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OBJECTIVE: Tumor necrosis factor-α (TNF-α) is expressed primarily in adipocytes, and elevated levels of this cytokine have been linked to obesity and insulin resistance. Recently, the A allele of a polymorphism in the 5'-flanking region of the TNF-α gene (G-308A) has been reported to be more frequent in obese than in lean subjects and has also been associated with increased expression of this cytokine in fat tissue and influences fat mass and insulin resistance. We, therefore, examined the relationship between this variant and obesity in a German Caucasian population. SUBJECTS AND METHODS: We genotyped 176 index subjects recruited within the framework of the BErG (Berlin Ernährung Geschwister)- Study for the TNF-α-G-308A polymorphism. Subjects were characterized for weight, height, waist and hip circumference, body mass index (BMI), body composition, glucose tolerance, leptin and angiotensinogen levels. RESULTS: The frequency of the -308A allele (0.18) was similar to that reported previously and genotype distribution was in Hardy-Weinberg equilibrium (GG, n = 118; GA, n = 53; AA, n = 5). There was a significant difference in allele frequencies of the polymorphism by BMI quartiles (I, < 27.3 kg/m²; II, 27.3-31.9 kg/m²; III, 31.9-36.5 kg/m²; IV, > 36.5 kg/m², in each quartile n = 44) with -308A allele carriers having a higher BMI than G allele carriers (P = 0.013). Despite previous smaller studies that have related insulin resistance to the G-308A polymorphism, we found no relationship between glucose and insulin response during an oral glucose tolerance test (OGTT) and the polymorphism. Furthermore, none of the plasma parameters were related to the polymorphism. CONCLUSION: Our findings support the hypothesis that the G-308A polymophism of the TNF-α gene is associated with BMI. The G-308A polymorphism may, therefore, represent a genetic marker for increased susceptibility for obesity in Caucasians. [ABSTRACT FROM AUTHOR]

Salt-sensitive normotensive men exhibit an enhanced pressor response to mental stress. Although an enhanced pressor response is associated with higher affective startle modulation in men, an association between salt sensitivity of blood pressure and affective startle modulation has not been studied so far. We studied reactivity to mental stress and startle modulation in 14 salt-sensitive healthy white male students and 14 salt-resistant control subjects, who were well matched for age, body mass index, physical fitness, and family history of hypertension. Subjects performed a computerized information-processing task under time pressure (manometer test), while heart rate and blood pressure were continuously registered. In a separate session, subjects viewed a series of 42 pictures of the International Affective Picture System (IAPS), varying in pleasure and arousal, while acoustic startle probes were administered randomly, and electromyogram activity of the orbicular eye muscle was continuously recorded. Startle modulation was calculated as the difference between startle responses under negative and positive affective stimuli. In contrast to salt-resistant subjects, salt-sensitive subjects showed significantly enhanced startle amplitudes under negative stimuli and diminished amplitudes under positive stimuli. Thus, salt-sensitive subjects displayed a significantly higher startle modulation than did salt-resistant subjects (P<0.05). Subjective ratings of the presented IAPS pictures did not differ between the groups. The increased startle modulation of salt-sensitive subjects suggests an enhanced activity of the central nucleus of the amygdala. This enhanced central nervous responsiveness may contribute to higher sympathetic pressor reactivity and, thus, to the later development of hypertension in salt-sensitive individuals.

The course of energy expenditure after a meal can vary widely with regard to the slope of onset, amplitude, and duration of the thermic effect. The aim of the present study was to explore the relationship between the thermic effect of food (TEF), as characterized by kinetic analysis of postprandial energy expenditure, body composition, and variables related to the metabolic syndrome including central obesity, hypertension, and glucose tolerance. A total of 181 men and women (body mass index [BMI] range, 19.4 to 52.2 kg/m2) were characterized for body composition, blood pressure, oral glucose tolerance, and energy expenditure after a test meal. Energy expenditure, as measured by indirect calorimetry, was analyzed over a 6-hour period by 3-parameter curve fitting using equations derived from kinetics describing a biphasic reaction involving 2 consecutive first-order reactions (A-->B-->C). Apart from total thermic effect of food (TEFk), the curve also provided an estimate of time of peak (Tp) and amplitude of peak (Ap) for each subject. Multiple stepwise regression analysis with TEFk, Ap, and Tp as dependent variables showed significant effects of sex, age, body weight, body fat, beta-blockade, and body composition on TEF curve parameters. Cluster analysis based on Tp shown 2 distinct clusters with significant differences in age and body fat mass. This study shows that kinetic analysis of postprandial energy expenditure can be used to examine the determinants of the time course of the thermic effect of food in man.

There is substantial evidence that obesity is a prime risk factor for the development of hypertension. Although hyperinsulinemia and an increased activity of the sympathetic nervous system have been implicated in the pathogenesis of "obesity hypertension," their effects on energy metabolism have not been studied thus far. In the present study, we therefore examined resting metabolic rate (RMR) and basal substrate oxidation in subjects with obesity and obesity-related hypertension. A total of 166 subjects were characterized for RMR and basal substrate use through indirect calorimetry. Blood pressure was measured at rest and with 24-hour ambulatory monitoring. Blood samples were collected for the measurement of plasma catecholamines, leptin, and the insulin response to an oral glucose load. In our study population, 116 subjects were defined as hypertensive and 91 were defined as obese. Hypertensive patients under beta-adrenergic blockade (n=42) had a significantly lower RMR than did patients without beta-blockade (P<0. 05) and were therefore excluded from further analyses. Univariate regression analysis revealed a significant relationship between RMR and body fat mass, as well as body fat-free mass, in both groups. Compared with obese normotensive control subjects (n=27), obese hypertensives (n=43) had a 9% higher RMR (P<0.05), higher plasma catecholamine (P<0.05) and leptin (P<0.05) levels, and an increased insulin response to oral glucose (P<0.01). Together, these findings are compatible with the idea that chronic neurogenic and metabolic adaptations related to obesity may play a role in the development of obesity hypertension in susceptible individuals.

Background: Dietary salt restriction is currently widely recommended as an important non-pharmacological measure for the treatment of hypertension. However, the relationship between dietary salt intake and post-transplant hypertension has not been extensively investigated., Patients and Methods: We examined the relationship between dietary salt intake and the prevalence of hypertension in 129 renal transplant patients with stable allograft function (serum creatinine < 400 micromol/l, variation in serum creatinine during the preceding two months < 20%). Salt intake was assessed by measuring 24-hour urinary excretion of sodium on an unrestricted diet. Hypertension was defined based on the prescription of antihypertensive medication, and the number of antihypertensive drugs was considered a surrogate marker for severity of hypertension. Patients were divided into tertiles based on urinary sodium excretion and analyzed by chi2-testing., Results: The prevalence of hypertension was 74% and the mean sodium excretion was 178 mmol/d (range: 56 to 603). There was no statistical difference in the frequency of antihypertensive medication between patients with low (76%, UNa = 107 mmol/d), medium (73%, UNa = 178 mmol/d), or high sodium (73%, UNa = 272 mmol/d) excretion. Furthermore, the number of antihypertensive drugs (in treated patients) was similar between the tertiles. There was also no correlation between urinary sodium excretion and systolic (r = -0.05) or diastolic (r = 0.08) blood pressure levels., Conclusion: We conclude that dietary salt intake in transplant patients with stable allograft function is higher than currently recommended. There is, however, no relationship between salt intake and the prevalence of hypertension in these patients. These data do not support the hypothesis that the prevalence or severity of post-transplant hypertension is markedly affected by dietary salt intake.

Salt-sensitive subjects (SS) increase their blood pressure with increasing salt intake. Because steroid hormones modulate renal sodium retention, we hypothesize that the activity of the 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) enzyme is impaired in SS subjects as compared with salt-resistant (SR) subjects. The 11betaHSD2 enzyme inactivates 11-hydroxy steroids in the kidney, thus protecting the nonselective mineralocorticoid receptor from occupation by glucocorticoids. We performed an association study using a recently identified single AluI polymorphism in exon 3 and a polymorphic microsatellite marker of the HSD11B2 gene in 149 normotensive white males (37 SS and 112 SR). The activity of the enzyme 11betaHSD2 was assessed by determining the urinary ratio of cortisol (THF+5alphaTHF) to cortisone (THE) metabolites by gas chromatography in all the 37 SS subjects and in 37 age- and body habitus-matched SR volunteers. Mean (THF+5alphaTHF)/THE ratio was markedly elevated in SS subjects compared with SR subjects (1.51 +/- 0.34 vs. 1.08 +/- 0.26, P < 0.00001), indicating enhanced access of glucocorticoids to the mineralocorticoid receptor in SS subjects. In 58% of SS subjects this ratio was higher than the maximum levels in SR subjects. The salt-induced elevation in arterial pressure increased with increasing (THF+5alphaTHF)/THE ratio (r2 = 0.51, P < 0.0001). A total of 12 alleles of the polymorphic microsatellite marker were detected. Homozygosity for the allele A7 was higher in SS subjects than in SR subjects (41 vs. 28%, P < 0.005), whereas the occurrence of the allele A7 with allele A8 was lower in SS subjects than in SR subjects (8 vs. 15%, P < 0.03). The prevalence of salt sensitivity was 35% in subjects with allele A7/A7, whereas salt sensitivity was present in only 9% of the subjects with allele A7/A8. The (THF+5alphaTHF)/THE ratio was higher in subjects homozygous for the A7 microsatellite allele as compared with the corresponding control subjects. The prevalence of the AluI allele was 8.0% in SR subjects and 5.4% in SS subjects and did not correlate with blood pressure. The decreased activity of the 11betaHSD2 in SS subjects indicates that this enzyme is involved in salt-sensitive blood pressure response in humans. The association of a polymorphic microsatellite marker of the gene with a reduced 11betaHSD2 activity suggests that variants of the HSD 11B2 gene contribute to enhanced blood pressure response to salt in humans.

Personality traits such as anxiety and anger have long been associated with essential hypertension. However, the results of past studies have been criticised for selection bias, and it has not been clarified whether psychological traits are causes or consequences of high blood pressure. We studied emotional state and trait patterns and reactivity to mental stress in 16 healthy salt-sensitive volunteers at genetic risk of developing hypertension, and a well-matched control group. We have previously reported increased blood pressure reactivity to mental stress in those individuals. In this paper, we present the results of several standardized psychological questionnaires in which salt-sensitive individuals displayed increased anxiety (p < 0.01), emotional irritation (p < 0.01) and a lower level of anger control (p < 0.01). Thus, an elevated level of anxiety and irritation, as well as an increased blood-pressure response to mental stress may play a role in the development of salt-sensitive hypertension.

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.

Objective: To examine the effect of sodium chloride- and sodium bicarbonate-rich mineral water on blood pressure and parameters of glucose and lipid metabolism in elderly normotensive individuals., Methods: We examined 21 healthy men and women aged 60-72 years in a randomized, placebo-controlled, double-blind crossover trial. After reducing dietary salt intake to below 100 mmol/day, study participants were randomly assigned to drink 1.5 l daily of a sodium chloride-rich (sodium 84.5 mmol/l, chloride 63.7 mmol/l, bicarbonate 21.9 mmol/l), a sodium bicarbonate-rich (sodium 39.3 mmol/l, chloride 6.5 mmol/l, bicarbonate 48.8 mmol/l) and a low-sodium (placebo: sodium, chloride and bicarbonate < 0.02 mmol/l) mineral water for 4 weeks each in a three-phase crossover order. Each phase was separated by a 2-week washout period in which the study participants remained on a low-salt diet. Compliance was assessed by biweekly urinary electrolyte excretion and five study participants were excluded from analysis for failing to complete the trial or to fulfil the compliance criteria., Results: Mean arterial blood pressure was significantly lower during the periods of consuming low-sodium -7.0 +/- 7.2 mmHg, P < 0.001) or sodium bicarbonate-rich (-5.7 +/- 6.4 mmHg, P < 0.05) water than at baseline. In contrast, blood pressure during the phase of drinking sodium chloride-rich water was identical to that at baseline. Ambulatory 24 h blood pressure, oral glucose tolerance and plasma lipids were not affected by the different regimens. Urinary calcium excretion was significantly reduced by drinking low-sodium or sodium bicarbonate-rich water but was unchanged under the sodium chloride-rich water., Conclusion: Consumption of sodium chloride-rich mineral water can abolish the blood pressure reduction induced by dietary salt restriction in elderly individuals. Sodium bicarbonate-rich mineral water in conjunction with a low-salt diet may have a beneficial effect on calcium homeostasis.

Salt sensitivity is not only found in patients with essential hypertension but also in normotensive individuals. These salt-sensitive normotensives are believed to be genetically predisposed to the development of hypertension. In this paper we present data from our studies in such normotensive salt-sensitive individuals, thereby focusing on the relationship between salt sensitivity and familial history of hypertension and on insulin sensitivity. Salt-sensitivity was associated with a positive familial history of hypertension, a finding that supports the hypothesis that salt sensitivity in normotensive individuals points to a genetic predisposition for the development of hypertension. Also, salt-sensitive subjects displayed a hyperinsulinaemic response to an oral glucose load and a decreased insulin-mediated glucose disposal, as assessed by the insulin suppression test. The latter finding implies that insulin resistance is present in otherwise healthy, hypertension-prone individuals before overt hypertension develops. Assuming that there is a pathophysiological relationship between insulin resistance and salt sensitivity, our findings suggest that early recognition of insulin resistance and the implementation of measures aimed at improving insulin sensitivity could contribute to the prevention of cardiovascular disease in these individuals.

The purpose of this study was to compare the blood pressure response to two commonly used protocols for the assessment of salt sensitivity in normotensive men, involving either the rapid intravenous administration of a saline load followed by diuretic-induced salt depletion, or the more physiologic but time-consuming approach involving dietary salt depletion and repletion. Twenty-two healthy male volunteers (22-35 years old) were given a saline load (2 L of 0.9% NaCl over 4 h, i.v.), and on the following day, a low-salt diet (20 mmol NaCl) and furosemide (3 x 40 mg, po). Resting mean arterial blood pressure (MABP) was assessed after the saline load and on the morning following salt depletion. After a 2-week wash-out period, subjects were given a low-salt diet (20 mmol/day NaCl) for 2 weeks, supplemented by either 220 mmol/day NaCl or placebo for 1 week each. At the end of each week, resting MABP was assessed in the supine subjects. Although MABP changes were quite variable (iv, mean -2.1 mm Hg; range, -9.1 to +5.6; diet, mean -2.0 mm Hg; range, -14.3 to +7.2), there was a significant correlation between the salt-induced changes in MABP (r = 0.56, P < .01) and diastolic blood pressure (r = 0.56, P < .01) between the two protocols. However, in individual subjects, blood pressure response to the intravenous protocol did not uniformly predict the blood pressure response to the dietary protocol.(ABSTRACT TRUNCATED AT 250 WORDS)

The blood pressure-raising effect of sodium chloride in salt-sensitive individuals depends on the administration of both sodium and chloride. While sodium chloride is well known to suppress the activity of the renin-angiotensin-aldosterone and the sympathetic nervous system, the effects of nonchloride sodium salts on the response of these systems to physiological stimuli have not been previously studied. We therefore examined the effect of dietary intake of sodium chloride or sodium citrate on the activity of the renin-angiotensin-aldosterone and the sympathetic nervous system during rest and following stimulation by active orthostasis in normotensive salt-sensitive (n = 7) and salt-resistant (n = 8) subjects. The subjects were given a low-salt diet (20 mmol/day) for 3 weeks, to which a supplement of 200 mmol sodium per day, provided as either sodium chloride or sodium citrate, or a placebo, was added for 1 week each. We found that sodium chloride raised blood pressure in the salt-sensitive subjects (P < .005), while sodium citrate did not. Both salts, however, led to a similar suppression of the plasma levels of renin activity, angiotensin II, aldosterone, and norepinephrine (P < .01). Both sodium salts attenuated the renin response to orthostasis in salt-sensitive and salt-resistant individuals (P < .01), but the orthostasis-induced rise in renin activity was significantly smaller in the salt-sensitive than in the salt-resistant group under both sodium salts (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)