Bożenna Wocial

Plasma neuropeptide Y and catecholamines in women and men with essential hypertension.

Neuropeptide-Y (NPY) is a peptide proposed to modulate the effect of the sympathetic nervous system on blood pressure control and contribute to the development of essential hypertension. To assess the possible influence of gender on its role, we evaluated plasma NPY, noradrenaline (NA) and adrenaline (A) concentrations in men and women with essential hypertension. No difference in NPY concentration was found between genders, but NPY concentration was elevated in both hypertensive men and women. NA levels were similar in all investigated hyper- and normotensives, while A was increased only in hypertensive men. These results suggest various patterns of sympatho-adrenal activity in gender subgroups of patients with essential hypertension.

Dopamine and dopa urinary excretion in patients with pheochromocytoma: Diagnostic implications

Pheochromocytoma, a potentially life-threatening disease, is a rare cause of hypertension. Most pheochromocytomas secrete excessive amounts of noradrenaline and adrenaline. It has been suggested by some authors that high circulating levels of dopamine and the catecholamine precursor dihydroxyphenylalanine (dopa) are more often associated with malignant rather than benign pheochromocytomas. Therefore the aim of this study was to evaluate urinary excretion of dopamine and dopa in patients with pheochromocytoma and to determine their role as a potential marker for malignancy of the tumour. We retrospectively analysed 120 consecutive patients (mean age 41 - 12 years) with histopathologically confirmed pheochromocytomas. All subjects were divided as follows: group 1 included patients with both elevated and normal dopamine urinary excretion; group 2 was characterized by increased and normal dopa urinary excretion. Dopamine urinary excretion was increased in all patients with malignant pheochromocytoma, but higher levels were also observed in some patients with a benign tumour included in group 1. Urinary excretion of dopa was in the normal range in all subjects with malignant pheochromocytoma. The results indicate that in some pheochromocytoma patients excessive dopamine excretion may point to malignant tumour, but is not a discriminating marker for malignancy in the whole studied group.

Homocysteine, Adrenergic Activity and Left Ventricular Mass in Patients with Essential Hypertension

Objective: Assessment of relationship between homocysteine (Hcy) and noradrenaline (NA), adrenaline (A) concentration and left ventricular mass index (LVMI) in patients with essential hypertension (EH). Design and methods: Samples obtained from 37 patients (14 female, 23 male) with mild EH (according to WHO criteria) (mean age 43.6 - 13.2 years) and 37 healthy volunteers (18 female, 19 male; mean age 38.2 - 10.6 years) were evaluated for Hcy (ELISA), NA and A (HPLC). Each patient underwent echocardiographic investigation with LVMI measurement (Penn convention). The examinations were performed in the outpatient clinic. Results: Hcy was significantly higher in patients with EH (8.7 - 2.4 vs 6.6 - 1.3 µmol/l; p < 0.01). NA and A levels were significantly elevated in the EH group (A: 43.9 - 26.4 vs 36.9 - 29.4 pg/ml; NA: 428.5 - 148.8 pg/ml vs 314.6 - 103.4 pg/ml; both p < 0.05). LVMI was also significantly higher in EH group (96.6 - 19.5 vs 83.4 - 16.0 g/m 2; p < 0.01). There was no significant correlation between Hcy and other analysed parameters in the studied groups. Conclusion: High levels of Hcy appear together with increased left ventricular mass and augmented adrenergic activity in patients with EH. Coexistence of high Hcy concentration, left ventricular hypertrophy and increased adrenergic activity increases the risk of atherosclerosis and cardiovascular disease in patients with EH. Key words:

Incidence and clinical relevance of RET proto-oncogene germline mutations in pheochromocytoma patients.

Background Autosomal dominant cancer syndrome – multiple endocrine neoplasia type 2 (MEN 2), may exist more often than expected in patients with pheochromocytoma. Germline mutations identified recently in MEN 2 can be revealed by genetic screening. Objective To evaluate the frequency of RET (rearranged during transfection) mutations in patients with pheochromocytoma. Design and methods We genetically screened germline mutations in the RET protooncogene and clinically reevaluated patients with pheochromocytoma. A pentagastrin test and other biochemical studies were performed in all patients. Setting Department of Internal Medicine and Hypertension, The Medical University of Warsaw, Warsaw, Poland and the Department of Nephrology and Hypertension, Albert Ludwigs University, Freiburg, Germany. Participants Seventy seven unselected patients with pheochromocytoma (19 men, 58 women, mean age: 51.55 ± 1.5 years; pheochromocytoma confirmed histopathologically) out of 162 diagnosed and treated in the years 1957–1998 in the Department of Internal Medicine and Hypertension in Warsaw, Poland. The other 85 patients did not respond to the written invitation. Main outcome measures The finding of RET mutations and diagnosis of MEN 2 in patients with pheochromocytoma. Results Genetic testing revealed germline mutations in the RET protooncogene in six patients (7.8%). All carriers had mutation of exon 11, codon 634: TGC to CGC. In four patients with this mutation, medullary thyroid carcinoma (MIC) was diagnosed and in three cases, surgically treated. Biochemical parameters: parathormone 31.88 ± 2.87 pg/ml, calcitonin: 0 min 0.23 ± 0.14 ng/ml; 2 min 0.49 ± 0.21 ng/ml; 5 min 0.48 ± 0.21 ng/ml, metoxycatecholamines: 601.62 ± 42.71 μg/24h, epinephrine: 1.94 ± 0.17 μg/24h, norepinephrine 13.96 ± 1.3 μg/24h, carcinoembryonic antigen (CEA) 9.94 ± 4.3 ng/ml. Ambulatory blood pressure monitoring (ABPM): systolic blood pressure (SBP): 116 ± 1.9 mmHg, diastolic blood pressure (DBP): 73.7 ± 0.9 mmHg. Clinical, biochemical and imaging procedures did not reveal any recurrence of pheochromocytoma in the 77 patients studied. Conclusions Patients with pheochromocytoma should be genetically screened for mutations of the RET protooncogene. These patients should undergo clinical screening for MEN 2. In addition, genetic studies can be useful for the screening of the families of the carriers.

Plasma Atrial Natriuretic Peptide (ANP) Concentration in Patients with Pheochromocytoma

The interaction between catecholamines (CA) and ANP is not clearly established. The effects of excess endogenous CA on ANP secretion can be investigated in patients with pheochromocytoma. We studied 27 patients with surgically and histologically proven pheochromocytoma (P) aged 19-70 years. In 16 of these patients plasma ANP study was repeated after surgical removal of the tumour. The control group (C) consisted of 20 healthy volunteers aged 21-48 years. Moreover, 42 patients with uncomplicated mild to moderate essential hypertension (EH) aged 18-48 years were also studied. In P higher plasma ANP concentration versus C, EH was found (51.9 +/- 8.1; 25.5 +/- 1.5; 19.3 +/- 1.5 fmol/ml, respectively). In 16 patients with P, increased plasma ANP level (mean 63.3 +/- 12.6 fmol/ml) declined after surgical removal of the tumour (mean 22.4 +/- 2.9 fmol/ml). In the P patients no relationship was found between plasma ANP and hormonal patterns of the tumour or between plasma ANP and plasma catecholamines, whereas significant positive correlations between plasma ANP and both systolic and diastolic blood pressure and heart rate were demonstrated. These results suggest that excess CA produced by the chromaffin tumour induce ANP secretion via stimulation of adrenergic receptors. However, influence of the haemodynamic changes evoked by CA cannot be excluded. It is suggested that increased secretion of ANP may be of some importance in maintaining blood pressure homeostasis in patients with pheochromocytoma.

Do catecholamines influence the level of plasma leptin in patients with phaeochromocytoma

Abstract The relationship between plasma leptin and catecholamine concentrations during chronic and acute catecholamine excess is studied. Patients with phaeochromocytoma, divided according to gender, were examined under basal conditions (n=18) and at selected time-points during surgical removal of the tumour (n=12). Appropriate controls were used (n=23) for the basal study. Plasma leptin was determined by radioimmunoassay (RIA) and plasma noradrenaline (NA) and adrenaline (A) by highperformance liquid chromatography (HPLC). Statistical evaluation employed Student’s t-test, Wicoxon test and Spearman’s correlation coefficient. Gender-related differences in plasma leptin in normal subjects was confirmed, and these were maintained in the patients. Phaeochromocytoma patients had normal plasma leptin levels in the basal state and decreased levels following the massive catecholamine surge provoked by surgery. Plasma leptin concentration did not correlate with plasma NA or A in either group studied. In the patients with phaeochromocytoma, acute but not chronic catecholamine excess affected plasma leptin, suggesting a role for sympathetic activity in modulating leptin release.

Heart rate variability in pheochromocytoma

The results of our study show that parasympathetic tone was higher in patients with pheochromocytoma than in patients with primary hypertension. An unusual spectral form of vagal activity was seen during excessive beta-adrenergic stimulation, while persistent hypertension with an excessive alpha-adrenergic stimulation was responsible for low cardiac sympathetic tone, probably due to desensitization of beta-adrenergic receptors.

Analysis of PTEN mutation in non-familial pheochromocytoma

Abstract:  PTEN, a tumor suppressor gene, is frequently mutated in a variety of human tumors. In mice, monoallelic inactivation of this gene predisposes animals to neoplasia of multiple organs. Interestingly, Pten heterozygous mice develop bilateral hyperplasia of the adrenal medulla. In this report we demonstrate that these neoplasms are hormonally active pheochromocytomas that secrete increased amounts of bioactive catecholamines: norepinephrine and epinephrine. To test a possibility that PTEN might be one of the genes responsible for human sporadic pheochromocytoma, we performed mutation analysis of DNA obtained from tumors of 29 patients. However, direct sequencing of all nine exons of the PTEN gene, including the splice junctions, revealed no mutations. Examination of protein expression by immunohistochemistry using 8 normal adrenals and 11 sporadic pheochromocytomas showed no decrease in the PTEN protein expression in the tumor tissue, but upregulation of insulin‐like growth factor II, a peptide implicated in growth of adrenal tissue, was observed in four cases (36%).

Alterations in plasma neuropeptide Y immunoreactivity and catecholamine levels during surgical removal of pheochromocytoma.

Background Neuropeptide Y, an abundant neurohormone present with catecholamines in the adrenal medulla, is a potent non-adrenergic vasoconstrictor and a vascular growth factor. Objective To determine the mechanism of the release from, and possible role of neuropeptide Y in, pheochromocytomas, compared with those of catecholamines. Methods Plasma and tumour levels of neuropeptide Y-immunoreactivity (by, radioimmunoassay) and of noradrenaline and adrenaline (by a radioenzymatic method) in 29 patients (19 women and 10 men, aged 22–68 years) were measured during surgical removal of the tumour, during α-adrenergic and β-adrenergic blockade. Arterial systemic blood samples were withdrawn before the ligation of the vessels supplying the tumour, during its surgical manipulations and after its removal, while haemodynamics was monitored. Results Plasma neuropeptide Y levels in 17 patients(58.6%, group I) significantly increased during manipulations of the pheochromocytoma and returned completely to normal after its removal. This response was independent of the plasma neuropeptide Y immunoreactivity manipulation and was correlated to increases in plasma noradrenaline (r = 0.638, P < 0.02) but not adrenaline levels. Manipulation-induced increases in plasma neuropeptide Y-immunoreactivity were associated with greater neuropeptide Y content in tumours (r = 0.508, P < 0.05) but neither plasma nor tumour levels of neuropeptide Y immunoreactivity were correlated to tumour mass. Plasma levels of neuropeptide Y immunoreactivity in the remaining 12 patients (41.4%, group II) remained unchanged throughout the experimental period, while levels of circulating catecholamine rose. In all, in spite of our attempt at complete adrenergic blockade, tumour manipulation elevated arterial blood pressure and these changes were significantly correlated to increases in levels of catecholamines in patients in both groups but also to plasma neuropeptide Y immunoreactivity in patients in group I. Conclusion Pheochromocytomas exhibit different patterns of secretion. For about half of the patients either the secretion of neuropeptide Y is uncoupled from that of catecholamines or its secretion could be obscured by an increase in degradation of neuropeptide Y to inactive fragments undetectable by radioimmunoassay.

Plasma β-Endorphins and Catecholamines Before and After Clonidine in Essential Hypertension and Pheochromocytoma

&NA; To investigate the possible release of &bgr;‐endorphins (&bgr;EN) from tumors and to investigate their possible involvement in the hypotensive mechanism of clonidine (CLO) in pheochromocytoma (PHEO), as compared with essential hypertension (EH), we studied 12 patients with PHEO, 17 patients with uncomplicated stable EH (SEH), nine patients with borderline EH (BEH), and seven healthy volunteers (N). All subjects were hospitalized and excreted normal amounts of sodium. Mean blood pressure (MAP) and plasma &bgr;EN, norepinephrine (NE), epinephrine (E), and dopamine (DA) were measured before and 180 min after an oral dose of 0.3 mg CLO. Following CLO, a significant (p < 0.01) decrease in MAP was present in all groups. Plasma NE and E decreased (p < 0.02 to p < 0.01) in N, BEH, and SEH, but not in PHEO. DA did not change in any group. Pretreatment &bgr;EN did not differ significantly between the groups, and following CLO it did not change in N or PHEO, while it increased significantly in BEH (p < 0.01) and in SEH (p < 0.02). Absolute changes in MAP correlated with those of &bgr;EN only in the SEH group. Changes in NE or E did not correlate with changes in MAP in either group. Likewise, changes in NE or E were not correlated with those of &bgr;EN, in N or EH, but a correlation between resting plasma E and resting &bgr;EN concentrations was demonstrated in PHEO. These results support a role of &bgr;EN in the hypotensive action of CLO in EH, but not in N or PHEO. They do not demonstrate unequivocally an increase of plasma &bgr;EN in PHEO, which could reflect release from tumors or other sources, but they do suggest that in patients with PHEO &bgr;EN and E might be released from a common source, possibly the tumor itself.