Ulrike Schorr

Relationship between angiotensinogen, leptin and blood pressure levels in young normotensive men

Background and aims Although the relationship between an increase in adipose tissue and a rise in blood pressure has long been recognized, the mechanism linking these two phenomena has yet to be fully understood. Recently, it has become evident that adipose tissue is a rich source of metabolically active molecules, including free fatty acids, leptin and angiotensinogen, the precursor of angiotensin II. The latter finding has prompted speculation on the possible role of adipocyte-derived angiotensinogen in the relationship between body weight and blood pressure. Therefore we examined the relationship between blood pressure, angiotensinogen, body mass index (BMI) and leptin levels in healthy normotensive subjects who are genetically predisposed to the development of hypertension. Subjects and methods We studied 40 subjects with a positive family history of hypertension and 51 subjects with a negative family history. After the blood pressure measurements, blood samples were collected for the assessment of angiotensinogen, leptin, glucose, insulin, renin activity and electrolytes. Oral glucose tolerance was studied by an oral glucose tolerance test (75 g glucose). Results Plasma angiotensinogen was significantly correlated with both BMI (r = 0.29, P < 0.01) and plasma leptin (r = 0.40, P < 0.001). While plasma angiotensinogen and blood pressure were positively correlated only in subjects with a positive family history of hypertension (r = 0.33, P < 0.05), plasma leptin was related to blood pressure in both groups (r = 0.26, P = 0.01). Furthermore, the insulin response to an oral glucose load was significantly related to both plasma angiotensinogen (r = 0.22, P < 0.05) and plasma leptin (r = 0.47, P < 0.001). Conclusions These findings support the hypothesis that circulating angiotensinogen levels are related to adipose mass in young, normotensive, nonobese men. Further studies on the relationship between adipose tissue and systemic or local renin-angiotensin systems appear warranted.

Angiotensinogen M235T variant and salt sensitivity in young normotensive Caucasians.

BACKGROUND AND AIMS A single-nucleotide variant of the angiotensinogen gene (AGT 235T) has been associated with essential hypertension and increased plasma levels of angiotensinogen. This variant may also serve as a genetic marker for the increased blood pressure response to dietary salt intake, but the relationship between AGT genotype and salt sensitivity has not been studied until now. We therefore examined the relationship between the AGT 235T genotype and the blood pressure response to short-term dietary salt restriction in young normotensive men. SUBJECTS AND METHODS A total of 187 young normotensive men were characterized for family history of hypertension, salt sensitivity, plasma parameters of the renin-angiotensin system under high- and low-salt diets, and the AGT 235T genotype. RESULTS While the T allele was significantly associated with a positive family history of hypertension (chi2 = 7.0; P< 0.03) and higher plasma angiotensinogen levels (P< 0.015) and renin activity (P < 0.037), blood pressure under both diets was not significantly affected by the AGT genotype. When the subjects were classified into salt-resistant and salt-sensitive groups, genotypic distribution was nearly identical between both groups (frequency of T allele: 0.45 versus 0.46). CONCLUSION Our findings demonstrate that the AGT 235T allele is significantly associated with a positive family history of hypertension, but is not an important determinant of the blood pressure response to dietary salt intake in young normotensive subjects. It is therefore unlikely that the AGT 235T genotype can serve as an early genetic marker of salt sensitivity.

Psychophysiological reactivity of salt-sensitive normotensive subjects.

Objective To evaluate the psychophysiological response to mental stress of young healthy salt-sensitive normotensive subjects. Methods Thirty-two healthy volunteers who had previously been phenotyped for salt sensitivity were selected for the study. The 16 salt-sensitive and 16 salt-resistant subjects, who were matched for age, body mass index and family history of hypertension, underwent a mental stress test consisting of an information-processing task performed under time pressure (the Manometer test). During the experimental session the blood pressure, heart rate and pulse-wave velocity were registered continuously. Before and after the mental task subjects were instructed to complete several standardized psychological state and trait questionnaires. Results Mental stress resulted in a greater rise in blood pressure (P < 0.05) and in pulse-wave velocity (P < 0.01) in salt-sensitive than in salt-resistant individuals. Salt-sensitive subjects also displayed significantly higher levels of anxiety (P < 0.01) and a lower level of control of anger (P < 0.01) than did salt-resistant subjects. Furthermore, the level of irritation of the salt-sensitive subjects was higher both before (P < 0.01) and after (P < 0.05) the stress test. Conclusions An increased responsiveness of the blood pressure to mental stress and an increased level of irritation are associated with salt sensitivity in normotensive subjects. These findings are in line with the hypothesis that psychophysiological traits play a role in the development of salt-sensitive hypertension.

Renal acid-base excretion in normotensive salt-sensitive humans.

Reduced extracellular pH and bicarbonate levels recently have been reported in normotensive salt-sensitive subjects. To assess the possible role of altered renal acid-base handling in the perturbation of acid-base status in these individuals, we measured the renal acid-base excretion after an acute oral administration of either an alkali or acid load in normotensive salt-sensitive and salt-resistant men. Twenty-four young (22 to 29 years old), healthy male volunteers were placed on a low-salt diet (20 mmol NaCl per day) for 2 weeks with either 220 mmol NaCl or placebo added to the low-salt diet for 1 week each in a randomized single-blind crossover order. Salt sensitivity was defined as a significant drop in mean arterial pressure (> 3 mm Hg, mean of 60 readings taken on the seventh day of each diet, P < .05) during the low-salt diet. On the fifth and seventh days of each week, subjects were given an oral load of either sodium citrate (0.7 mmol/kg) or ammonium chloride (2.2 mmol/kg), respectively, in a randomized order, and arterial and urinary acid-base status was assessed at baseline and followed for 8 hours thereafter. According to the above definition, 13 subjects were considered salt sensitive. During the high-salt diet, mean arterial pressure was higher in the salt-sensitive than in the salt-resistant group (P < .01). Cumulative urinary bicarbonate excretion after the administration of sodium citrate was lower in the salt-sensitive than in the salt-resistant subjects during both the low-salt (46%, P < .001) and high-salt (32%, P < .01) diets.(ABSTRACT TRUNCATED AT 250 WORDS)

Hpa II polymorphism of the atrial natriuretic peptide gene and the blood pressure response to salt intake in normotensive men.

Objective To test the hypothesis that the Hpa II variant of the atrial natriuretic peptide gene (ANP), which has been reported to be more common among black hypertensives than it is among normotensive controls, is related to the response of blood pressure to salt intake in normotensive Caucasians. Methods One hundred and three young (aged 19–35 years) male volunteers were fed a low-salt diet (20 mmol NaCl/day) for 2 weeks and a supplement of either 200 mmol NaCl/day (slow sodium) or placebo for 1 week each in a randomized double-blind cross-over order. Salt sensitivity was defined as a significant (P < 0.05) decrease in resting mean arterial blood pressure by > 3 mmHg under the low-salt diet. The genotype was determined by amplification of genomic DNA extracted from peripheral leukocytes and subsequent digestion of the amplicon with Hpa II restriction enzyme. Results According to the above definition, 27 subjects were salt sensitive. There were no significant differences in age, body-mass index and waist: hip ratio between the salt-sensitive and salt-resistant groups. Only salt-sensitive subjects displayed a significantly higher blood pressure under the high-salt diet (increase in mean arterial pressure 5.6 ± 2.4 mmHg, P < 0.001). The prevalence of the ANP-Hpa II wild-type (w) allele did not differ between the salt-sensitive (qw = 1.0, qm = 0) and the salt-resistant group (qw = 0.96, qm = 0.04). Furthermore, the salt-induced response of blood pressure did not differ between homozygotes (ww) and heterozygotes (wm). Conclusions Our findings do not support the hypothesis that the ANP-Hpa II polymorphism is a marker for salt sensitivity in young Caucasian normotensives.

G-protein β3 subunit 825T allele and response to dietary salt in normotensive men

Background and aims A functional single-nucleotide variant of the gene encoding the β3 subunit of heterotrimeric G proteins (Gβ3 C825T), associated with enhanced G-protein activation and increased activity of the sodium-proton exchanger (NHE1), has been implicated in the development of hypertension. Given the possible involvement of NHE1 in sodium homeostasis, we tested the hypothesis that the Gβ3 825T allele determines the response of the renin-angiotensin system and blood pressure to dietary salt restriction. Methods Young normotensive men (20–30 years old, n = 193) were recruited within the framework of the Berlin Salt-Sensitivity Trial and studied on low- (20 mmol/day) and high-salt (220 mmol/day) dietary protocols. Subjects were characterized for parameters of the renin-angiotensin system and blood pressure response and genotyped for the Gβ3 C825T polymorphism. Results The genotype distribution was in Hardy-Weinberg equilibrium (CC = 90, CT = 81 and TT = 22). The responses of the renin-angiotensin system and blood pressure to the dietary protocol were virtually identical between the genotypic groups. Furthermore, when subjects were classified as salt-resistant (n = 145) or salt-sensitive (n = 48), genotype distribution was comparable between the two groups (salt-resistant: TT = 17, CT = 60, CC = 68, qT = 0.32; salt-sensitive: TT = 5, CT = 21, CC = 22, qT = 0.32). Conclusion These findings do not support the hypothesis that the Gβ3 C825T polymorphism determines the response of the renin-angiotensin system to salt depletion or can serve as an early genetic marker of salt sensitivity in young normotensive men.

Salt-sensitivity and other predictors of stress-related cardiovascular reactivity in healthy young males.

Individuals whose mean arterial blood pressure is depending on oral salt intake are considered salt-sensitive and are at risk of developing essential hypertension. This study investigates the role of salt-sensitivity with respect to systolic blood pressure reactions under standardized mental stress. Forty-three healthy young males, previously characterized as salt-sensitive (n=16) or salt-resistant (n=27) by a dietary regimen, were subjected to multimodal physiological measurement during a computerized stress test and underwent comprehensive psychometrical testing. The most important predictors for systolic blood pressure reactions to stress were the degree of salt-sensitivity, body mass index and psychological characteristics like anxiety. The highest correlations with the degree of salt-sensitivity were found for the parameters age, systolic blood pressure reaction under stress, high frequency band of heart rate variability and two psychological variables. The concept of salt-sensitivity is a novel biological component that might contribute to reactivity research in subjects at high risk for essential hypertension.

Relationship between ambulatory and resting blood pressure responses to dietary salt restriction in normotensive men

Objective To examine the relationship between changes in resting and ambulatory blood pressures induced by dietary salt restriction in 90 young normotensive men. Methods Subjects were given a standardized low-salt diet containing 20 μmol sodium chloride per day for 14 days. To this diet, a daily supplement of 20 tablets of slow sodium (10 μmol NaCl per tablet) or placebo was added in a randomized single-blind cross-over fashion for 7 days. The ambulatory blood pressure was measured on the sixth day and the resting blood pressure was measured on the seventh day of each dietary period. Results Although salt intake did not affect blood pressure levels in the whole group, the response of the blood pressure was quite variable among individual subjects. Salt-induced changes in resting systolic (r = 0.30, P = 0.006) and mean (r = 0.27, P = 0.014) blood pressures, but not diastolic blood pressure, were correlated positively to changes in daytime ambulatory blood pressure. The changes in resting systolic and mean blood pressures were also correlated significantly to the nocturnal falls in systolic (r = 0.26, P = 0.015) and mean (r = 0.27, P = 0.012) blood pressure levels and heart rate (r = 0.26, P = 0.015) under the high-salt diet. Diet-induced changes in resting mean blood pressure were correlated significantly to the daytime ambulatory blood pressure (r = 0.30, P < 0.005) and the resting heart rate (r = 0.24, P < 0.02) under the high-salt diet. Conclusion Salt-induced changes in resting blood pressure in young normotensive men are correlated positively to changes in ambulatory daytime blood pressure levels as well as to the daytime ambulatory blood pressure and the nocturnal fall in blood pressure under a high-salt diet. These findings suggest that dietary salt-intake restriction can lower both resting and daytime ambulatory blood pressure levels in some normotensive individuals who may be predisposed to the development of hypertension.

Effect of dietary salt restriction on urinary serotonin and 5-hydroxyindoleacetic acid excretion in man.

Objective: To determine the effect of dietary salt restriction on urinary excretion of serotonin and its principal metabolite 5-hydroxyindoleacetic acid (5-HIAA) in man Design: We studied 16 healthy male volunteers (age range 20-28 years) who ate a standard diet containing 20mmol/day NaCl, to which either 220mmol/day NaCl or placebo was added as a supplement for 1 week each, according to a randomized, single-blind crossover design Methods: Urinary excretion of serotonin, 5-HIAA, noradrenaline and vanillylmandelic acid (VMA) were measured during the low- and high-salt periods using reverse-phase high-performance liquid chromatography Results: During the low-salt diet, 24-h urinary excretion of serotonin increased by 42%, accompanied by a 52% rise in the excretion of 5-HIAA. Salt restriction also increased noradrenaline excretion by 77% and VMA excretion by 40%. Regression analysis revealed a strong positive relationship between the excretion of serotonin and of noradrenaline (r=0.84, P< 0.001) and between that of 5-HIAA and of VMA (r=0.74, P< 0.001) Conclusions: Salt restriction stimulates the serotonergic system in man. Stimulation of this system, in conjunction with the sympathetic nervous system, may contribute to renal sodium conservation during dietary salt restriction in man

Identification of a Renin Threshold and Its Relationship to Salt Intake in a Patient With Pure Autonomic Failure

Animal studies have demonstrated a threshold below which renin release increases proportionally to a decrease in renal perfusion pressure. Demonstration of a similar mechanism in humans, however, has proved difficult, as any attempt to lower blood pressure below the putative renin threshold results in renin release mediated by reflex activation of the sympathetic nervous system. In this study, we report on our observations in a 71-year-old woman who presented with a 20-year history of faintness and syncope and was diagnosed as having pure autonomic failure. Graded head-up tilting resulted in a stepwise reduction in mean arterial blood pressure to a minimum of 54 mm Hg, with no signs of increased sympathetic activity. A fall in blood pressure below 80 mm Hg resulted in a distinct rise in plasma renin activity, and a similar threshold pressure was observed under both a 50- and a 100-mmol/d sodium chloride diet. Below the threshold, response to changes in perfusion pressure was proportionally greater under the 50-mmol/d diet than under a 100- or 200-mmol/d diet. These observations demonstrate that a pressure threshold for renin release at 10 to 15 mm Hg below ambient blood pressure, as described previously in animal studies, is also present in humans. The significance of this pressure-dependent mechanism of renin release for the long-term regulation of blood pressure and water and mineral balance in humans remains to be determined.