Plasma Concentrations Of Normetanephrine Research Articles

Optimized procedures for testing plasma metanephrines in patients on hemodialysis

Diagnosis of pheochromocytomas and paragangliomas in patients receiving hemodialysis is troublesome. The aim of the study was to establish optimal conditions for blood sampling for mass spectrometric measurements of normetanephrine, metanephrine and 3-methoxytyramine in patients on hemodialysis and specific reference intervals for plasma metanephrines under the most optimal sampling conditions. Blood was sampled before and near the end of dialysis, including different sampling sites in 170 patients on hemodialysis. Plasma normetanephrine concentrations were lower (P < 0.0001) and metanephrine concentrations higher (P < 0.0001) in shunt than in venous blood, with no differences for 3-methoxytyramine. Normetanephrine, metanephrine and 3-methoxytyramine concentrations in shunt and venous blood were lower (P < 0.0001) near the end than before hemodialysis. Upper cut-offs for normetanephrine were 34% lower when the blood was drawn from the shunt and near the end of hemodialysis compared to blood drawn before hemodialysis. This study establishes optimal sampling conditions using blood from the dialysis shunt near the end of hemodialysis with optimal reference intervals for plasma metanephrines for the diagnosis of pheochromocytomas/paragangliomas among patients on hemodialysis.

Incremental "Therapeutic" Myocardial Exposure to Catecholamines: Incidence and Impact in Takotsubo Syndrome.

Although Takotsubo syndrome (TS) was once considered to be rare and largely benign, it is now recognized to represent a major cause of cardiac morbidity and mortality, especially in ageing women. The biochemical precipitant of attacks of TS is an increase in catecholamine concentrations within the myocardium, engendering inflammatory activation via biased post-receptor signalling at myocardial β2-adrenoceptor level. Cases of TS have been reported in patients treated with catecholamines, and with antidepressants which limit catecholamine re-uptake. In the current investigation, we sought to delineate the extent and potential impact of this "iatrogenic" form of TS. Patients' data from a regional registry of 301 consecutive cases of TS were evaluated after exclusion of patients (n = 20) in whom TS had occurred in association with life threatening extracardiac disease states. A total of 55 (18%) of patients were identified as having antecedent exposure to potentially "iatrogenic" agents (tricyclic antidepressants in 24 cases, β2-adrenoceptor agonists in 15). Demographics, including proportion of male patients, did not differ significantly between patients with and without "iatrogenic" TS, but plasma concentrations of the catecholamine metabolite normetanephrine tended to be greater (median 1149pmol/L vs 938pmol/L; p = 0.03). Long-term survival (median follow-up 3years) was marginally (p = 0.13) worse for patients with "iatrogenic" TS. Potentially iatrogenic precipitation of TS attacks (via iatrogenic elevation of catecholamine levels and β2-adrenoceptor stimulation) is common, associated with greater elevation of plasma normetanephrine concentrations, and also with a trend towards increased long-term mortality when compared to the remainder of TS patients.

Age-specific pediatric reference intervals for plasma free normetanephrine, metanephrine, 3-methoxytyramine and 3-O-methyldopa: Particular importance for early infancy

BackgroundAvailability of appropriately established reference intervals for biochemical tests can be troublesome in pediatrics. Here we establish age-specific continuous reference intervals for catecholamine O-methylated metabolites in children evaluated for catecholamine producing tumors, particularly younger children with suspected neuroblastoma. MethodsPlasma concentrations of 3-methoxytyramine, normetanephrine, metanephrine, and 3-O-methyldopa were analyzed by liquid chromatography tandem mass spectrometry in 533 children aged 2 days to 18 years. ResultsConcentrations of plasma free normetanephrine, 3-methoxytyramine and 3-O-methyldopa were higher in neonates up until six months of age, but thereafter declined steeply to levels after one year that were <38% those of neonatal concentrations and to further lower concentrations in teenagers that were <23% those in neonates. In contrast, concentrations of plasma free metanephrine showed a reciprocal pattern with 50% lower concentrations in infants below one year compared to later in childhood. ConclusionThe dynamic reciprocal changes in plasma concentrations of normetanephrine, 3-methoxytyramine and 3-O-methyldopa compared to metanephrine during early childhood suggest underlying developmental changes in extra-adrenal and adrenal chromaffin tissue that must be considered for pediatric reference intervals, particularly in infants. With such reference intervals at hand, biochemical testing for catecholamine producing tumors in young children is substantially improved.

Postexercise cold water immersion modulates skeletal muscle PGC-1α mRNA expression in immersed and nonimmersed limbs: evidence of systemic regulation.

Mechanisms mediating postexercise cold-induced increases in PGC-1α gene expression in human skeletal muscle are yet to be fully elucidated but may involve local cooling effects on AMPK and p38 MAPK-related signaling and/or increased systemic β-adrenergic stimulation. Therefore, we aimed to examine whether postexercise cold water immersion enhancement of PGC-1α mRNA is mediated through local or systemic mechanisms. Ten subjects completed acute cycling (8 × 5 min at ~80% peak power output) followed by seated-rest (CON) or single-leg cold water immersion (CWI; 10 min, 8°C). Muscle biopsies were obtained preexercise, postexercise, and 3 h postexercise from a single limb in the CON condition but from both limbs in CWI [thereby providing tissue from a CWI and nonimmersed limb (NOT)]. Muscle temperature decreased up to 2 h postexercise following CWI (-5°C) in the immersed limb, with lesser changes observed in CON and NOT (-3°C, P < 0.05). No differences between limbs were observed in p38 MAPK phosphorylation at any time point (P < 0.05), whereas a significant interaction effect was present for AMPK phosphorylation (P = 0.031). Exercise (CON) increased gene expression of PGC-1α 3 h postexercise (~5-fold, P < 0.001). CWI augmented PGC-1α expression above CON in both the immersed (CWI; ~9-fold, P = 0.003) and NOT limbs (~12-fold, P = 0.001). Plasma normetanephrine concentration was higher in CWI vs. CON immediately postimmersion (860 vs. 665 pmol/l, P = 0.034). We report for the first time that local cooling of the immersed limb evokes transcriptional control of PGC-1α in the nonimmersed limb, suggesting increased systemic β-adrenergic activation of AMPK may mediate, in part, postexercise cold induction of PGC-1α mRNA.NEW & NOTEWORTHY We report for the first time that postexercise cold water immersion of one limb also enhances PGC-1α expression in a contralateral, nonimmersed limb. We suggest that increased systemic β-adrenergic stimulation, and not localized cooling per se, exerts regulatory effects on local signaling cascades, thereby modulating PGC-1α expression. Therefore, these data have important implications for research designs that adopt contralateral, nonimmersed limbs as a control condition while also increasing our understanding of the potential mechanisms underpinning cold-mediated PGC-1α responses.

Urinary and plasma catecholamines and metanephrines in dogs with pheochromocytoma, hypercortisolism, nonadrenal disease and in healthy dogs.

BackgroundDiagnosis of pheochromocytoma (PC) is based on a combination of clinical suspicion, finding an adrenal mass, increased plasma, and urine concentrations of catecholamine metabolites and is finally confirmed with histopathology. In human medicine, it is controversial whether biochemically testing plasma is superior to testing urine.ObjectivesTo measure urinary and plasma catecholamines and metanephrines in healthy dogs, dogs with PC, hypercortisolism (HC), and nonadrenal diseases (NAD) and to determine the test with the best diagnostic performance for dogs with PC.AnimalsSeven PC dogs, 10 dogs with HC, 14 dogs with NAD, 10 healthy dogs.MethodsProspective diagnostic clinical study. Urine and heparin plasma samples were collected and stored at −80°C before analysis using high‐pressure liquid chromatography (HPLC) coupled to electrochemical detection or tandem mass spectrometry were performed. Urinary variables were expressed as ratios to urinary creatinine concentration.ResultsDogs with PC had significantly higher urinary normetanephrine and metanephrine : creatinine ratios and significantly higher plasma‐total and free normetanephrine and plasma‐free metanephrine concentrations compared to the 3 other groups. There were no overlapping results of urinary normetanephrine concentrations between PC and all other groups, and only one PC dog with a plasma normetanephrine concentration in the range of the dogs with HC and NAD disease. Performances of total and free plasma variables were similar. Overlap of epinephrine and norepinephrine results between the groups was large with both urine and plasma.Conclusion and clinical importanceMeasurement of normetanephrine is the preferred biochemical test for PC and urine was superior to plasma.

Seasonal variation of plasma free normetanephrine concentrations: implications for biochemical diagnosis of pheochromocytoma

Background: Higher plasma concentrations of catecholamines in winter than in summer are established; whether this impacts plasma concentrations of metanephrines used for the diagnosis of pheochromocytoma is unknown. Objective: In this study, we examined seasonal variations in plasma concentrations of metanephrines, the impact of this on diagnostic test performance and the influences of forearm warming (‘arterialization’ of venous blood) on blood flow and measured concentrations. Methods: Measurements of plasma concentrations of metanephrines were recorded from 4052 patients tested for pheochromocytoma at two clinical centers. Among these patients, 107 had tumors. An additional 26 volunteers were enrolled for measurements of plasma metanephrines and forearm blood flow before and after forearm warming. Results: There was no seasonal variation in the plasma concentrations of metanephrines among patients with pheochromocytoma, whereas among those without tumors, plasma concentrations of normetanephrine were higher (P!0.0001) in winter than in summer. Lowest concentrations of normetanephrine were measured in July, with those recorded from December to April being more than 21% higher (P!0.0001). These differences resulted in a twofold higher (PZ0.0012) prevalence of false-positive elevations of normetanephrine concentrations in winter than in summer, associated with a drop in overall diagnostic specificity from 96% in summer to 92% in winter (PZ0.0010). Forearm warming increased blood flow and lowered (PZ0.0020) plasma normetanephrine concentrations. Conclusions: Plasma concentrations of normetanephrine are subject to seasonal variation with a resulting higher prevalence of false-positive results in winter than in summer. Lowered plasma concentrations of normetanephrine with forearm warming suggest an effect of temperature. These results have implications for considerations of temperature to minimize false-positive results.

Takotsubo cardiomyopathy presenting as S–T elevation myocardial infarction: Not gone but forgotten?

myocardial edema on cMRI, together with the presence of characteristic (usually peri-apical or mid ventricular) hypokinesis. Elevation of NT-Pro BNP levels and characteristic ECG changes were utilized in screening. Plasma concentrations of normetanephrine and metanephrine were measured on admission. We also examined potential differences in demographics and biomarkers between TTC patients presenting with and without initial S–T elevation. Comparisons between the subsets of TTC patients were made utilizing Student's non-paired t tests.

Biochemical diagnosis of phaeochromocytoma using plasma‐free normetanephrine, metanephrine and methoxytyramine: importance of supine sampling under fasting conditions

To document the influences of blood sampling under supine fasting versus seated nonfasting conditions on diagnosis of phaeochromocytomas and paragangliomas (PPGL) using plasma concentrations of normetanephrine, metanephrine and methoxytyramine. Biochemical testing for PPGL was performed on 762 patients at six centres, two of which complied with requirements for supine sampling after an overnight fast and four of which did not. Phaeochromocytomas and paragangliomas were found in 129 patients (67 noncompliant, 62 compliant) and not in 633 patients (195 noncompliant, 438 compliant). Plasma concentrations of normetanephrine and methoxytyramine did not differ between compliant and noncompliant sampling conditions in patients with PPGL but were 49-51% higher in patients without PPGL sampled under noncompliant compared with compliant conditions. The 97·5 percentiles of distributions were also higher under noncompliant compared with compliant conditions for normetanephrine (1·29 vs 0·79 nmol/l), metanephrine (0·49 vs 0·41 nmol/l) and methoxytyramine (0·42 vs 0·18 nmol/l). Use of upper cut-offs established from seated nonfasting sampling conditions resulted in substantially decreased diagnostic sensitivity (98% vs 85%). In contrast, use of upper cut-offs established from supine fasting conditions resulted in decreased diagnostic specificity for testing under noncompliant compared with compliant conditions (71% vs 95%). High diagnostic sensitivity of plasma normetanephrine, metanephrine and methoxytyramine for the detection of PPGL can only be guaranteed using upper cut-offs of reference intervals established with blood sampling under supine fasting conditions. With such cut-offs, sampling under seated nonfasting conditions can lead to a 5·7-fold increase in false-positive results necessitating repeat sampling under supine fasting conditions.

N-Terminal Pro-Brain Natriuretic Protein Levels in Takotsubo Cardiomyopathy

Takotsubo cardiomyopathy (TTC) is characterized by reversible left ventricular (LV) systolic dysfunction independent of fixed coronary disease or coronary spastic pathogenesis. A number of investigators have documented marked elevation of natriuretic peptide levels at presentation in such patients. We sought to determine the pattern, extent, and determinants of the release of N-terminal pro-B type natriuretic peptide/B type natriuretic peptide (NT-proBNP/BNP) in patients with TTC. We evaluated NT-proBNP/BNP release acutely and during the first 3 months in 56 patients with TTC (96% women, mean age 69 ± 11 years). The peak plasma NT-proBNP levels were compared to the pulmonary capillary wedge pressure and measures of regional and global LV systolic dysfunction (systolic wall stress, wall motion score index, and LV ejection fraction) as potential determinants of NT-proBNP/BNP release. In patients with TTC, the plasma concentrations of NT-proBNP (median 4,382 pg/ml, interquartile range 2,440 to 9,019) and BNP (median 617 pg/ml, interquartile range 426 to 1,026) were substantially elevated and increased significantly during the first 24 hours after the onset of symptoms (p = 0.001), with slow and incomplete resolution during the 3 months thereafter. The peak NT-proBNP levels exhibited no significant correlation with either pulmonary capillary wedge pressure or systolic wall stress. However, the peak NT-proBNP level correlated significantly with the simultaneous plasma normetanephrine concentrations (r = 0.53, p = 0.001) and the extent of impairment of LV systolic function, as measured by the wall motion score index (r = 0.37, p = 0.008) and LV ejection fraction (r = -0.39, p = 0.008). In conclusion, TTC is associated with marked and persistent elevation of NT-proBNP/BNP levels, which correlated with both the extent of catecholamine increase and the severity of LV systolic dysfunction.

Pheochromocytoma in a Patient With End-Stage Renal Disease

Pheochromocytoma is a rare tumor. To our knowledge only 15 cases have been reported in patients with end-stage renal disease (ESRD). We describe a 46-year-old woman with ESRD and a history of paroxysmal and difficult-to-control hypertension. During anesthesia for a surgical procedure, the patient experienced blood pressure lability with systolic blood pressures ranging from 76 to 360 mm Hg. Serum catecholamine concentrations were 2,698 pg/ mL (reference value, <750 pg/mL) for norepinephrine, 33 pg/mL (<110 pg/mL) for epinephrine, and 55 pg/mL (<30 pg/mL) for dopamine. The concentrations of plasma metanephrines were 6.84 nmol/L (<0.50 nmol/L) for metanephrine and 14.64 nmol/L (<0.90 nmol/L) for normetanephrine. Abdominal computed tomography showed a right-sided, 4-cm mass posterior to the infrahepatic inferior vena cava. Following blood pressure control with alpha- and beta-adrenergic blockade, the mass was removed. Pathologic examination demonstrated the mass was a pheochromocytoma. The maximum postoperative systolic blood pressure was 160 mm Hg. Postoperative plasma normetanephrine concentration was 2.80 nmol/L, and metanephrine was obscured by interfering substances. This case report and literature review emphasizes the difficulty in diagnosing pheochromocytomas in patients with ESRD despite the myriad of available diagnostic tests.

Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia type 2.

The detection of pheochromocytomas in patients at risk for these tumors, such as patients with von Hippel-Lindau disease or multiple endocrine neoplasia type 2 (MEN-2), is hindered by the inadequate sensitivity of commonly available biochemical tests. In this study we evaluated measurements of plasma normetanephrine and metanephrine for detecting pheochromocytomas in patients with von Hippel-Lindau disease or MEN-2. We studied 26 patients with von Hippel-Lindau disease and 9 patients with MEN-2 who had histologically verified pheochromocytomas and 50 patients with von Hippel-Lindau disease or MEN-2 who had no radiologic evidence of pheochromocytoma. Von Hippel-Lindau disease and MEN-2 were diagnosed on the basis of germ-line mutations of the appropriate genes. The plasma concentrations of normetanephrine and metanephrine were compared with the plasma concentrations of catecholamines (norepinephrine and epinephrine) and urinary excretion of catecholamines, metanephrines, and vanillylmandelic acid. The sensitivity of measurements of plasma normetanephrine and metanephrine for the detection of tumors was 97 percent, whereas the other biochemical tests had a sensitivity of only 47 to 74 percent. All patients with MEN-2 had high plasma concentrations of metanephrine, whereas the patients with von Hippel-Lindau disease had almost exclusively high plasma concentrations of only normetanephrine. One patient with von Hippel-Lindau disease had a normal plasma normetanephrine concentration; this patient had a very small adrenal tumor (<1 cm). The high sensitivity of measurements of plasma normetanephrine and metanephrine was accompanied by a high level of specificity (96 percent). Measurements of plasma normetanephrine and metanephrine are useful in screening for pheochromocytomas in patients with a familial predisposition to these tumors.

Disprocynium24, a novel inhibitor of the extraneuronal monoamine transporter, has potent effects on the inactivation of circulating noradrenaline and adrenaline in conscious rat.

The role of extraneuronal uptake in terminating the actions of catecholamines has been difficult to evaluate in vivo, largely because of lack of suitable inhibitors. The compound, 1,1'-diisopropyl-2,4'-cyanine iodide or disprocynium24 (D24), is a novel inhibitor of extraneuronal uptake with a high degree of potency in vitro. This study examined the actions of D24 on the inactivation and metabolism of circulating noradrenaline and adrenaline in conscious rats. Animals received i.v. infusions of 3H-labelled noradrenaline and adrenaline, and their extraneuronal O-methylated metabolites, normetanephrine and metanephrine. Plasma concentrations of endogeneous and 3H-labelled catecholamines and metanephrines were measured before and after D24. D24 caused large increases in plasma concentrations of noradrenaline and adrenaline, effects due to both decreases in their plasma clearances and increases in their rates of release into plasma. Plasma concentrations of normetanephrine and metanephrine also increased due to their decreased clearance from plasma. Increased release of normetanephrine into plasma did not contribute to increased plasma concentrations of normetanephrine. In fact, the contribution of extraneuronal O-methylation to noradrenaline clearance decreased substantially after D24. The data indicate that D24 is a potent inhibitor of the extraneuronal catecholamine transporter in vivo and that this process contributes importantly to the removal of circulating catecholamines and their O-methylated amine metabolites. Increased release of noradrenaline into plasma may reflect an increase in the proportion of transmitter that escapes from sites of release into the circulation. However, increased adrenaline release indicates that the drug also causes sympathoadrenal activation.

Determination of metanephrines in plasma by liquid chromatography with electrochemical detection

Metanephrines are O-methylated metabolites of catecholamines. We report the use of liquid chromatography with electrochemical detection to determine plasma concentrations of normetanephrine (NMN) and metanephrine (MN). Plasma NMN and MN in 32 normal volunteers and inpatients were compared with concentrations in 23 patients with pheochromocytoma. Metanephrines were adsorbed from plasma onto a cation-exchange column and eluted with ammoniacal methanol. The dried residue was dissolved in mobile phase and injected onto a reversed-phase column. Recoveries of NMN and MN from 1 mL of plasma averaged 50-70%, and results varied linearly with quantity injected over a range of 0.13-55 pmol. The detection limit was 25 fmol for NMN and 50 fmol for MN. Intra-assay CVs were < 5%. In normal volunteers and inpatients, plasma concentrations of NMN ranged between 0.12 and 0.73 nmol/L (mean 0.38 nmol/L), and MN between 0.06 and 0.63 nmol/L (mean 0.19 nmol/L). Plasma NMN concentrations were increased in all 23 patients with pheochromocytoma (range 1-172 nmol/L), whereas MN concentrations (range 0.10-382 nmol/L) were increased in only 9 patients. The assay method is reliable and sensitive and offers an approach to examine the extraneuronal metabolism of catecholamines. The method may also be useful in the diagnosis of pheochromocytoma.

Plasma normetanephrine: A biochemical marker of sympathetic nerve function in man

The concentration of the catecholamines in plasma are regarded by many investigators as biochemical markers of sympathoadrenal activity in man. This study was designed to: 1) assess the relationship of normetanephrine (NMN), the metabolite of norepinephrine (NE) most likely to represent degration of newly synthesized and released “active” norepinephrine, to that of norepinephrine in plasma of normal volunteers and 2) to determine regional variations in plasma normetanephrine concentrations at venous and arterial sites of patients undergoing cardiac catherization. The findings suggest that 1) plasma normetanephrine reflects sympathoadrenal activity and neurotransmitter production at both peripheral neuronal and adrenal medullary sites and 2) there is net removal of normetanephrine by liver and kidney. Plasma normetanephrine should provide assistance in the biochemical assessment of sympathoadrenal tone in man and in patients with various autonomic disorders.

Increased plasma normetanephrine in spontaneously hypertensive rats.

Plasma catecholamine and total plasma normetanephrine concentrations were determined in 11 spontaneously hypertensive rats (SHR) and in 11 age and sex matched Wistar Kyoto control rats (WKy). Plasma norepinephrine concentration, obtained from tail vein blood of restrained rats, was 356 +/- 67 pg/ml in SHR and 297 +/- 61 in WKy (NS), whereas epinephrine was 1079 +/- 117 in SHR and 695 +/- 107 in WKy (p < 0.05). Total plasma normetanephrine concentration was 1825 +/- 472 pg/ml in SHR and 535 +/- 109 in WKy (p < 0.02). Since normetanephrine is mainly an extraneuronal metabolite of norepinephrine, its plasma concentration could reflect the amount of the neurotransmitter which reaches effector cell sites suggesting enhanced sympathetic function accounts for blood pressure elevation in SHR. A simple and specific radioenzymatic assay for measurement of total plasma normetanephrine in rat was described.

Increased plasma and urinary normetanephrine in young patients with primary hypertension.

1. Normetanephrine was measured in small samples of plasma and urine of hypertensive patients and normal volunteers (age 20-60 years) by a specific radioenzymatic assay with bovine adrenal phenylethanolamine N-methyltransferase and tritiated S-adenosylmethionine. 2. Noradrenaline was measured simultaneously in plasma and urine. 3. Plasma normetanephrine and noradrenaline concentrations varied in direct proportion to activation or suppression of sympathetic nerve function. 4. Both plasma and urinary normetanephrine concentrations were elevated in patients with phaeochromocytoma. 5. Plasma normetanephrine concentrations were related to plasma noradrenaline concentrations of hypertensive subjects. 6. Plasma normetanephrine and noradrenaline concentrations and urinary normetanephrine excretion rates were increased in some young patients with primary hypertension, suggesting that sympathetic nerve hyperactivity is a pathogenic factor in these patients.