Ferruccio Galletti

Plasma Ouabain-Like Factor During Acute and Chronic Changes in Sodium Balance in Essential Hypertension

Abstract—An ouabain-like factor has been implicated repeatedly in salt-sensitive hypertension as a natriuretic agent. However, the response of plasma ouabain-like factor to acute and chronic variation of body sodium is unclear. We studied 138 patients with essential hypertension who underwent an acute volume expansion/contraction maneuver (2 days) and 20 patients who entered a blind randomized crossover design involving chronically controlled sodium intake and depletion (170 to 70 mmol/d; 2 weeks each period). In both studies, plasma levels of ouabain-like factor were higher during sodium depletion (acute: 338.8±17.4 and 402.7±22.8 pmol/L for baseline and low sodium, respectively, P <0.01; chronic: 320.4±32.0 versus 481.0±48.1 pmol/L, P =0.01). No significant change in plasma ouabain-like factor was observed after a 2-hour saline infusion (333.4±23.9 pmol/L) or controlled sodium (402.1±34.9 pmol/L). When patients were divided into salt-sensitive or salt-resistant groups, no differences in plasma ouabain-like factor were observed in the 2 groups at baseline or in response to the 2 protocols: salt resistant (n=69, 340.1±25.9 pmol/L) versus salt sensitive (n=69, 337.4±23.6 pmol/L) and chronic salt resistant (n=11, 336.0±53.2) versus salt sensitive (n=9, 301.1±331.4 pmol/L). However, circulating ouabain-like factor was increased by sodium depletion in both groups. These results demonstrate that circulating ouabain-like factor is raised specifically by maneuvers that promote the loss of body sodium. Acute expansion of body fluids with isotonic saline is not a stimulus to plasma ouabain-like factor. Moreover, basal levels of plasma ouabain-like factor do not differ among patients with salt-sensitive or salt-resistant hypertension. Taken together, these new results suggest that ouabain-like factor is involved in the adaptation of humans to sodium depletion and argue against the hypothesis that ouabain-like factor is a natriuretic hormone.

Altered renal sodium handling in men with abdominal adiposity: a link to hypertension.

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.

Abnormalities of renal sodium handling in the metabolic syndrome. Results of the Olivetti Heart Study.

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.

NaCl sensitivity of essential hypertensive patients is related to insulin resistance.

Objective To evaluate insulin sensitivity of essential hypertensive patients with different salt sensitivities of blood pressure in the absence of confounding factors such as obesity, glucose intolerance and the inclusion both of normotensive and of hypertensive subjects that have affected most previous studies. Patients Ninety-nine patients with untreated mild or moderate essential hypertension, World Health Organization class I–II, participated in the study. Methods Salt sensitivity was estimated using the Weinberger protocol with minor modifications and the patients were classified into tertiles of salt sensitivity. Results Patients with high NaCl sensitivities were slightly older and had somewhat higher blood pressures than did subjects with low salt sensitivities. Plasma renin activity significantly decreased with increasing salt sensitivity. There were no differences among the three groups in terms of body mass index, fasting blood glucose and insulin plasma levels. There were no differences among the groups in the integrated glucose and insulin response to a standard oral-glucose tolerance test. However, there was a significant difference in insulin sensitivity between two subgroups of the upper and lower tertile of salt sensitivity, the salt-sensitive hypertensives having a markedly lower utilization of glucose than did the salt-resistant ones, with a minor overlap (5.4 ± 0.6 versus 7.4 ± 0.3 mg/kg per min, P < 0.01). Conclusions This study showed that essential hypertensive patients with high NaCl sensitivities were relatively insulin resistant compared with those with low NaCl sensitivities, independently of confounding factors such as age, obesity and glucose intolerance. Insulin resistance was not associated with overt hyperinsulinaemia among these patients.

Altered Renal Handling of Sodium in Human Hypertension Short Review of the Evidence

Abstract—A pathogenic role of the kidney in hypertension has been strongly supported by experimental studies by Guyton and Dahl since the 1960s. In the early 1980s, de Wardener and MacGregor proposed that in hypertensive patients the ability of the kidneys to excrete a sodium load could be genetically impaired. Since then, “sodium-sensitive” hypertension has been the object of numerous studies, mostly on animal models because of the difficulty to investigate the renal handling of sodium in humans. More recently, considerable progress in this field has been made thanks to the in vivo study of segmental renal tubular function by the clearance of lithium and to the growing knowledge of the genetics of renal tubular sodium transport systems. The scope of this review is to briefly review the most relevant information gathered by the investigation of segmental renal tubular sodium handling in humans as related to blood pressure regulation and hypertension. In aggregate, the results of these studies strongly support the association between altered renal sodium handling and high blood pressure and suggest a causal role of genetic, nutritional, metabolic, and neurohormonal factors. All of these factors, alone or in combination, may be able to impair the normal renal tubular sodium handling and influence blood pressure homeostasis. The paradigm of the pathogenic role of the kidney in hypertension is thus relentlessly shifting toward the definition of inherited as well as acquired renal tubular defects and molecular alterations, providing a plausible explanation for the alteration in blood pressure levels.

Circulating leptin levels predict the development of metabolic syndrome in middle-aged men: an 8-year follow-up study.

Background Because high circulating plasma leptin is associated with many features of the metabolic syndrome (MS), such as abdominal obesity, insulin resistance and high blood pressure (BP), we analysed the ability of plasma leptin concentration to predict the risk of developing MS in a prospective investigation of adult male participants of the Olivetti Heart Study (OHS). Methods and results Three hundred and sixty out of 907 men participating in the 1994–95 and 2002–04 OHS examinations (mean age at baseline 50.4 years, range 25–73 years) were free of MS at first visit according to NCEP-ATP III criteria (modified for the lack of high-density lipoprotein cholesterol measurement at baseline). During an average follow-up period of 8 years, there were 52 incident cases of MS (14.5%) due, in particular, to a rise in the prevalence of high BP (+42.4%), abdominal obesity (+16.4%) and impaired fasting glucose (IFG, +6.1%). In multivariate analyses, a one standard deviation difference in baseline plasma leptin concentration was associated with a 1.58-fold greater risk of developing MS (95% confidence interval = 1.10–2.30, P = 0.016) accounting for age, waist circumference, homeostatic assessment model index, smoking, alcohol consumption and physical activity. In particular, plasma leptin was positively associated with the risk of developing high BP (0.006) and IFG (0.014), after adjustment for confounders. Conclusion In this sample of an adult male population free of MS at baseline, circulating plasma leptin was a significant predictor of the risk of MS and, in particular, of its high BP and IFG components, independently of potential confounders.

High-Circulating Leptin Levels Are Associated with Greater Risk of Hypertension in Men Independently of Body Mass and Insulin Resistance: Results of an Eight-Year Follow-Up Study

BACKGROUND We previously reported a significant association between plasma leptin (LPT) concentration and blood pressure (BP), which was partly independent of serum insulin levels and insulin resistance. The aims of this study were to detect whether serum LPT levels predict the development of hypertension (HPT) in the 8-yr follow-up investigation of a sample of an adult male population (the Olivetti Heart Study), and to evaluate the role of body mass index (BMI) and insulin resistance in this putative association. PATIENTS AND METHODS The study population was made up of 489 untreated normotensive subjects examined in 1994-1995 (age: 50.1 +/- 6.7 yr; BMI: 26.3 +/- 2.8 kg/m(2); BP: 120 +/- 10/78 +/- 6 mm Hg; and homeostatic model assessment index: 2.1 +/- 1.6). RESULTS The HPT incidence over 8 yr was 35%. The participants with incident HPT had similar age but higher BMI (P < 0.001), serum LPT (P < 0.001), and BP (P < 0.01) at baseline. One sd positive difference in baseline serum LPT log was associated at univariate analysis with a 49% higher rate of HPT [95% confidence interval (CI) 22-83; P < 0.001]). In three different models of multivariable logistical regression analysis, LPT was respectively associated with a 41% greater risk to develop HPT (95% CI 15-74; P < 0.001) upon adjustment for age and baseline BP, with a 48% (95% CI 20-81) greater risk when adding the homeostatic assessment model index to the model, and with 33% greater risk (95% CI 6-67; P < 0.02) upon adjustment for BMI. CONCLUSIONS In this sample of originally normotensive men, circulating LPT level was a significant predictor of the risk to develop HPT over 8 yr, independently of BMI and insulin resistance.

Associations of selenium status with cardiometabolic risk factors: An 8-year follow-up analysis of the Olivetti Heart Study

OBJECTIVE High selenium status has been associated with adverse cardiometabolic outcomes in selenium-replete populations such as the US. In populations with lower selenium status such as in Italy, there is little epidemiological evidence about the association of selenium with cardiometabolic risk factors. We therefore examined cross-sectional and prospective relationships of serum selenium concentrations with cardiometabolic risk factors including blood pressure, diabetes and blood lipids in the Olivetti Heart Study. METHODS The study population consisted of 445 adult male individuals for whom baseline serum selenium measurement and cardiometabolic risk factors at baseline (1994-1995) and follow-up examination (2002-2004: average follow-up=8 years) were available. Serum selenium was measured by atomic absorption spectrophotometry. RESULTS Average serum selenium concentration at baseline was 77.5 ± 18.4 μg/L. In cross-sectional analyses, serum selenium levels were positively associated with serum total cholesterol (p for trend <0.0001) and prevalent diabetes (p for trend <0.05). In prospective analysis, serum selenium at baseline was likewise a strong predictor of serum total cholesterol (p=0.002) and LDL-cholesterol (p=0.001) at follow-up, after adjustment for age, BMI, cigarette smoking, physical activity, and lipid-lowering medication. These associations, however, were no longer significant after additional adjustment for baseline blood lipids. Selenium at baseline did not predict changes in total cholesterol levels between the baseline and follow-up examinations [β-coefficient (± SE)= 0.09 ± 0.12 (p=0.46)]. CONCLUSION These findings corroborate previous cross-sectional associations of high selenium status with adverse blood lipid profile and diabetes. However, prospective analyses do not support the causality of these relations. Randomized and experimental evidence is necessary to clarify the mechanisms underlying the observed cross-sectional associations.

Impact of the renin-angiotensin system on lipid and carbohydrate metabolism.

Purpose of reviewThis review is intended to provide an update of the impact of the renin-angiotensin system on lipid and carbohydrate metabolism and of its relationship with adipose-tissue and skeletal muscle activities. Recent findingsThe components of the renin-angiotensin system are fully represented in the adipose tissue and appear to be upregulated in obesity-a condition associated with enhanced circulating angiotensinogen levels. The local renin-angiotensin system plays a role in adipocyte differentiation and possibly in body-fat accumulation. In humans, angiotensin II produced by mature adipocytes appears to inhibit the differentiation of adipocyte precursors, thus decreasing the percentage of small insulin-sensitive adipocytes. In turn, the lipid-storage capacity of adipose tissue could become reduced and triglycerides might accumulate in liver and skeletal muscle, contributing to insulin resistance. Randomized controlled trials indicating that pharmacological renin-angiotensin system blockade improves insulin sensitivity and reduces the risk of type 2 diabetes are in keeping with this possibility. The local renin-angiotensin system in skeletal muscle may affect exercise performance and the individual response to different types of muscular performance. The concept that the local renin-angiotensin system plays a role in body-fat storage and in lipid and carbohydrate metabolism is further supported by genetic studies showing that susceptibility to weight gain and possibly insulin resistance is greater in individuals carrying certain renin-angiotensin system allelic variants associated with alterations in systemic and local angiotensinogen levels and angiotensin-converting enzyme activity. SummaryIn summary, the aforementioned data imply that the renin-angiotensin system plays a substantial role in obesity, insulin resistance and the associated increase in blood pressure.

Excess dietary sodium and inadequate potassium intake in Italy: Results of the MINISAL study

OBJECTIVE As excess sodium and inadequate potassium intake are causally related to hypertension and cardiovascular disease, the MINISAL-GIRCSI Program aimed to provide reliable estimates of dietary sodium and potassium intake in representative samples of the Italian population. DESIGN AND METHODS Random samples of adult population were collected from 12 Italian regions, including 1168 men and 1112 women aged 35-79 yrs. Electrolyte intake was estimated from 24 hour urine collections and creatinine was measured to estimate the accuracy of the collection. Anthropometric indices were measured with standardised procedures. RESULTS The average sodium excretion was 189 mmol (or 10.9 g of salt/day) among men and 147 mmol (or 8.5 g) among women (range 27-472 and 36-471 mmol, respectively). Ninety-seven % of men and 87% of women had a consumption higher than the WHO recommended target of 5g/day. The 24 h average potassium excretion was 63 and 55 mmol, respectively (range 17-171 and 20-126 mmol), 96% of men and 99% of women having an intake lower than 100 mmol/day (European and American guideline recommendation). The mean sodium/potassium ratio was 3.1 and 2.8 respectively, i.e. over threefold greater than the desirable level of 0.85. The highest sodium intake was observed in Southern regions. Sodium and potassium excretion were both progressively higher the higher the BMI (p < 0.0001). CONCLUSIONS These MINISAL preliminary results indicate that in all the Italian regions thus far surveyed dietary sodium intake was largely higher and potassium intake lower than the recommended intakes. They also highlight the critical association between overweight and excess salt intake.