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In 106 patients with essential hypertension and different plasma renin activity several hormonal and metabolic factors were studied: urinary excretion of catecholamines, blood levels of cholesterol and triglycerides, levels of glycaemia and insulinaemia after glucose load and plasma fibrinolytic activity. The plasma renin activity in 46.2 percent of patients was normal, whereas in 25.5 percent it was low, and in 28.3 percent it was high. In patients with high plasma renin activity the excretion of noradrenaline and adrenaline was relatively high while that of dopamine was low. Significantly lower triglyceride levels were found in patients with low plasma renin activity in comparison with those with high and normal plasma renin activity. There was also a statistically significant difference in the euglobulin lysis time which was shorter in patients with low and longest in patients with normal plasma renin activity. The results of the study show that patients with different plasma renin activity may also differ in some hormonal and metabolic values. [ABSTRACT FROM PUBLISHER]

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%).

Circadian blood pressure (BP) rhythm is often disturbed in patients with secondary forms of hypertension. The aim of the present article was to investigate changes in circadian BP profile parameters using two-step statistical approach by Fourier analysis in relation to day and night urinary catecholamine excretion in 35 patients with pheochromocytoma (mean age 42+/-19 years). Twenty-four-hour ambulatory BP measurements (ABPM) were obtained using the SpaceLabs 90,207 monitor. Daytime and night-time urine collection was obtained in all patients to determine circadian catecholamine excretion. Fourier analysis was applied to estimate measures of BP circadian rhythm in ABPM, including the highest (Max) and lowest (Min) systolic (SBP) and diastolic (DBP) BP values, norad (ampSBP, ampDBP), and early acrophase (APSBP, APDBP). The Fourier indices of circadian BP rhythm were: MaxSBP 153+/-28 mm Hg, MaxDBP 99+/-16 mm Hg, MinSBP 117+/-17 mm Hg, MinDBP 69+/-11 mm Hg, ampSBP 18+/-8 mm Hg, ampDBP 14+/-5 mm Hg, APSBP 10+/-5 (h), and APDBP 11+/-3 (h). Urine noradrenaline (NA), adrenaline (A), and dopamine (DA) excretion during the day (d) and night (n) were: dNA 103.5+/-89.8 microg/14 h, nNA 52+/-70.8 microg/10 h, dA 13.2+/-17.9 microg/14 h; nA 6.13+/-9.6 microg/10 h, dD 181.8+/-87.3 microg/14 h, and nD 89.3+/-59.8 microg/10 h. A positive correlation was observed between urine dNa excretion and MaxDBP (r=0.37, P<0.05), and urine nNA and urine dA excretion were correlated with APDBP (r=0.47, r=0.35, respectively, both P<0.05). Thus, in addition to the effect on mean 24-h BP values, catecholamines released by tumor may also disturb circadian BP rhythm in patients with pheochromocytoma.

Background: There are numerous data indicating a significant role of the sympathoadrenal system and the reninangiotensin- aldosterone system in the regulation of blood pressure and the pathogenesis of essential hypertension. However, the genetic background of essential hypertension remains unclear., Aim: To determine the effects of genetic factors on selected indicators of the activity of the sympathoadrenal system and the renin-angiotensin-aldosterone system in twins., Methods: We studied 39 monozygotic twin pairs (age 33+/-7 years) and 37 same-gender dizygotic twin pairs (age 36+/-7 years). We measured blood and urine adrenaline (A), noradrenaline (NA), dopamine (DA) and aldosterone (ALD) levels, as well as plasma renin activity (PRA) and serum angiotensin-converting enzyme (ACE) activity. Parameters of the genetic models for age- and gender-adjusted data were estimated by model fitting and path analysis technique using LISREL 8., Results: The effects of genetic factors on the variability of blood and urine catecholamine levels were 69% and 65% for A, 42% and 76% for NA, and 58% and 40% for DA, respectively. We also found shared environmental components for blood NA (28%) and urine DA (17%). Genetic factors accounted for 36% of the variability of PRA and 80% of the variability of ACE. ALD levels were related only to environmental factors (including a shared environmental component, estimated at 25%, for urine ALD)., Conclusions: We found significant effects of genetic factors on the activity of the sympathoadrenal system, as indicated by blood and urine catecholamine levels. We also found the effect of genetic factors on PRA and ACE, but not on aldosterone levels.

Unlabelled: Left ventricular hypertrophy (LVH) in patients with arterial hypertension is closely related to the levels of blood pressure (BP), catecholamines, angiotensin II and other mitogenic peptides. Pheochromocytoma (pheo) is a type of hypertension caused by excessive production of catecholamines. The aim of this study was to determinate if left ventricular hypertrophy in patients with pheochromocytoma is related to catecholamines and neuropeptide Y (NPY)., Methods: 29 patients with pheochromocytoma (22 F, age 40 +/- 13 years), plasma concentration of neuropeptide Y immunoreactivity, noradrenaline (NA), and adrenaline (A) were determined. Twenty-four hour urine collection for determination of noradrenaline and adrenaline were performed. Every patient had echocardiographic examination and 24 h ambulatory blood pressure monitoring., Results: Left ventricular hypertrophy was diagnosed in 14 patients. No differences in systolic and diastolic blood pressure in patients with and without left ventricular hypertrophy were found. Plasma noradrenaline and adrenaline levels did not differ between both groups, while plasma neuropeptide Y immunoreactivity was higher in patients with left ventricular hypertrophy than in patients without left ventricular hypertrophy (18.46 +/- 13.26 vs. 9.3 +/- 5.9 fmol/ml (p = 0.02)). Left ventricular mass index (LVMI) correlated with plasma neuropeptide Y-immunoreactivity (r = 0.42 p = 0.023), however, no relationship between left ventricular mass index and plasma or urine noradrenaline and adrenaline levels were found., Conclusion: Our results indicate that mitogenic effect of neuropeptide Y may play a role in pathogenesis of left ventricular hypertrophy in patients with pheochromocytoma., (Copyright 2004 Elsevier B.V.)

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.

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 micromol/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/m2; 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.

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 aim of the study was to define features indicating malignancy in pheochromocytoma through analysis of clinical data, immunomorphological and nuclear DNA ploidy patterns with flow cytometry. The studied group consisted of 33 patients with hypertension and adrenal gland tumor. In all patients 24 hr measurements of adrenaline, noradrenaline, dopamine and their metabolites were taken and the content of these substances in the tumor tissue was measured. Morphologically most pheochromocytomas displayed alveolar pattern with polyhedral cells with clear cytoplasm. Nuclear pleomorphism was infrequent and mitotic figures were rare. In 5 tumors areas of ganglioneuromatous differentiation were present with neurofilament expression. Morphological features indicating malignancy were noted--vascular emboli of tumor cells, capsular infiltration and foci of necrosis. However, in the patient with metastases evident during operation, none of those features was found in the tumor sample. All pheochromocytomas expressed neuroendocrine markers (chromogranin A, synaptophysin and NSE) and most also vimentin. Reactivity of other markers was negligible. In DNA ploidy studies in 22/33 cases there was DNA diploid (normal) pattern. The patient with metastases belonged to this group. In 3 cases there were aneuploid tumor cells on histograms and in 8 increased number of tetraploid cells. The follow-up period of our patients was 1-43 months.

Hemorrheological and humoral abnormalities and excessive platelet activity can predict the development of cardiovascular complications in patients with essential hypertension. A study was conducted to assess the influence of gender on these factors and the interrelations between changes in hemorrheology and the sympatho-adrenal system in 54 patients (18 women, 36 men) with essential hypertension (aged 39.6 +/- 9.7 years) and 25 healthy volunteers (10 women, 15 men; aged 36.0 +/- 7.2 years). A decrease in erythrocyte deformability (p < 0.01) was found in the hypertensive men compared with the hypertensive women. Hematocrit (p < 0.01), blood viscosity at the shear rates of 0.3 s-1 (p < 0.01) and 6 s-1 (p < 0.01), plasma viscosity (p < 0.01), erythrocyte aggregation (p < 0.01), and neuropeptide Y (p < 0.02) concentrations were higher in the hypertensive men than in the hypertensive women. A positive correlation between blood fibrinogen and serotonin was found in the pooled hypertensive group and in the hypertensive men (p < 0.01) and between blood viscosity (shear rate 6 s-1) and neuropeptide Y in the pooled hypertensive group (p < 0.01). Neuropeptide Y correlated with filtration time of 1 mL blood in the hypertensive men (p < 0.05) and in the pooled normotensive group (p < 0.01) and with beta-thromboglobulin in the hypertensive women (p < 0.001). A positive correlation was also found in the hypertensive men between erythrocyte and platelet aggregation (p < 0.01) and between beta-thromboglobulin and adrenaline (p < 0.01). Hemorrheological and humoral abnormalities are more pronounced in men than in women with essential hypertension and may contribute to the increased incidence of cardiovascular events in men.

In phaeochromocytoma, sudden hypertensive or arrhythmic episodes are believed to be associated with excessive free catecholamine excretion. However, lack of correlation between blood pressure (BP) and plasma catecholamine levels has been reported. Therefore an attempt was made to assess the sympathovagal balance before and during episodes of BP elevation or complex cardiac arrhythmias in this disease. Ten patients with phaeochromocytoma and 10 matched controls with essential hypertension underwent simultaneous 24 h Holter ECG and BP monitoring. BP elevation was diagnosed when the BP exceeded the mean 24 h values by 40 mm Hg systolic or 30 mm Hg diastolic, respectively. Heart rate variability (HRV) was measured for 5 min periods 1 h before, 15 min before and during 13 episodes of BP elevation in phaeochromocytoma and 13 episodes in the control group, as well as at 1 h, 15 min and immediately before five arrhythmic events in phaeochromocytoma. In phaeochromocytoma, vagal activity measured 1 h before BP elevation was markedly higher than in control hypertensives. However, in both groups at 15 min before and during the hypertensive events, the vagal tone decreased significantly. In contrast, just before the arrhythmic events HRV remained unaltered with a slight insignificant increase in sympathetic activity. We conclude that in phaeochromocytoma, pronounced BP elevations during daily activities are preceded by a parasympathetic withdrawal, similar to the findings in essential hypertension. Such a sequence does not seem to precede sudden complex arrhythmic events in phaeochromocytoma.

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.

There are strong experimental evidences that alpha 1-adrenergic stimulation significantly influences cardiac arrhythmogenesis, especially during myocardial ischaemia and reperfusion. However, anti-arrhythmic effects of alpha-blockade in humans were scarcely utilised. Thus the purpose of our study was to assess these effects in patients with phaeochromocytoma. In 22 patients simultaneous 24 h ECG and blood pressure (BP) monitoring, as well as estimation of the urinary 24 h free catecholamine excretion, were performed twice: before and during the treatment with the non-selective alpha-blocker, phenoxybenzamine. The heart rate variability was measured during four 5 min periods, at 10.00, 16.00, 22.00 and 04.00. During alpha-blockade systolic blood pressure (SBP) decreased from 137.6 +/- 23.8 to 126.5 +/- 15.7 mm Hg (P < 0.01), heart rate increased from 83.0 +/- 9.9 to 88.5 +/- 10.0/min (P < 0.02) and duration of QTc interval unsignificantly increased. Incidence of frequent or repetitive ventricular arrhythmias was significantly higher before treatment (in 9 vs 3 of 22 patients, P < 0.05). Heart rate variability significantly decreased during the treatment, with regard to all parameters, representing both the sympathetic and parasympathetic activity. We conclude that non-selective alpha-blockade significantly decreases the incidence of frequent or repetitive ventricular arrhythmias in patients with phaeochromocytoma, although the lack of QTc interval shortening suggests that the effect of class I drugs may participate in the anti-arrhythmic effects of phenoxybenzamine. Moreover, non-selective alpha-blockade in phaeochromocytoma significantly diminishes vagal activity.

The aim of the study was to investigate endothelin-1 (ET-1) and neuropeptide Y (NPY) plasma concentrations in renal venous blood of hypertensive patients with unilateral renal artery stenosis (URAS). The study was performed in 22 patients with URAS and 18 patients diagnosed as essentially hypertensive. In each subject renal arteriography and renal vein catheterisation was performed. Blood samples for ET-1, NPY and plasma renin activity (PRA) were withdrawn from renal veins and vena cava inferior, and for ET-1 and NPY from the aorta. Patients with URAS were divided in two subgroups according to the renal vein renin ratio. Both in nine patients with URAS and ratio > 1.5 and in 13 patients with URAS and ratio < 1.5, ET-1 and NPY plasma concentrations evaluated in renal venous blood of the ischaemic kidney were not different from those assessed in the contralateral side, in vena cava inferior and in the aorta. In essential hypertension, the mean ET-1 and NPY plasma concentrations of both renal veins were not different from the ET-1 and NPY plasma values assessed in renal vein of stenosed and contralateral side, vena cava and aorta of patients with URAS with and without activation of the renin system. Our study indicates that chronic ischaemia does not affect ET-1 and NPY plasma concentrations in renal venous blood of hypertensive URAS patients both with and without activation of the renin system.

Pheochromocytoma is a unique type of hypertension caused by excessive production of catecholamines by the chromaffin tumor. Pheochromocytoma, a potentially life-threatening disease, is a rare cause of hypertension. The incidence varies from 0.1 to 0.8% of hypertensive population. The author's experience is based on 138 patients treated in one institution from 1956 to 1995. Hormonal activity of pheochromocytoma varies considerably, influencing the pattern, of blood pressure and the clinical symptoms. It is emphasized that different other humoral mechanisms may play a role in the pathophysiology of this type of endocrine hypertension. Biochemical tests and non-invasive localizing methods are essential for the definite diagnosis of pheochromocytoma. A great progress has been made in this respect during the last three decades. Surgical removal of the tumor is the only definite therapy with low morbidity and mortality.

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.

Neuropeptide Y (NPY) is a vasoconstrictor sympathetic cotransmitter and a modulator of adrenergic function whose role in hypertension is yet unknown. We studied the co-release of NPY and noradrenaline (NA) in patients with essential hypertension (13 females, 11 males, age 42 +/- 13 years) by measuring plasma levels of NPY-immunoreactivity (-ir, radioimmunoassay) and NA (radioenzymatic method) following administration of clonidine (CL 300 micrograms, p.o.). At rest, only NPY-ir levels significantly correlated with diastolic blood pressure (DBP, r = 0.42, p < 0.05). Three hours after CL, there were a decrease in mean arterial pressure and plasma NA (by 31 +/- 14 mmHG, p < 0.05 and 92 +/- 10 pg/ml, p < 0.01) but no change in NPY-ir levels. Patients were subsequently subdivided into groups with high (> or = 90 mmHg) or normal DBP (< or = 89 mmHg) and with or without elevated plasma NA levels (above or below 414 pg/ml, a normotensive mean +1 standard deviation). In hypertensives, but not in those with normal DBP, plasma NPY-ir correlated not only with DBP but also with systolic and mean blood pressure (r = 0.53 and r = 0.60, respectively) at rest. Hypertensives with "high" NA had significantly lower resting plasma NPY-ir levels than those with "low" NA (7.1 +/- 3.6 vs 14.7 +/- 6.0 fmol/ml, p < 0.05). In the former group, CL evoked the greatest fall in plasma NA, and also decreased NPY-ir levels by 50% (p < 0.05). Thus, patients with essential hypertension were found to display differential patterns of changes in sympathetic cotransmitters to clonidine. NPY may contribute to the increased blood pressure in hypertensives and together with NA, mediate hypotensive action of clonidine but only in the hyperadrenergic subgroup of hypertensives.

Objective: The purpose of this study was to evaluate the postural stimulation test before and after surgical treatment in patients with aldosterone-producing adenomas., Design: The retrospective study was made on patients with aldosterone producing adenomas., Patients: The postural stimulation test was analysed in 60 patients with surgically proven aldosterone producing adenoma and in 15 healthy volunteers., Measurements: The postural stimulation test was based on measurements of plasma aldosterone, cortisol and renin activity (PRA) at 0800 h and at noon after 4 hours ambulation., Results: The patients were divided into two groups according to the individual pattern of plasma aldosterone concentration following the postural test. Plasma aldosterone concentration decreased or did not change after 4 hours of standing in 42 patients (group 1, 70% of total) and increased in 18 patients (group 2, 30% of total). Mean plasma aldosterone was significantly higher in group 1 than in group 2 (1325 +/- 164 pmol/l (mean +/- SE) and 538 +/- 53 pmol/l, respectively). Mean plasma cortisol concentration after 4 hours of upright posture in both groups remained low (242 +/- 35 vs 401 +/- 63 nmol/l (group 1) and 317 +/- 46 vs 367 +/- 43 nmol/l (group 2)). Mean PRA in both groups was suppressed after 4 hours of upright posture (0.2 +/- 0.04 vs 0.2 +/- 0.04 pmol/l/s and 0.3 +/- 0.06 vs 0.1 +/- 0.02 pmol/l/s, respectively)., Conclusion: Diverse changes in plasma aldosterone and cortisol found in response to the postural test may indicate pathogenetic heterogeneity amongst patients with aldosterone producing adenomas and should be considered during diagnosis of primary aldosteronism.

Background: Endothelin-1 (ET-1) may play an important role in the development and maintenance of hypertensive states. In patients with essential hypertension, ET-1 plasma concentration increases or remains unchanged. The aim of the present study was to investigate ET-1 plasma concentration in patients with mild-to-moderate essential hypertension and its interrelationship with catecholamines, neuropeptide Y and atrial natriuretic peptide (ANP)., Methods: The study included 37 patients (mean age 38.2 +/- 1.6 years) with mild-to-moderate essential hypertension. The control group consisted of 21 healthy volunteers (mean age 35.6 +/- 1.4 years). ET-1, neuropeptide Y and ANP were determined by radioimmunoassay methods and catecholamine plasma concentration was determined radioenzymatically., Results: Our study shows that plasma ET-1 and neuropeptide Y levels are elevated in patients with essential hypertension compared with a control group. No correlation was found in either of the groups between plasma ET-1 level and plasma neuropeptide Y, catecholamine or ANP concentrations., Conclusion: Our results suggest that ET-1 is relevant in the development and maintenance of elevated blood pressure.