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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 proto-oncogene and clinically re-evaluated 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 proto-oncogene 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 microg/24h, epinephrine: 1.94 +/- 0.17 microg/24h, norepinephrine 13.96 +/- 1.3 microg/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 proto-oncogene. 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.

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%).

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 high-performance 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.

Assessment of relationship between homocysteine (Hcy) and noradrenaline (NA), adrenaline (A) concentration and left ventricular mass index (LVMI) in patients with essential hypertension (EH).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.Hcy was significantly higher in patients with EH (8.7 +/- 2.4 vs 6.6 +/- 1.3 micromol/l; p0.01). 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 p0.05). LVMI was also significantly higher in EH group (96.6 +/- 19.5 vs 83.4 +/- 16.0 g/m2; p0.01). There was no significant correlation between Hcy and other analysed parameters in the studied groups.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.

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.

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 β-adrenergic stimulation, while persistent hypertension with an excessive α-adrenergic stimulation was responsible for low cardiac sympathetic tone, probably due to desensitization of β-adrenergic receptors.

To investigate the possible release of beta-endorphins (beta 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 beta 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 less than 0.01) decrease in MAP was present in all groups. Plasma NE and E decreased (p less than 0.02 to p less than 0.01) in N, BEH, and SEH, but not in PHEO. DA did not change in any group. Pretreatment beta 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 less than 0.01) and in SEH (p less than 0.02). Absolute changes in MAP correlated with those of beta 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 beta EN, in N or EH, but a correlation between resting plasma E and resting beta EN concentrations was demonstrated in PHEO. These results support a role of beta EN in the hypotensive action of CLO in EH, but not in N or PHEO.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND Atrial natriuretic peptide (ANP) has been extensively studied in cardiovascular disorders in recent years. Particular attention has been paid to the role of ANP in the pathogenesis of hypertension and congestive heart failure and in the neurohormonal response to myocardial infarction. However, no published data are available on the significance of ANP in hypertensive patients with acute myocardial infarction. METHODS We studied the relationship between plasma ANP concentration and systolic blood pressure, diastolic blood pressure, left atrial dimension, left ventricular diastolic dimension and left ventricular mass index in patients with essential hypertension in the acute phase of myocardial infarction. Plasma ANP concentrations were determined at 0, 4, 8, 16, 24, 48 and 72 h after admission in 40 patients with a first myocardial infarction (18 hypertensive patients, group 1; 22 normotensive patients, group 2). Left atrial dimension and left ventricular diastolic dimension were assessed echocardiographically within the first 48 h of acute myocardial infarction. RESULTS Maximum and mean plasma ANP values at 0, 4, 8, 16, 24, 48, and 72 h as well as mean ANP concentrations within the 72 h period were higher in group 1 than in group 2 (P < 0.001). Plasma ANP concentration, left atrial dimension (r = 0.59) and left ventricular diastolic dimension (r = 0.56) were positively correlated in both groups. CONCLUSION Acute myocardial infarction is characterized by a more pronounced rise in plasma ANP concentration in hypertensive patients than in those without a history of hypertension. Plasma ANP concentration correlates with left heart chamber sizes.

Plasma atrial natriuretic factor (ANF) and catecholamine concentrations were determined in 11 untreated patients with uncomplicated essential hypertension and seven normotensive subjects during graded submaximal exercise on a treadmill (loads: I 40%, II 60%, III 80% of maximal oxygen consumption). No significant differences in plasma ANF and catecholamine concentrations were found between the hypertensive and the normotensive subjects. The results do not support the presence of significant differences in the release of ANF and catecholamines during dynamic exercise between patients with uncomplicated essential hypertension and normotensive subjects.