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Seawater is rich in minerals which may help confer good palatability to foods, favouring the use of smaller amounts of salt, a recognized measure of cardiovascular prevention. The aim of this study was to investigate the nutritional properties, sensory characteristics and metabolic effects of a typical Neapolitan pizza prepared with seawater (SWP) in place of common salt, in comparison with Standard traditional Pizza (StP). The nutritional characteristics and the chemical profile of the SWP and StP were assessed by chemical analyses and the use of Food Composition Tables. Twelve healthy volunteers were recruited for a Randomized Controlled Trial, with the consumption of one StP and one SWP using a balanced crossover design. The satiating power and palatability of the two pizzas were tested by the administration of Visual Analogue Scales. Serum glucose, insulin and sodium were measured every 30 min and 3 h urines were collected after each meal. SWP contained nearly 50% less NaCl and a larger amount of micronutrients compared with StP. No significant differences were detected between the two pizzas with regard to satiating power, pleasantness and glycemic and insulinemic response. However, a significant difference was found in the urine volume collected over the 3 h after the two meals (194 mL after StP vs. 292 mL after SWP, p = 0.018) and in the 3 h sodium balance (+1.6 g after StP vs. +0.5 g after SWP, p = 0.002). Conclusions: SWP appears to be a food with favourable nutritional characteristics, very good acceptability and healthy metabolic properties: these results warrant confirmation by a larger intervention trial.

Renal tubular sodium (Na) handling plays a key role in blood pressure (BP) regulation. Several cross-sectional studies reported a positive association between higher proximal tubule fractional reabsorption of Na and BP, but no prospective investigation has been reported of this possible association. Hence, the purpose of this study was to estimate the predictive role of renal Na handling on the risk of incident hypertension and the changes in BP occurring in the 8-year follow-up observation of a sample of initially normotensive men (The Olivetti Heart Study). The study included 294 untreated normotensive non-diabetic men with normal renal function examined twice (1994-95 and 2002-04). Renal tubular Na handling was estimated by exogenous lithium clearance. Fractional reabsorption of Na in proximal and distal tubules was calculated and included in the analysis. At baseline, there was no association between BP and either proximal or distal fractional reabsorption of Na. At the end of the 8-year follow-up, direct associations were observed between baseline proximal (but not distal) Na fractional reabsorption and the changes occurred in systolic and diastolic BP over time (+2.79 and +1.53 mmHg, respectively, per 1SD difference in proximal Na-FR; p<0.01). Also multivariable analysis showed a direct association between baseline proximal Na fractional reabsorption and risk of incident hypertension, independently of potential confounders (OR: 1.34, 95%CI:1.06-1.70). The results of this prospective investigation strongly suggest a causal relationship between an enhanced rate of Na reabsorption in the proximal tubule and the risk of incident hypertension in initially normotensive men., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: PS is President of the Italian Society of Human Nutrition, scientific coordinator of the Interdisciplinary Working Group for Reduction of Salt Intake in Italy (GIRCSI), a member of the committee for the preparation of the Italian Nutritional Guidelines and an unpaid member of WASH (World Action in Salt and Health). FPC is Head of the World Health Organization Collaborating Centre for Nutrition, Vice-President and Trustee of the British Hypertension Society and unpaid member of CASH, WASH and the UH Health Forum. The remaining authors do not disclose any conflict of interest.

Genetic variation in alpha-adducin cytoskeletal protein is implicated in the polymerization and bundling of actin and alteration of the Na/K pump, resulting in abnormal renal sodium transport and hypertension in Milan hypertensive rats and humans. To investigate the molecular involvement of alpha-adducin in controlling Na/K pump activity, wild-type or mutated rat and human alpha-adducin forms were, respectively, transfected into several renal cell lines. Through multiple experimental approaches (microscopy, enzymatic assays, coimmunoprecipitation), we showed that rat and human mutated forms increased Na/K pump activity and the number of pump units; moreover, both variants coimmunoprecipitate with Na/K pump. The increased Na/K pump activity was not due to changes in its basolateral localization, but to an alteration of Na/K pump residential time on the plasma membrane. Indeed, both rat and human mutated variants reduced constitutive Na/K pump endocytosis and similarly affected transferrin receptor trafficking and fluid-phase endocytosis. In fact, alpha-adducin was detected in clathrin-coated vesicles and coimmunoprecipitated with clathrin. These results indicate that adducin, besides its modulatory effects on actin cytoskeleton dynamics, might play a direct role in clathrin-dependent endocytosis. The constitutive reduction of the Na/K pump endocytic rate induced by mutated adducin variants may be relevant in Na-dependent hypertension.

Objective: The mechanisms underlying high blood pressure in the framework of metabolic syndrome (MS) are not clarified: we thus analyzed the relationship of MS and its components to renal tubular sodium handling among participants of the Olivetti Heart Study, an epidemiological investigation of a representative sample of adult white male population in southern Italy., Methods: Proximal (FPRNa) and distal (FDRNa) fractional sodium reabsorption were estimated by the clearance of exogenous lithium in 702 participants aged 25-75 years examined in 1994-1995. Blood pressure and relevant anthropometric and biochemical variables were also measured. The diagnosis of MS was based on modified National Cholesterol Education Program (NCEP)-Adult Treatment Panel III (ATP III) criteria., Results: FPRNa, but not FDRNa, was directly associated with body mass index (BMI), waist circumference, diastolic pressure, serum triglyceride and uric acid, independently of age and of antihypertensive treatment. After adjustment for age, FPRNa, but not FDRNa, was significantly greater in individuals with MS, as compared to those without [77.6% (95% confidence interval = 76.7-80.1) versus 74.4% (73.7-75.1), P < 0.001]. A similar difference was observed after the exclusion of participants on current antihypertensive treatment (P = 0.018). In untreated individuals, a significant interaction was observed between obesity and insulin resistance as related to FPRNa (P = 0.002): the highest age-adjusted levels of FPRNa were detected in obese hypertensive and obese insulin-resistant participants., Conclusion: In this sample of an adult male population, MS was associated with an increased rate of FPRNa. This finding is relevant to the pathophysiology of MS and possibly to the prevention of its cardiovascular and renal consequences.

Genes of the renin-angiotensin-aldosterone system (RAAS) are natural candidates for sodium homeostasis and blood pressure regulation. To investigate the effect of a combination of polymorphisms of RAAS genes on renal sodium handling and blood pressure, 918 participants to the Olivetti Heart Study were genotyped for the following polymorphisms: I/D of angiotensin converting enzyme (ACE), M235T of angiotensinogen (AGT), A1166C of angiotensin II type-1 receptor (AT1R), and C-344T of aldosterone synthase (CYP11B2). The segmental renal sodium handling was evaluated by the fractional excretions of exogenous lithium (FE-Li), uric acid (FE-UA), and sodium (FE-Na). Twenty-eight carriers of triple homozygosity for M (AGT), A (AT1R), and C (CYP11B2) in the presence of the D allele of ACE (DD/ID) showed lower FE-Li (20.0%+/-5.9% versus 25.0%+/-7.5%; P=0.004; mean+/-sD), FE-UA (6.3%+/-2.0% versus 8.2%+/-2.7%; P=0.001), and FE-Na (0.96%+/-0.41% versus 1.22%+/-0.61%; P=0.004) as compared with all other allelic combinations (n=890), independently from age and body mass, suggesting an enhanced rate of proximal tubular sodium reabsorption. The carriers of the MM, AA, CC, DD/ID combination showed a substantially higher probability of being hypertensive (OR: 3.4 [(99% CI: 1.1 to 10.1]), independently of age and body mass. This relatively rare combination of allelic variants of candidate genes of the RAAS is associated with a significant alteration in proximal renal sodium handling and with higher risk of hypertension, suggesting that a combination of polymorphic variants at different candidate loci may affect phenotypic expression even in the absence of detectable effects of each variant at any single locus.

Objectives: Central adiposity, insulin resistance and hypertension are clearly interrelated but the mechanisms underlying this association have not been thoroughly elucidated. As renal sodium handling plays a central role in salt-sensitive forms of hypertension, we investigated the relation of renal tubular sodium handling to abdominal adiposity, blood pressure and insulin sensitivity., Design: Population-based study., Participants: Five hundred and fifty-five untreated Olivetti male workers, aged 25-75 years., Setting: Olivetti factory medical centers in Pozzuoli and Marcianise (Naples, Italy), Main Outcome Measures: Anthropometric indices, serum insulin, homeostatic model assessment index of insulin sensitivity, blood pressure, fractional excretions of uric acid and exogenous lithium (as markers of renal tubular sodium handling)., Results: In univariate analysis, measures of central adiposity (i.e. sagittal abdominal diameter and umbilical circumference) were directly correlated with serum insulin (P < 0.001) and blood pressure levels (P < 0.001) and inversely associated with the fractional excretions of uric acid and lithium (P = 0.01-0.001). In multiple linear regression analysis, the same anthropometric indices but not the measures of peripheral adiposity (arm circumference and tricipital skinfold thickness), were significant predictors of the fractional excretion of uric acid and lithium, independently of age, blood pressure and serum insulin levels (P = 0.01-0.001)., Conclusions: Abdominal adiposity was associated with altered renal tubular sodium handling apart from insulin resistance and high blood pressure. The data indicate that men with prevalent abdominal adiposity have an enhanced rate of tubular sodium reabsorption, mainly at proximal sites. These findings provide a possible mechanistic link between central adiposity and salt-dependent hypertension.

A higher prevalence of hypertension has been associated with the G-->A/GT (Gly40Ser) polymorphism of the glucagon receptor gene (GCGR) in two population studies. As the mutated receptor is less responsive to glucagon, it has been speculated that the increased susceptibility to hypertension is due to deprivation of the recognized natriuretic effect of the hormone. To test this hypothesis we determined the frequency of the polymorphic variant and evaluated the segmental renal sodium handling by the clearances of uric acid and of exogenous lithium in the Olivetti Heart Study participants (n=971). The polymorphic variant was present only in heterozygous form in 37 individuals (3.8%). After controlling for age and body mass index, the carriers of the variant were twice more likely to be hypertensive and almost three times more likely to be on antihypertensive treatment at the time of examination. Compared to participants carrying the wild type, those carrying the Gly40Ser allele had higher serum uric acid and lower fractional excretion of uric acid and exogenous lithium, independently of age, body mass, and current pharmacological treatment. We conclude that the Gly40Ser polymorphism of the GCGR gene is associated with higher risk of hypertension and with enhanced proximal tubular sodium reabsorption, a factor possibly contributing to hypertension in this group.

An elevated red blood cell (RBC) sodium-lithium countertransport (Na-Li CT) is associated with high blood pressure (BP) in cross-sectional investigations; however, its value as a predictor of future hypertension, and thus of cardiovascular risk, has not been defined. The present study evaluated the association between Na-Li CT and risk of future hypertension in a sample of 106 untreated normotensive middle-aged men participating in the Olivetti Prospective Heart Study in southern Italy. BP, anthropometric and metabolic variables, and RBC Na-Li CT were measured at baseline in 1987 and at a follow-up visit in 1994 through 1995. Na-Li CT was stable over time (r=0.85) and was significantly associated to systolic BP in both visits. Of the 106 initially normotensive participants, 14 were found to be hypertensive at the 8-year follow-up examination. Eleven of these 14 hypertensives were in the highest tertile of systolic BP at baseline, and 9 of 11 also had an elevated baseline Na-Li CT. In multiple logistic regression analysis, baseline BP, Na-Li CT, and age were all significant predictors of the risk of future hypertension. Individuals with baseline systolic BP in the highest tertile had a 60% risk of developing hypertension if their Na-Li CT was also high, whereas their risk was only 5% if Na-Li CT was in the two lowest tertiles (P=0.003). RBC Na-Li CT was a valuable predictor of subsequent hypertension in middle-aged men with a high-normal BP level for their age.

An elevated red blood cell Na/Li countertransport (Na/Li CT) is often associated with high blood pressure and metabolic abnormalities. Recent studies suggested that a reduction in serum TG levels is associated with a decrease in Na/Li CT activity. However, it is still unclear if this phenomenon could be originated from systemic metabolic alterations or from modifications of the membrane dynamic properties. Aim of the present study was to investigate whether dietary or pharmacological TG lowering therapy might have a different effect on Na/Li CT activity and related metabolic parameters. Twenty normotensive hyper-TG patients were recruited from the Lipid outpatient Clinic: they had a baseline Na/Li CT activity significantly higher compared with age- and BMI-matched normolipidemic controls (386+/-33 vs 274+/-39 umol/l RBC/h, p<0.05). The patients were randomly prescribed one of the following two-months treatment: Group 1)-triglyceride lowering diet; Group 2)-lipid lowering drug (Gemfibrozil 600 mg b.i.d.). Na/Li CT and metabolic and anthropometric variables were measured at baseline and after 1 and 2 months of treatment. At the end of intervention, there was in both groups a significant and comparable fall in plasma triglyceride (group 1: -2.61+/-0.73 mmol/l p<0.01; group 2: -4.29+/-1.20 mmol/l p<0.01). In the diet-treated group there were, in addition small but significant reductions in body weight (-3.7+/-0.8 kg p<0.01), fasting glucose (-0.36+/-0.14 mmol/l p<0.05) and insulin levels (-2.1+/-0.5 mU/l, p<0.01), while no such changes were observed in the fibrate treated patients. Na/Li CT activity was significantly and comparably reduced at the end of treatment in both groups (group 1: -97+/-28 umol/l cell/h, p<0.01; group 2: -89+/-30 umol/l cell/h, p<0.01). In conclusion, these results indicate that the decrease in Na/Li CT associated with both dietary and drug treatment of hypertriglyceridemia is to be traced to a direct effect of plasma TG concentration on this transport system (probably as a result of modification in the membrane lipid environment) rather than to changes in plasma insulin levels or insulin resistance.

A significant and positive association between red blood cell sodium lithium countertransport (Na-Li CT) and blood pressure has been found in numerous studies. However, the majority of the studies presented to date are cross-sectional in nature and limited information exists on the longitudinal association between Na-Li CT and blood pressure. The present study analyzes the longitudinal association between Na-Li CT and blood pressure in 124 men participants in the Olivetti Heart Study and normotensives at the baseline examination. The Na-Li CT measured at the 12 year follow-up examination was analyzed in regard to the blood pressure changes over time during the 12 year follow-up. Na-Li CT (measured at follow-up examination) was positively related to changes over time in systolic pressure (r = 0.16) and diastolic pressure (r = 0.07) and changes in body mass index (r = 0.18). When blood pressure changes over time were analyzed by tertiles of Na-Li CT, the highest tertile group exhibited on the average significantly higher increases in systolic blood pressure compared with participants of the lowest tertile of the Na-Li CT distribution. This difference remained statistically significant after adjusting for the changes in weight observed during the 12 years follow-up. These findings indicate that the Na-Li CT distribution is related to blood pressure changes over time. However, the usefulness of Na-Li CT as a predictor of incidence of hypertension remains to be established.

The present study was designed to investigate whether non-insulin-dependent diabetic hypertensive patients exhibit abnormalities in intracellular sodium metabolism similar to those described for essential hypertensive patients. Both normotensive and hypertensive non-insulin-dependent diabetic patients had similar average values of both Na+-Li+ countertransport and Na+-K+ cotransport compared with nondiabetic controls. Within the group of diabetic patients, hypertensive patients did not exhibit any abnormalities in either of the sodium transport pathways studied. The possible implications of these findings are addressed.

The relationship between segmental renal tubular sodium handling (using the renal clearance of ingested lithium as a marker of proximal tubular sodium handling) and circulating plasma levels of atrial natriuretic factor (ANF) was studied in a sample of 295 untreated men drawn from a male population at work under their usual living conditions. Plasma ANF was positively and significantly related to sodium excretion at the distal nephron, indicating that this hormone interacts with a distal renal tubular site to influence the control of sodium excretion in man.

The present report evaluates a method for the determination of the maximal velocity of the outward sodium, potassium, chlorine (Na-K-Cl) cotransport in erythrocytes. The loading procedure was carried out using the ionophore nystatin. The technical error for this assay, based on concurrent analysis of randomized blind duplicate samples, was 8.04% of the sample mean and 27.5% of the sample standard deviation. The assay was stable over time and reproducible. Fasting was not necessary. The ratio of intra- to interindividual variances was small. The cells can be safely preserved in an appropriate preservation solution without modification of the ion transport assay. The assay appears to be adequate for use in large-scale field trials.

1. It has been proposed that the enhanced erythrocyte Na+/Li+ countertransport observed in many patients with essential hypertension could be a marker of abnormal renal proximal tubular function. We thus investigated the relationship of blood pressure and Na+/Li+ countertransport to an index of proximal tubular function such as renal Li+ clearance. 2. The study was carried out in a sample of 299 untreated male subjects (aged 21-59 years) randomly selected from a population at work. Na+/Li+ countertransport was measured in a representative sub-group of 176 men. 3. We did not detect statistically significant correlation of either blood pressure or Na+/Li+ countertransport (Vmax) with fractional excretion of Li+, while confirming the existence of a significant continuous association of blood pressure and body mass index with Na+/Li+ countertransport (P less than 0.01). 4. A sub-sample of 57 participants belonging to the lowest or the highest quintiles of Na+/Li+ countertransport distribution repeated the Li+ clearance study after moderate Na+ restriction. 5. Although fractional excretions of Na+ and Li+ were reduced on the low Na+ diet (both P less than 0.001), they did not differ significantly between groups. 6. Our results are at variance with the findings of a recent case-control study in a young age group and suggest that further studies are necessary before a conclusion can be drawn as to the suitability of Na+/Li+ countertransport as a marker of Na+ reabsorption in the renal proximal tubule.

The relationship of red blood cell (RBC) Na/Li countertransport to the renal handling of lithium and uric acid was investigated in a sample of 176 untreated men. Subjects in the upper quintile of the Na/Li countertransport distribution (n = 40), compared to those in the two lower quintiles (n = 72), had higher serum uric acid levels (0.34 +/- 0.06 v 0.29 +/- 0.05 mmol/L, P less than 0.001) and systolic blood pressure (131 +/- 19 v 123 +/- 16 mm Hg, P less than 0.02) and slightly lower fractional excretion of uric acid (7.5 +/- 1.5 v 8.4 +/- 2.6%, P less than 0.08). The lithium fractional excretion was not significantly related to either blood pressure or RBC Na/Li countertransport. The altered uric acid metabolism in individuals with high RBC Na/Li countertransport could be the expression of an abnormality of renal tubular function.

The variability of 24-hour urinary sodium, potassium, and calcium excretion was studied in a sample of 22 Neapolitan men with mild blood pressure elevation. On 5 days within a 1-month period, 24-hour urine specimens were collected by each subject. The estimated ratio of intraindividual-to-interindividual variance was 1.12 for urinary sodium, 2.46 for urinary potassium, and 0.52 for urinary calcium. Based on these values, five 24-hour urine collections are necessary to reduce to less than 10% the diminution of the correlation coefficient between urinary sodium and another related variable; this number is substantially lower than that found in previous studies in a North American population sample, but similar to the one reported for Chinese population samples. Ten urinary collections are needed for potassium excretion. A different and more favorable situation is observed for 24-hour calcium excretion, as only two collections are necessary for the adequate characterization of individuals in a population.

This study focuses on the relationship between some aspects of intra-erythrocytic sodium metabolism (intra-erythrocytic Na content, Na,Li-countertransport), blood pressure, and family history of hypertension, in a group of 84 randomly selected school children (45 males, 39 females). Na,Li-countertransport was significantly related to both systolic blood pressure (SBP) and diastolic blood pressure (DBP) only in boys at the univariate level, but both of these associations lost statistical significance after the possible confounding role of weight and height were taken into consideration. In both sexes, participants with a family history of hypertension had similar values of both intra-erythrocytic Na content and Na,Li-countertransport to participants with no family history. We conclude that family history of hypertension does not seem to play an important role in the determination of either intra-erythrocytic Na content or Na,Li-countertransport at this age. Although the positive association between Na,Li-countertransport and blood pressure observed in adult males is already present in childhood, this probably is still, at least in part, dependent upon body size.

The renal fractional excretion of uric acid was determined for both a habitual diet and an NaCl-restricted diet in two groups of untreated subjects with low (117-207 mumol per litre of cells per h) and high (373-598 mumol per litre of cells per h) erythrocyte Na-Li countertransport identified in a population-based survey of middle-aged male workers. The group with high Na-Li countertransport had a higher mean blood pressure (P less than 0.05); this group also had a significantly reduced fractional excretion of uric acid with the NaCl-restricted diet even after adjustment for the difference in blood pressure (P less than 0.03). These findings are compatible with an abnormality in kidney tubular function and possibly in the renal handling of sodium in subjects with elevated erythrocyte Na-Li countertransport.