Dynamic genetic linkage of intermediate blood pressure phenotypes during postural adaptations in a founder population.

Blood pressure (BP) is a dynamic phenotype that varies rapidly to adjust to changing environmental conditions. Standing upright is a recent evolutionary trait, and genetic factors that influence postural adaptations may contribute to BP variability. We studied the effect of posture on the genetics of BP and intermediate BP phenotypes. We included 384 sib-pairs in 64 sib-ships from families ascertained by early-onset hypertension and dyslipidemia. Blood pressure, three hemodynamic and seven neuroendocrine intermediate BP phenotypes were measured with subjects lying supine and standing upright. The effect of posture on estimates of heritability and genetic covariance was investigated in full pedigrees. Linkage was conducted on 196 candidate genes by sib-pair analyses, and empirical estimates of significance were obtained. A permutation algorithm was implemented to study the postural effect on linkage. ADRA1A, APO, CAST, CORIN, CRHR1, EDNRB, FGF2, GC, GJA1, KCNB2, MMP3, NPY, NR3C2, PLN, TGFBR2, TNFRSF6, and TRHR showed evidence of linkage with any phenotype in the supine position and not upon standing, whereas AKR1B1, CD36, EDNRA, F5, MMP9, PKD2, PON1, PPARG, PPARGC1A, PRKCA, and RET were specifically linked to standing phenotypes. Genetic profiling was undertaken to show genetic interactions among intermediate BP phenotypes and genes specific to each posture. When investigators perform genetic studies exclusively on a single posture, important genetic components of BP are missed. Supine and standing BPs have distinct genetic signatures. Standardized maneuvers influence the results of genetic investigations into BP, thus reflecting its dynamic regulation.

Salt-sensitive hypertension: contribution of chloride.

The effect of the anion associated with sodium loading on the development of hypertension in the Dahl salt-sensitive rat was determined. For 5 weeks rats were fed a diet containing normal or high concentrations of sodium chloride or high concentrations of sodium provided as a mixture of sodium bicarbonate, phosphate, and amino acids. After 1 week on these diets and until the end of the study the rats receiving high concentrations of sodium chloride had higher systolic blood pressures than the rats in the other two groups. There were no statistically significant group differences in plasma volume, arterial pH, or plasma concentrations of Na+, K+, Cl-, Ca2+, or creatinine, or in renomedullary prostaglandin E2 production. Compared to the animals receiving normal concentrations of sodium chloride, those receiving high concentrations of sodium chloride or amino acids showed decreased plasma renin activity and plasma aldosterone concentrations. Thus, the anion ingested with sodium alters the development and severity of hypertension in the Dahl salt-sensitive rat.

Effect of acute and chronic calcium administration on plasma renin.

To evaluate the effect of Ca(++) on renin release, plasma renin activity (PRA) was measured after acute and chronic Ca(++) administration. 1% CaCl(2) was infused into one renal artery of 10 anesthetized dogs (0.3 mg/kg/min). The excreted fraction of filtered calcium (EF(ca++)) and EF(Na+) from the infused kidney were elevated (P < 0.04) during three successive 15-min infusion periods. Serum calcium concentration was significantly elevated (P < 0.001). Creatinine clearance, systemic arterial pressure, and renal blood flow did not change (P > 0.10). Compared to control (45 ng/ml/h+/-5.2 SE), renal venous PRA was suppressed (P < 0.0001) after infusion of Ca(++) for 15, 30, and 45 min (20 ng/ml/h+/-4.6, 16 ng/ml/h+/-4.0, and 13 ng/ml/h+/-2.7, respectively). 15 and 30-min after infusion, PRA did not differ from control (P > 0.20). Chronic Ca(++) loading was achieved in Sprague-Dawley rats by replacing drinking water with 1% CaCl(2) for 17 days. At sacrifice, serum Ca(++), Na(+), and K(+) of controls (n = 12) did not differ (P > 0.60) from Ca(++)-loaded rats (n = 12). Ca(++) excretion (467 mueq/24 h+/-51) was elevated (P < 0.001) compared to controls (85 mueq/24 h+/-12). PRA (8.6 ng/ml/h+/-1.4) and renal renin content of Ca(++)-loaded rats did not differ from controls (P > 0.80). However, after 8 days of sodium deprivation, both PRA and renal renin content of calcium-loaded animals were significantly lower than the respective values in pair-fed controls (P < 0.005). During the period of sodium deprivation, calcium-drinking animals were in greater negative sodium balance than controls (P < 0.005). The data are consistent with the hypothesis that acute and chronic calcium administration inhibit renin secretion.

Distribution of renin activity and angiotensinogen in rat brain. Effects of dietary sodium chloride intake on brain renin.

The purpose of this study was to investigate the biochemistry and the regulation of the brain renin-angiotensin system in the Sprague-Dawley rat. Renin activity and angiotensinogen concentrations (direct and indirect radioimmunoassays) were measured in several brain areas and in neuroendocrine glands. Regional renin activities were measured in separate groups of rats on high and low NaCl diets. Mean tissue renin activities ranged from 2.2 +/- 0.6 to 54.4 +/- 19.7 fmol/mg protein per h (mean of 7 +/- SD), with the highest amounts in pineal, pituitary, and pons-medulla. NaCl depletion increased renin activity in selected regions; based on estimates of residual plasma contamination (despite perfusion of brains with saline), increased renin activity of pineal gland and posterior pituitary was attributed to higher plasma renin. To eliminate contamination by plasma renin, 16-h-nephrectomized rats were also studied. In anephric rats, NaCl depletion increased renin activity by 92% in olfactory bulbs and by 97% in anterior pituitary compared with NaCl-replete state. These elevations could not be accounted for by hyperreninemia. Brain renin activity was low and was unaffected by dietary NaCl in amygdala, hypothalamus, striatum, frontal cortex, and cerebellum. In contrast to renin, highest angiotensinogen concentrations were measured in hypothalamus and cerebellum. Overall, angiotensinogen measurements with the direct and the indirect assays were highly correlated (n = 56, r = 0.96, P less than 0.001). We conclude that (a) NaCl deprivation increases renin in olfactory bulbs and anterior pituitary of the rat, unrelated to contamination by plasma renin; and (b) the existence of angiotensinogen, the precursor of angiotensins, is demonstrated by direct radioimmunoassay throughout the brain and in neuroendocrine glands.

Influence of alterations in loading produced by lower body negative pressure on aortic blood flow acceleration.

The objectives of this study were to evaluate the effects of alterations in loading induced by lower body negative pressure on aortic blood flow velocity and acceleration. Twenty-seven normal men were studied during various levels of lower body negative pressure (0 to -60 mm Hg) during which echocardiographic, Doppler and hormonal measurements were obtained. Lower body negative pressure induced a decrease in left ventricular diastolic diameter from 5.18 +/- 0.08 to 4.41 +/- 0.1 cm (p less than 0.0001) and in left ventricular systolic diameter from 3.33 +/- 0.09 to 2.84 +/- 0.1 cm (p less than 0.0001). Shortening fraction remained unchanged. The decrease in diastolic diameter resulted in a reduction in flow velocity integral from 13.8 +/- 0.8 to 7.5 +/- 0.4 cm (p less than 0.0001) and, therefore, in stroke volume from 89.6 +/- 4.7 to 49.5 +/- 2.8 ml (p less than 0.0001). Heart rate reflexly increased from 62.5 +/- 1.9 to 82.2 +/- 2.3 beats/min (p less than 0.0001) as did systemic vascular resistance from 1,280.8 +/- 69.5 to 1,863.4 +/- 121.4 dyne.s.cm-5 (p less than 0.0001). The increase in heart rate was insufficient to maintain cardiac output, which decreased from 5.53 +/- 0.29 to 3.99 +/- 0.21 liters/min (p less than 0.0001). Systolic, diastolic and mean arterial blood pressure was maintained. The negative pressure resulted in a concomitant significant increase in norepinephrine levels from 1.46 +/- 0.09 to 2.056 +/- 0.2 nmol/liter (p = 0.0019) but no change in plasma epinephrine: 0.845 +/- 0.22 to 0.78 +/- 0.11 nmol/liter (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction of left ventricular preload by lower body negative pressure alters Doppler transmitral filling patterns.

The objective of this study was to evaluate the effect of alterations in preload induced by lower body negative pressure on Doppler transmitral filling patterns. Echocardiograms and Doppler recordings were performed in 18 normal young men (aged 23 to 32 years) during various levels of lower body negative pressure (0, -20 and -50 mm Hg). Lower body negative pressure induced a reduction in diastolic velocity integral (from 12.17 +/- 0.79 to 8.42 +/- 0.71 cm, p = 0.0067) and consequently left ventricular diastolic diameter (from 5.11 +/- 0.09 to 4.45 +/- 0.1 cm, p less than 0.0001). There was a significant reflex increase in heart rate from 59.9 +/- 1.9 to 77.1 +/- 2.4 beats/min (p less than 0.0001), but blood pressure was unchanged. This reduction in preload altered Doppler transmittral filling patterns as follows: 1) peak early velocity (E) decreased from 59.2 +/- 3.8 to 39.1 +/- 1.7 cm/s (p less than 0.0001); 2) atrial filing velocity (A) was unchanged (35.58 +/- 1.5 to 33.52 +/- 1.4 cm/s, p = 0.517); 3) E/A ratio decreased from 1.7 +/- 0.13 to 1.19 +/- 0.08 (p = 0.0087); 4) mean acceleration (from 482 +/- 37 to 390 +/- 27 cm/s2, p = 0.03) and mean deceleration (from 327 +/- 31 to 169 +/- 21 cm/s2, p less than 0.001) of the early filling wave were significantly reduced; and 5) peak acceleration (from 907 +/- 42 to 829 +/- 29 cm/s2) and peak deceleration (from 771 +/- 94 to 547 +/- 76 cm/s2) also decreased, but not significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Antithyroid drugs and radioactive iodine. Fifteen years' experience with Graves' disease.

The population for this study included 186 patients who were treated between 1962 and 1977 for diffuse toxic goiter. Patients were divided into two groups according to the primary mode of therapy, which was either thioamides or sodium iodide I 131. Of 96 patients who were treated with primary drug therapy, only 16% experienced a prolonged remission (more than two years) of hyperthyroidism. Except for a greater likelihood of remission among patients with mild hyperthyroidism, no other clinical features of Graves' disease were predictive of the long-term response to drug therapy. Among the 90 patients who received primary sodium iodide I 131 therapy, those who were pretreated with thioamides required a higher total dose to achieve a cure (13.8 mCi vs 9.6 mCi) and had a lower initial incidence of hypothyroidism (54% vs 73%).

Hyperprolactinemia--a review of recent clinical advances.

Since the radioimmunoassay for serum prolactin became available eight years ago, prolactin has become a hormone of considerable clinical interest. An elevated serum prolactin concentration is the most frequent hormone marker for pituitary tumors. Secreted in excess, prolactin causes dysfunction of the hypothalamic-pituitary axis, the gonads, and the adrenal cortex. In women, menstrual disturbances, galactorrhea, infertility, and hirsutism result. Impotence, oligospermia, and decreased libido are common in men. These metabolic abnormalities attributed to prolactin excess are corrected when prolactin concentrations are lowered by either medical or surgical therapy. The availability of effective therapy mandates early recognition and proper management of the patient with hyperprolactinemia.

Impact of diet on blood pressure and age-related changes in blood pressure in the US population: analysis of NHANES III.

BACKGROUND: The impact of diet on blood pressure and the age-related changes in blood pressure have been difficult to detect within one population. We designed this analysis to study the association of major dietary factors with blood pressure and with age-related changes in blood pressure in a representative sample of the US population. METHODS: Data were obtained on all individuals 20 years or older (n = 17 030) surveyed in the Third National Health and Nutrition Examination Survey (NHANES III), including demographic data, anthropometric data, dietary intake (sodium, potassium, calcium, magnesium, protein, alcohol, and total energy) based on 24-hour recall, and blood pressure. Multivariate models relating diet to blood pressure were constructed using stepwise regression, best subset regression, and multiple regression. RESULTS: Systolic blood pressure was positively associated with higher sodium, alcohol, and protein intakes (P<.05) and negatively associated with potassium intake (P =.003). Diastolic blood pressure was negatively associated with potassium and alcohol intakes (P<.001). Pulse pressure was positively associated with sodium, protein, and alcohol intakes (P<.001). A higher intake of calcium (P =.01) was associated with a lower rate of rise in systolic blood pressure with age. CONCLUSION: A diet low in sodium, alcohol, and protein is associated with lower systolic blood and pulse pressure. Potassium intake was associated with lower systolic and diastolic blood pressure, whereas alcohol intake was associated with lower diastolic blood pressure. In addition, the age-related changes in systolic blood pressure were attenuated by higher calcium and protein intakes. Magnesium was not associated with any changes in blood pressure.

Peripheral beta-receptor responsiveness in patients with essential hypertension.

Peripheral beta-adrenergic receptor sensitivity was characterized in 24 patients with essential hypertension and in 13 age-matched normotensive subjects using an isoproterenol hydrochloride bolus dose-response technique. Decreased beta-receptor responsiveness to this exogenously administered beta-agonist was observed in hypertensive patients; for an equivalent chronotropic effect, higher doses of isoproterenol were required in hypertensive subjects than in normal subjects. Among "normal-renin" hypertensive patients, beta-receptor responsiveness was directly related to furosemide-stimulated plasma renin activity (PRA), suggesting that independently stimulated PRA may provide an indirect estimate of endogenous beta-receptor sensitivity. Hypertensive patients whose mean arterial pressure fell at least 10 mm Hg after four weeks of treatment with hydrochlorothiazide had even further depression in beta-receptor responsiveness, whereas receptor sensitivity was unchanged in patients whose blood pressure was unaffected. Thus, it is unlikely that this decreased receptor responsiveness in patients with untreated essential hypertension is a direct consequence of elevated arterial pressure.

Renin and aldosterone in the cardiomyopathic hamster in congestive heart failure.

The renin-aldosterone system was studied in cardiomyopathic hamsters (CMH) before and after the onset of untreated clinical congestive heart failure. Age-matched random-bred hamsters (RB) served as controls. Before heart failure, there were no differences in body weight accretion, sodium balance, plasma renin activity or in vitro aldosterone production. After the onset of heart failure in CMH, body weight increased at a greater rate than in RB and positive sodium balance was nearly twice control levels. Although plasma renin activity was greater (P less than 0.005) in CMH than in RB (23.4+/-4.2 (mean+/-SEM) vs. 3.8+/-1.8 ng/ml/h), aldosterone production (101+/-15 vs. 95+/-16 ng/h) did not differ. Plasma aldosterone was low or undetectable in RB and in CMH in heart failure. In response to angiotensin stimulation, aldosterone production increased in both strains and did not differ. No difference in muscle potassium content, potassium balance or excretion was detected. Thus, in CMH, congestive heart failure is attended by increased plasma renin activity without a significant increase in aldosterone production, a dissociation which does not appear to be due to adrenal unresponsiveness to angiotensin II or to potassium depletion.

Effect of adrenalectomy on renin release in the rat.

The purpose of this study was to evaluate the mechanism of increased renin secretion in the adrenalectomized (Adx) rat. Plasma renin concentration (PRC) responses to acute infusion of 0.9% NaCl (5% of body weight) were compared in three groups of rats: Adx, Adx rats treated with dexamethasone (Adx + Dex), and sham controls. During the 7 days after adrenalectomy and before acute infusion. Adx animals drank 0.9% NaCl; sham animals drank water. Despite a more positive sodium balance over the 7 days, preinfusion PRC was higher in Adx than in the other two groups (P less than 0.01) and did not decrease with NaCl infusion [31.2 +/- 9.6 (+/-SE) U/30 min to 30.4 +/- 9.5]. PRC was suppressed by NaCl infusion in Adx + Dex (10.2 +/- 2.4 to 4.1 +/- 1.2) and sham controls (9.7 +/- 0.9 to 2.6 +/- 0.5). In separate groups of animals, PRC decreased (P less than 0.01) in response to volume expansion with 25% albumin (1% of body weight) in both Adx (42.6 +/- 8.9 to 23.1 +/- 6.1) and sham controls (10.2 +/- 1.2 to 2.1 +/- 0.7). These results are consistent with the hypothesis that altered responsiveness to NaCl, in the absence of volume contraction, contributes to increased renin release in adrenal insufficiency. Glucocorticoid replacement restored renin responsiveness to NaCl.

Importance of dietary chloride for salt sensitivity of blood pressure.

Recent evidence indicates that the anion accompanying sodium plays an important role in determining the magnitude of the blood pressure increase in response to a high dietary intake of NaCl. The purpose of this review is to describe studies of blood pressure responses to selective dietary sodium loading (without chloride) and to selective dietary chloride loading (without sodium) in several experimental models of salt-sensitive hypertension and in hypertensive humans. The full expression of salt sensitivity depends on high dietary intakes of both sodium and chloride. This observation has implications for understanding mechanisms contributing to NaCl-induced hypertension.

Relative contributions of dietary Na+ and Cl- to salt-sensitive hypertension.

The effect of dietary NaCl on blood pressure has generally been attributed to the sodium ion. However, recent evidence indicates that the anion accompanying sodium plays an important role in determining the magnitude of the blood pressure increase in response to a high dietary intake of NaCl. The purpose of this review is to describe studies of blood pressure responses in several experimental models of salt-sensitive hypertension and in hypertensive humans to selective dietary sodium loading (without chloride) and to selective dietary chloride loading (without sodium). The full expression of salt sensitivity depends on high dietary intakes of both sodium and chloride. This observation has implications for understanding mechanisms contributing to NaCl-induced hypertension in the susceptible host.

Dietary sodium chloride increases blood pressure in obese Zucker rats.

In the rat, elevated arterial pressure is not consistently associated with obesity. The purpose of this study was to compare measurements of blood pressure, cardiac output, and total peripheral resistance in obese and lean Zucker rats on different NaCl intakes. Obese and lean rats drank either water or isotonic NaCl for 18 days. Tail systolic blood pressures of saline-drinking obese rats were higher than all other groups (p less than 0.05). NaCl intake did not affect blood pressure in lean rats, and blood pressures of water-drinking obese rats did not differ from those of lean controls. In a subsequent experiment, direct arterial pressures and cardiac outputs (thermodilution) were measured in separate groups of conscious rats that had been maintained on a 1% or 4% NaCl intake for 12 weeks. Arterial pressure was higher (p less than 0.01) in obese rats fed 4% NaCl (130 +/- 4 mm Hg) than in obese rats fed 1% NaCl (118 +/- 2 mm Hg) or than in lean rats fed either NaCl intake (118 +/- 3 mm Hg and 116 +/- 3 mm Hg, respectively). Cardiac output of obese rats was higher than that of lean rats (p less than 0.01); however, the NaCl-induced increase of blood pressure was accounted for by an increase of peripheral resistance (p less than 0.01). Thus, in contrast to the lean Zucker rat, arterial pressure of the obese Zucker rat is increased by a high dietary intake of NaCl.

Effect of dietary salt on the skeletal muscle microvasculature in Dahl rats.

The purpose of this study was to identify microvascular alterations that could contribute to increased peripheral vascular resistance in the Dahl salt-sensitive rat with salt-induced hypertension. Intravital microscopy was used to study the spinotrapezius muscle arteriolar network in anesthetized salt-sensitive rats fed either a high salt (7% sodium chloride) or low-normal salt (0.45% sodium chloride) diet for 4 weeks. Age-matched Dahl salt-resistant rats on high and low-normal salt diets served as controls. The high salt diet had no effect on arterial pressure in salt-resistant rats but increased arterial pressure in salt-sensitive rats. Mean resting diameter of arcade arterioles in salt-sensitive rats on high salt diet was reduced by 25% compared with salt-sensitive rats on low salt or salt-resistant rats on either diet. After abolition of vascular tone with 10(-3) M adenosine, arcade diameters were comparable in all groups. No difference among groups was found in either resting or passive diameter of the more distal transverse arterioles. Measurement of vessel lengths and numbers in cleared muscle specimens revealed no differences among groups in the anatomic density of either arcade or transverse arterioles. These data suggest that a reduction in the resting diameter of arcade, but not transverse, arterioles may increase spinotrapezius muscle vascular resistance in hypertensive salt-sensitive rats. The similarity in vascular densities among groups indicates that structural rarefaction of arterioles does not contribute to any increase in spinotrapezius muscle resistance at this stage of salt-induced hypertension.

Role of epinephrine in the development of hypertension in Dahl salt-sensitive rats.

The present experiments were designed to test the hypothesis that adrenal epinephrine contributes to the development of hypertension in the Dahl salt-sensitive (DS) rat. All studies were carried out in conscious male DS and Dahl salt-resistant (DR) rats weighing 200-240 g. An indwelling femoral arterial catheter was placed for blood sampling and measurement of blood pressure. After 5 days of either a high salt (7% NaCI) or a normal salt (1% NaCl) dietary regimen, DS and DR rats were subjected to an acute stress paradigm (graded electrical footshock). There were no differences in basal plasma catecholamine concentrations or in the acute pressor responses to graded footshock between the four substrain/diet groups. However, in both DS and DR rats, plasma epinephrine responses to acute footshock were greater on a 7% than on a 1% NaCl diet. Additional groups of DS rats were treated with an inhibitor of adrenal phenylethanolamine N-methyltransferase, SK&F 29,661 (1-2 g/kg body wt/day) or with vehicle. Three days after placement of an arterial catheter, rats were placed on a 7% NaCl diet, and blood pressure was measured daily for an additional 3 weeks. Although SK&F 29,661 treatment was effective in reducing adrenal epinephrine content and apparent release by approximately 80%, treatment did not alter the time course of salt-induced changes in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Sucrose does not raise blood pressure in rats maintained on a low salt intake.

Diets high in sucrose or fructose have been shown by others to induce a modest elevation of blood pressure in rats. The present experiments were conducted to determine whether the sucrose-induced increase of blood pressure is dependent on the intake of sodium chloride. Four groups of Sprague-Dawley rats were studied: 1) a group maintained on a low salt diet and distilled water (0.45% sodium chloride, no added sucrose), 2) a low salt-high sucrose group (0.45% sodium chloride diet and 7% sucrose in distilled water), 3) a high salt group (4% sodium chloride diet and distilled water), and 4) a high salt-high sucrose group on a diet adjusted daily to maintain the same high intakes of sodium chloride and sucrose as those of groups 2 and 3. Systolic blood pressures were measured by tail-cuff plethysmography during weeks 1-3 of treatment, and direct mean arterial blood pressures were recorded in conscious animals during week 4. Animals on the high salt diet gained weight more slowly than those on the low salt intake. On the low sodium chloride intake, blood pressures were not affected by high dietary sucrose (group 1 versus 2). In contrast, on the high sodium chloride intake, blood pressures were 10-14 mm Hg higher in sucrose-drinking animals than in water-drinking animals (group 3 versus 4). The increments in blood pressures of the high sodium chloride-high sucrose group were not accompanied by greater increments in body weight compared with the animals on the high sodium chloride intake alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive effect of pioglitazone is not invariably associated with increased insulin sensitivity.

Hypertension is often associated with insulin resistance, and several chemically diverse agents that increase insulin sensitivity attenuate the development of experimental hypertension. We undertook the present study to determine whether attenuation of hypertension by pioglitazone, a thiazolidinedione derivative that increases insulin sensitivity without increasing insulin secretion, is specifically related to its effect on insulin-mediated glucose uptake. Pioglitazone administered daily by oral gavage (20 mg/kg per day) for 3 weeks attenuated the development of hypertension in both the Dahl salt-sensitive (DS) rat (an insulin-resistant model of hypertension) and the one-kidney, one clip rat (a model of hypertension not associated with insulin resistance). Based on euglycemic insulin clamp studies in conscious animals, the glucose clearance rate was increased (P < .05) in pioglitazone-treated DS rats (36 +/- 3 mg/kg per minute) compared with control DS rats (27 +/- 1 mg/kg per minute). However, pioglitazone did not affect the glucose clearance rate in one-kidney, one clip hypertensive rats. Metformin, an unrelated agent that also improves glucose tolerance, had no significant effect on blood pressure or glucose clearance rate in either DS or one-kidney, one clip rats. Thus, the hypotensive effect of pioglitazone is not invariably associated with its capacity to improve insulin-induced glucose utilization.

Nutrition and hypertension prevention.

Hypertension has been related to both obesity and a high salt intake. Evidence for the associations of blood pressure with body weight and dietary salt intake is summarized. In both adolescents and adults correlations between blood pressure and weight are highly significant, and in longitudinal studies change in blood pressure over time is correlated with change in weight. Correlations between salt intake and blood pressure are less striking, and the results of trials of modest salt restriction demonstrate a small but significant effect on blood pressure. Individuals vary in their susceptibility to salt, and hypertensive individuals are more responsive than normotensive individuals. Dietary deficiencies of potassium and calcium may amplify the effect of a high salt intake on blood pressure. Animal models provide compelling evidence for a genetic component to salt sensitivity of blood pressure. In two hypertension prevention trials, change in blood pressure was more convincingly related to change in weight than to change in dietary salt. Avoidance of obesity, or weight reduction in overweight individuals, should be key strategies for hypertension prevention. Avoidance of salt excess is also appropriate, although currently available trial data do not justify a recommendation of rigorous salt restriction for the entire population.