (AD) (P < 0.05). In another experiment, BM (1.0 g/100 g) lowered visceral fat mass but increased serum adiponectin concentration in HF diet-fed rats (P < 0.05). In the final study, rats were fed the HF diet with 0, 1.0 or 1.25% BM. Both groups of BM-supplemented rats had higher uncoupling protein 1 in brown adipose tissue (P < 0.05) and uncoupling protein 3 in red gastrocnemius muscle (P < 0.05), measured by Western blotting and RT-PCR, than the controls. The expression of the transcription coactivator PGC-1alpha in both tissues was also significantly elevated in the BM-supplemented rats (P < 0.05). The present results suggest that decreased adiposity in BM-supplemented rats may result from lower metabolic efficiency, a consequence of increased lipid oxidation and mitochondrial uncoupling.

Rebound Weight Gain as Associated With High Plasma Norepinephrine Levels That Are Mediated Through Polymorphisms in the β2-Adrenoceptor

A successful weight loss program is essential treatment for obesity-related diseases, but it is well known that the majority of individuals do not succeed in weight loss maintenance. The present study evaluates hormonal mechanisms and the relationship of beta2-adrenoceptor polymorphisms involved in individuals who regain weight after initially successful weight loss. Overweight Japanese men (n = 154) were enrolled in a 24-month weight loss program. Body mass index (BMI), total body fat mass, plasma norepinephrine (NE) and leptin levels, and beta2-adrenoceptor polymorphisms (Arg16Gly, Gln27Glu) were measured every 6 months for the 24-month period. Maintenance of weight loss was defined as significant weight loss (>or=10% reduction) from entry weight at 6 months and maintenance of the weight loss for an additional 18 months. Rebound weight gain was defined as significant weight loss at 6 months but subsequent regain of body weight during the next 18 months. The results showed that 37 subjects maintained weight loss during 24 months, whereas 36 subjects had rebound weight gain. The BMI at entry and calorie intake and physical activity at each period were similar between the two groups. Subjects who maintained weight loss had at entry a significantly lower fat mass and plasma NE levels compared to those with rebound weight gain. Body fat mass, NE, and leptin levels at entry predicted the degree of change in body weight during the 24-month study period. Subjects with rebound weight gain had a significantly higher frequency of the Gly16 allele for the beta2-adrenoceptor polymorphism compared to subjects who had a 24-month maintenance of weight loss. Subjects carrying the Gly16 allele also had significantly higher plasma NE, leptin, and body fat mass levels and a greater waist-to-hip ratio both at entry and throughout the study. A high initial degree of body fat mass and high plasma NE levels as determined by the Gly16 allele for the beta2-adrenoceptor polymorphisms predict those individuals who will have rebound weight gain after their initial successful weight loss.

Combined corticotropin-releasing hormone and glucocorticoid deficiency does not enhance counterregulatory responses after recurrent hypoglycemia in mice

Glucocorticoids and corticotropin-releasing hormone (CRH) have been proposed to inhibit counterregulatory responses to recurrent hypoglycemia. We used the CRH knockout (CRH KO) mouse to test the hypothesis that combined CRH and glucocorticoid deficiency would prevent development of counterregulatory deficits after repeated hypoglycemia. To develop a mouse model of recurrent hypoglycemia, we first tested the effects of daily lente insulin injection on counterregulatory responses to acute hypoglycemia in male C57BL/6 mice. Treatment with up to 250 U/kg per day lente insulin resulted in significantly greater decreases in plasma glucose, suggestive of impaired counterregulation, after hypoglycemia induced by acute insulin injection. Plasma catecholamine responses to hypoglycemia in repeatedly hypoglycemic C57BL/6 mice were unexpectedly higher than in naive mice, which we interpreted as a compensatory response to the greater decreases in plasma glucose. Lente insulin doses had to be reduced (50-75 U/kg per day) for CRH KO mice to survive repeated hypoglycemia. Wild-type (WT) mice treated with 50 to 75 U/kg per day lente insulin exhibited enhanced sympathetic activity after hypoglycemia, resembling the compensatory responses associated with impaired glucose homeostasis in C57BL/6 mice treated with 250 U/kg per day lente insulin. During acute hypoglycemia, CRH KO mice maintained higher plasma glucose levels that correlated with higher plasma norepinephrine and greater glycogen mobilization. Recurrent hypoglycemia did not enhance liver glycogen depletion or the markedly impaired glucocorticoid and epinephrine responses to hypoglycemia in CRH KO mice. Previously hypoglycemic CRH KO mice also did not display the further increases in sympathetic activity that in WT mice were suggestive of compensation for impaired counterregulation. Despite the apparent resistance of CRH KO mice to the counterregulatory effects of repeated hypoglycemia, their greater mortality after hypoglycemia tolerated by WT mice indicates that combined CRH and glucocorticoid deficiency does not significantly improve counterregulation after repeated hypoglycemia.

Clinical Epidemiology of Major Nontraditional Risk Factors in Peritoneal Dialysis Patients

End-stage renal disease (ESRD) is a situation with a cardiovascular (CV) risk profile of almost unique severity. While traditional risk factors dominate the scene in the general population, in chronic kidney disease (CKD), nontraditional risk factors play an increasingly important role, being perhaps dominant in ESRD patients. We review the role inflammation [C-reactive protein (CRP)], hyperhomocysteinemia, high plasma norepinephrine, and accumulation of the endogenous inhibitor of the nitric oxide synthase asymmetric dimethylarginine (ADMA) in the high all-cause and CV mortality of patients on continuous ambulatory peritoneal dialysis (CAPD). The association between CRP and clinical outcomes in patients on peritoneal dialysis (PD) was examined in six studies totaling 692 subjects. The largest of these studies in Caucasians indicates that the independent risk of CV events in patients in the top CRP quartile is about five times higher than in the bottom quartile. Seven prospective studies, including over 1000 hemodialysis and 176 CAPD patients, reported both positive and negative associations between homocysteine and mortality and/or CV events. Because homocysteine circulates bound to albumin, negative associations--rather than negating the vasculotoxicity of homocysteine--most likely reflect the very deleterious effects of malnutrition. Plasma norepinephrine is higher in CAPD than in hemodialysis patients, and multivariate analyses suggest the difference quantitatively entails a 16% higher risk of incident CV events. Likewise, ADMA is more elevated in CAPD patients and such an elevation corresponds to a 15% increase in risk. Nontraditional risk factors are far more prevalent in ESRD patients than in the general population. ADMA and norepinephrine may play a greater role in CV risk in CAPD than in hemodialysis patients.

The effects of acute loading with levodopa and levodopa with selegiline on blood pressure and plasma norepinephrine levels in chronic Parkinson's disease patients

Contradictory possible cardiovascular side effects of selegiline have been reported. Therefore, we studied the effect of acute administration of selegiline with levodopa (LD) compared with LD alone, on blood pressure, pulse and norepinephrine (NE) plasma levels, during an orthostatic test on chronically treated Parkinson's disease patients (PDpts) and controls. Twelve PDpts treated with LD (group D), 12 PDpts treated with selegiline and LD (group S) and eight volunteers (CTRL) underwent the orthostatic test. Patients repeated the test twice, before and after acute loading with 125 mg LD (group D) and 125 mg LD +5 mg selegiline (group S). Group S showed more episodes of postural hypotension (n = 10; two symptomatic) than group D (n = 4) and CTRL (n = 2), however not statistically significant. Plasma NE also rose significantly higher (P < 0.001) in group S. PD patients treated with selegiline showed more orthostatism and higher plasma NE after submission to the orthostatic test. These findings may be relevant to explain its deleterious effect.