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1.  Determination of erythrocyte sodium sensitivity in man 
Pflugers Archiv  2013;465(10):1459-1466.
Sodium buffer capacity of vascular endothelium depends on an endothelial glycocalyx rich in negatively charged heparan sulfate. It has been shown recently that after the mechanical interaction of blood with heparan sulfate-depleted endothelium, erythrocytes also lose this glycocalyx constituent. This observation led to the conclusion that the vascular sodium buffer capacity of an individual could be derived from a blood sample. A test system (salt blood test (SBT)) was developed based upon the sodium-dependent erythrocyte zeta potential. Erythrocyte sedimentation velocity was measured in isosmotic, biopolymer-supplemented electrolyte solutions of different sodium concentrations. Erythrocyte sodium sensitivity (ESS), inversely related to erythrocyte sodium buffer capacity, was expressed as the ratio of the erythrocyte sedimentation velocities of 150 mM over 125 mM Na+ solutions (ESS = Na+150/Na+125). In 61 healthy individuals (mean age, 23 ± 0.5 years), ESS ranged between 2 and 8. The mean value was 4.3 ± 0.19. The frequency distribution shows two peaks, one at about 3 and another one at about 5. To test whether ESS reflects changes of the endothelial glycocalyx, a cultured endothelial monolayer was exposed for 3 hours to a rhythmically moving blood layer (drag force experiment). When applying this procedure, we found that ESS was reduced by about 21 % when the endothelium was pretreated for 4 days with the glycocalyx protective agent WS 1442. In conclusion, the SBT could possibly serve as an in vitro test system for the evaluation of erythrocyte/vascular salt sensitivity allowing follow-up measurements in the prevention and treatment of vascular dysfunctions.
doi:10.1007/s00424-013-1289-x
PMCID: PMC3778990  PMID: 23686295
Erythrocyte glycocalyx; Heparan sulfate; Endothelial glycocalyx; Red blood cell sedimentation velocity; Vascular sodium sensitivity
2.  A physiological concept unmasking vascular salt sensitivity in man 
Pflugers Archiv  2012;464(3):287-293.
About one third of the population worldwide is supposed to be salt sensitive which is a major cause for arterial hypertension later in life. For preventive actions it is thus desirable to identify salt-sensitive individuals before the appearance of clinical symptoms. Recent observations suggest that the vascular endothelium consists of two salt-sensitive barriers in series, the glycocalyx that buffers sodium and the endothelial cell membrane that contains sodium channels. Glycocalyx sodium buffer capacity and sodium channel activity are conversely related to each other. For proof of concept, a so-called salt provocation test (SPT) was developed that should unmask vascular salt sensitivity in humans at virtually any age. Nineteen healthy subjects, ranging from 25 to 63 years of age, underwent two series of 1-h blood pressure measurements after acute ingestion of a salt cocktail with or without addition of a sodium channel blocker effective in vascular endothelium. Differential analysis of the changes in diastolic blood pressure (net ∆DP) identified 12 individuals (63 %) as being salt resistant (net ∆DP = −0.05 ± 0.62 mmHg) and seven individuals (37 %) as being salt sensitive (net ∆DP = +6.98 ± 0.75 mmHg). Vascular salt sensitivity was not related to the age of the study participants. It is concluded that the SPT could be useful for identifying vascular salt sensitivity in humans already early in life.
doi:10.1007/s00424-012-1128-5
PMCID: PMC3423571  PMID: 22744228
Epithelial sodium channel (ENaC); Amiloride; Hypertension; Endothelial glycocalyx; Salt provocation test
3.  Fenofibrate lowers blood pressure in salt-sensitive but not salt-resistant hypertension 
Journal of hypertension  2013;31(4):820-829.
Objective
Peroxisome proliferator-activated receptor α agonists reduce blood pressure in rodents, but clinical trials provide conflicting data regarding their effects in humans. We tested the hypothesis that the effect of fenofibrate on blood pressure depends on salt sensitivity.
Methods
Thirty-one hypertensive volunteers (17 salt-resistant, 14 salt-sensitive) completed a randomized, crossover, double-blind protocol with three dietary phases: low salt diet (10 mmol/day) followed by two consecutive high salt diets (200 mmol/day), each for 6 days. During high salt, volunteers were randomized to fenofibrate 160 mg/day or placebo. Hemodynamic and metabolic parameters were measured on the last morning of each treatment arm.
Results
Fenofibrate reduced triglycerides similarly in salt-sensitive and salt-resistant volunteers. Fenofibrate did not affect blood pressure in salt-resistant volunteers. In salt-sensitive volunteers, fenofibrate significantly decreased diastolic (P =0.02 versus placebo) and mean arterial (P = 0.04 versus placebo) blood pressure during high salt. In all volunteers, the decrease in systolic pressure during fenofibrate correlated inversely with the salt sensitivity of mean arterial pressure as a continuous variable. Fenofibrate significantly decreased heart rate, plasma renin activity, and renal vascular resistance during high salt in salt-sensitive volunteers, but not salt-resistant volunteers. Fenofibrate did not affect sodium excretion or weight gain during high salt. The effect of salt intake and fenofibrate on plasma and urine epoxyeicosatrienoic acid concentrations differed in salt-resistant and salt-sensitive volunteers.
Conclusion
Fenofibrate reduces blood pressure, heart rate and renal vasoconstriction in salt-sensitive volunteers, but not in salt-resistant volunteers. These findings have implications for the treatment of hyperlipidemia in hypertensive individuals.
doi:10.1097/HJH.0b013e32835e8227
PMCID: PMC3800119  PMID: 23385647
blood pressure; fenofibrate; hypertension; peroxisome proliferator-activated receptor α; salt
4.  Lack of Association between Self-reported Saltiness of Eating and Actual Salt Intake 
Background
Reducing salt intake is known to be an important factor for lowering blood pressure and preventing cardiovascular disease. Estimating amount of salt intake is a necessary step towards salt intake reduction. Self-reported saltiness of diet is a method most easily used to measure a patient's salt intake. The purpose of this study was to examine the value of self-reported saltiness of diet in measuring salt intake.
Methods
We used data from 681 participants who visited a health center at a university hospital between August 2003 and November 2005. A self-administered questionnaire was used to collect information on self-reported saltiness of diet, other dietary habits and lifestyle factors. Salt intake was estimated on the basis of 24-hour dietary recall with a computer-aided nutritional analysis program (CAN-Pro 2.0, Korean Nutrition Society).
Results
There was no statistically significant difference between the mean salt intake of the self-reported salty diet group (13.7 ± 4.8 g/d) and the self-reported unsalty diet group (13.3 ± 4.4 g/d). If we assume calculated salt intake as the gold standard, the sensitivity and specificity of self-reported saltiness were 39.5% and 63.6%, respectively. Salt intake was increased with higher calorie intake, frequency of eating breakfast (≥5 times/wk) and being satiated with usual diet in men, but it was increased only with higher calorie intake in women. Regardless of actual salt intake, the group satiated with a usual diet tended to be in the group of self-reported salty diet.
Conclusion
Self-reported saltiness of diet was not associated with actual salt intake. Further studies will be needed on the simpler and more objective tools to estimate salt intake.
doi:10.4082/kjfm.2012.33.2.94
PMCID: PMC3383500  PMID: 22745893
Saltiness; Salt Intake; Self Report; Diet Records
5.  Influence of salty food preference on daily salt intake in primary care 
Purpose
A salt preference questionnaire may be a convenient and cost-effective method for predicting salt intake; however, the influence of salt preference on daily salt intake is unclear. This study aimed at revealing the effectiveness of the salt preference question in determining the daily salt intake in primary care outpatients.
Patients and methods
This cross-sectional study included 1,075 outpatients (men, n=436, 40.6%) at six primary care institutions in Japan. Primary outcomes included a salty food preference assessed by using one question and a daily salt intake, assessed using early morning second urine samples. Multivariate analyses determined the relationships between the salt intake and the two salt preference levels.
Results
The mean age was 67.6±14.6 years, and 594 (55.3%) preferred salty foods. The daily salt intake was 12.3±4.0 g per day and 11.4±3.7 g per day in the salt preference and nonsalt preference groups, respectively (P<0.001). A salt intake <10 g per day was consumed by 169 (28.5%) and 181 (37.6%) patients (P=0.001), respectively, and <6 g salt per day was consumed by 28 (4.7%) and 26 (5.4%) patients (P=0.606), respectively. The patients who preferred salty foods consumed a significantly larger amount of salt per day than those who did not prefer salty foods (β coefficient, 0.621; 95% confidence interval [CI], 0.146–1.095). There was no difference in the number of patients who consumed <10 g salt per day (adjusted odds ratio [ad-OR], 1.29; 95% CI, 0.99–1.69) or <6 g salt per day (ad-OR, 1.39; 0.90–1.69) between the groups.
Conclusion
Preference for salty foods was positively associated with daily salt intake. However, daily salt intake was not always appropriate, even in the patients who did not prefer salty foods. Behavioral interventions for salt restriction after an assessment of daily salt intake are necessary for primary care patients, regardless of their preference for salty foods.
doi:10.2147/IJGM.S60997
PMCID: PMC3998866  PMID: 24790467
salt preference; daily salt intake; outpatients; primary care; salt restriction; spot urine method
6.  Modulation of Endothelial Glycocalyx Structure under Inflammatory Conditions 
Mediators of Inflammation  2014;2014:694312.
The glycocalyx of the endothelium is an intravascular compartment that creates a barrier between circulating blood and the vessel wall. The glycocalyx is suggested to play an important role in numerous physiological processes including the regulation of vascular permeability, the prevention of the margination of blood cells to the vessel wall, and the transmission of shear stress. Various theoretical models and experimental approaches provide data about changes to the structure and functions of the glycocalyx under various types of inflammatory conditions. These alterations are suggested to promote inflammatory processes in vessels and contribute to the pathogenesis of number of diseases. In this review we summarize current knowledge about the modulation of the glycocalyx under inflammatory conditions and the consequences for the course of inflammation in vessels. The structure and functions of endothelial glycocalyx are briefly discussed in the context of methodological approaches regarding the determination of endothelial glycocalyx and the uncertainty and challenges involved in glycocalyx structure determination. In addition, the modulation of glycocalyx structure under inflammatory conditions and the possible consequences for pathogenesis of selected diseases and medical conditions (in particular, diabetes, atherosclerosis, ischemia/reperfusion, and sepsis) are summarized. Finally, therapeutic strategies to ameliorate glycocalyx dysfunction suggested by various authors are discussed.
doi:10.1155/2014/694312
PMCID: PMC3997148  PMID: 24803742
7.  STUDIES UPON CALCAREOUS DEGENERATION  
It will be seen from the above that we have studied the conditions associated with the deposit of calcareous salts: (I) in connection with normal and pathological ossification, and (2) in pathological calcification as exhibited in (a) atheroma of the vessels; (b) calcification of caseating tubercular lesions; (c) calcification of inflammatory new growth, and (d) degenerating tumors; and we have induced experimentally deposits of calcareous salts in the lower animals: (a) within celloidin capsules containing fats and soaps; (b) in the kidney, and (c) in connection with fat necrosis. I. We have found that bone formation and pathological calcareous infiltration are wholly distinct processes. In the former there is no evidence of associated fatty change, and the cells associated with the process of deposition of calcium are functionally active. In the latter there is an antecedent fatty change in the affected areas, and the cells involved present constant evidences of degeneration. The view that would seem to account best for the changes observed in the latter case is that with lowered vitality the cells are unable to utilize the products brought to them by the blood, or which they continue to absorb, so that the normal series of decompositions associated with their metabolism fails to take place and hence they interact among themselves in the cytoplasm with the result that insoluble compounds replace soluble ones. II. Besides the fact that calcification is always preceded by fatty change within the cells, another fact should be emphasized. namely: that combination of the fats present with calcium salts to form calcium soaps tends to occur. The stages immediately preceding these are difficult to follow with anything approaching certainty, perhaps because the earlier stages vary under different conditions. In fat necrosis, for instance, the cells affected are normally storehouses for neutral fats, and as long as they remain healthy neutral fats alone are present in them. When they are subjected to the action of the pancreatic juice with its fat-splitting ferment the cells are killed and coincidently the neutral fats are decomposed, fatty acids being deposited. The fatty acids now slowly combine with the calcium salts. In degenerating lipomata the process would seem to be similar. But in other cases the cells are not obviously fat-containing in the normal state; nevertheless prior to calcification they undergo so-called fatty degeneration, which is really a form of cell degeneration accompanied by fat infiltration. As regards the source of the cell fats in general we may safely accept: 1. That fats are transported in the blood as diffusible soaps. 2. That taken up by the cells these soaps may either— (a) Be reconverted into neutral fats and become stored in the cytoplasm as such, or (b) undergo assimilation proper, becoming part and parcel of the cell substance, in which case they are not recognizable by the ordinary microchemical tests. 3. If these two possibilities be accepted it follows that the appearance of fats and soaps in the degenerating cell may be due to either— (a) Absorption or infiltration of soaps from the surrounding medium, the degenerating cell retaining the power of splitting off the fat but being unable to utilize this in metabolism. (b) Cytoplasmic disintegration with dissociation of the soap-albumen combination or, more broadly, liberation of the fats from their combination with the cytoplasm. The appearances seen in the cells of atheromatous areas indicate that the first of these does occur. III. In areas undergoing calcareous infiltration we have demonstrated. the presence of soaps, and this often in such quantities that they can be isolated and estimated by gross chemical methods. By microchemical methods also we have been able to show that after removing all the neutral fats and fatty acids by petroleum ether there remains behind a substance giving with Sudan III the reaction we associate with the presence of soap. And experimentally we have produced these soaps within the organism, more particularly by placing capsules containing fats and fatty acids within the tissues and after several days finding that the capsules contain calcium soaps and possess a calcium content far in excess of that of the normal blood and lymph. IV. While these are the facts, certain of the details of this reaction demand elucidation. The existence of sodium and it may be potassium soaps in the degenerated cells is comprehensible if we accept that these are present in the circulating lymph and simply undergoing absorption. But even then, as these are diffusible substances how is it to be explained that they become stored up in these particular areas? We have found that, as a matter of fact, in regions which give the reaction for soaps, but which give no reaction for calcium (which therefore presumably contain at most amounts of the insoluble calcium soap too small to need consideration, the ordinary solvents for potassium and sodium soaps do not forthwith remove the stainable material; they are relatively insoluble. The reason for this insolubility is suggested by the observations made in the test tube, that soap solutions mixed with solutions of white of egg or blood serum form a precipitate of combined soap and albumen, which likewise is insoluble in water and alcohol. The indications are therefore that in cells undergoing degeneration, with degeneration of the cytoplasm, certain albuminous molecules unite with the soaps present to form relatively insoluble soap-albuminate. V. With regard to calcium soaps, these are also present and in certain stages appear to be the dominating form in the affected tissues. Two questions suggest themselves, viz.: what is the source of calcium, and what is the process by which they become formed? As to the source, the amount present in well-marked calcification is far in excess of the normal calcium contents of the affected tissue. If in the kidneys of experimental calcification three hundred times as much calcium may be present as in the normal kidney (von Kossa), the calcium must be conveyed to the part by the blood and lymph, and that this is so is demonstrated, as we have pointed out, by the distribution of the infiltration in solid organs, that like ovarian fibroids have undergone necrosis, in which the earliest deposits are superficial. As to the process, there are three possibilities: 1. That sodium and potassium soaps and soap albuminates are first formed and that interaction occurs between them and the diffused calcium salts from the lymph, the less soluble-calcium replacing the sodium and potassium. 2. That under certain conditions the calcium salts act directly on the neutral fats present in the degenerating cells. 3. That the neutral fats are first broken down into fatty acids and that these react with the calcium salts to form the soaps. We are assured that the first process occurs and that because in the boundary zone of areas of calcification we can detect soapy particles devoid of calcium, identical in position and arrangement with the particles more deeply placed which give the calcium reactions. But this is not the only reaction. In case of fat necrosis we see clearly that the third process is in evidence. And we are far from being convinced that the second does not also obtain. We have been impressed by the large accumulation of neutral fats in the cells in cases of early atheroma and the absence at any stage of the process of recognizable fatty acid. While soaps, it is true, are compounds of fatty acids with alkalies, it is recognized in ordinary domestic life that they can be formed by the direct action of strong lye upon ordinary fats, and this even in the cold. It is quite possible therefore that there occurs a similar direct process in the organism. The point is worth noting, however, that this does not occur in healthy cells the seat of fatty infiltration. We therefore leave this an open question, only laying down that, as indicated by the hyalin albuminous matrix left when calcium salts are dissolved out of an area of calcification, there must exist a calcium soap- or fat-albuminate similar to the potassium and sodium soap-albuminates already mentioned—such an albuminate as we can form with calcium soaps in the test tube. VI. In old areas of calcification soaps are largely if not entirely wanting, although these are to be detected at the periphery, when the process is still advancing. The reactions given by these older areas are almost entirely those of calcium phosphate, though some calcium carbonate is at times to be made out. This seems surely to indicate that the final stage in calcification is an interaction between the calcium soap-albuminates and substances containing phosphoric and carbonic acids. Such substances, it is needless to say, are present in considerable amounts in the lymph and blood. We must conclude that the acid sodium phosphates of the lymph act on the calcium soap, the highly insoluble calcium phosphates being formed (plus the albuminous moiety of the original compound) and diffusible sodium soap being liberated, while similarly alkaline carbonates form calcium carbonate and liberate sodium and potassium soaps. Calcium phosphate and calcium carbonate thus become the insoluble earthy salts of old crystalline areas of calcification. VII. As already stated very little soap is to be found in these old areas. It is possibly worth suggestion that the soaps liberated in this last reaction, as they diffuse out, again react with diffusible calcium salts and form calcium soaps which once more react with the alkaline salts to produce the phosphates and carbonates; that, in short, they have a katalytic action. Certain it is that old calcareous areas are extraordinarily dense, and have a coarse crystalline structure, wholly at variance with the finely granular appearance of the more recent areas, and these large crystalline masses, it would seem, can only be formed by successive deposition of new material and eventual fusion, as the interspaces become filled in between the original masses.
PMCID: PMC2124594  PMID: 19867016
8.  A MECHANISM FOR SALT SENSITIVE HYPERTENSION: ABNORMAL DIETARY SODIUM MEDIATED VASCULAR RESPONSE TO ANGIOTENSIN II 
Journal of hypertension  2010;28(5):1020-1026.
Objectives
Several mechanisms have been proposed for salt-sensitive hypertension with most focusing on impaired renal sodium handling. We tested the hypothesis that abnormalities in peripheral vascular responsiveness to angiotensin-II might also exist in salt-sensitive hypertension because of the interplay of the renin-angiotensin system and dietary sodium.
Methods
Blood pressure response to angiotensin-II infusion was studied in 295 hypertensives and 165 normotensives after 7 days of high (200 mEq/day) and low (10 mEq/day) dietary sodium.
Results
Normotensives demonstrated higher blood pressure response to angiotensin-II on high-salt than low-salt diet whereas hypertensives had similar responses on both diets, i.e., the high-salt response was not enhanced compared to low-salt. Additionally, hypertensives had a significantly greater high-salt blood pressure response to norepinephrine than to angiotensin-II. There was no correlation between the high-salt hormone levels and the difference in blood pressure response to angiotensin-II between the two diets. When stratified by blood pressure response to dietary salt restriction, individuals with salt sensitivity of blood pressure demonstrated abnormal high-salt blood pressure responsiveness to angiotensin-II. To assess if this represented increased tissue renin-angiotensin system activity in the vasculature, blood pressure responses to angiotensin were compared before and after captopril in 20 hypertensives on a high-salt diet. Subjects with the greatest blood pressure lowering effect to captopril had similar high and low-salt blood pressure responses to angiotensin-II at baseline and a significant increase in the high-salt response after captopril.
Conclusion
Hypertensives have an abnormal vascular response to angiotensin-II infusion on a high-salt diet. Dysregulated tissue renin-angiotensin system activity may play a role in this abnormal response. These findings raise an intriguing novel possibility for the pathophysiologic mechanism of salt-sensitive hypertension.
doi:10.1097/HJH.0b013e3283375974
PMCID: PMC2945810  PMID: 20216091
hypertension; salt sensitivity; salt-sensitive; sodium; angiotensin II response; tissue renin-angiotensin system
9.  Lifestyle modifications to prevent and control hypertension. 5. Recommendations on dietary salt. Canadian Hypertension Society, Canadian Coalition for High Blood Pressure Prevention and Control, Laboratory Centre for Disease Control at Health Canada, Heart and Stroke Foundation of Canada 
OBJECTIVE: To provide updated, evidence-based recommendations concerning the effects of dietary salt intake on the prevention and control of hypertension in adults (except pregnant women). The guidelines are intended for use in clinical practice and public education campaigns. OPTIONS: Restriction of dietary salt intake may be an alternative to antihypertensive medications or may supplement such medications. Other options include other nonpharmacologic treatments for hypertension and no treatment. OUTCOMES: The health outcomes considered were changes in blood pressure and in morbidity and mortality rates. Because of insufficient evidence, no economic outcomes were considered. EVIDENCE: A MEDLINE search was conducted for the period 1966-1996 using the terms hypertension, blood pressure, vascular resistance, sodium chloride, sodium, diet, sodium or sodium chloride dietary, sodium restricted/reducing diet, clinical trials, controlled clinical trial, randomized controlled trial and random allocation. Both trials and review articles were obtained, and other relevant evidence was obtained from the reference lists of the articles identified, from the personal files of the authors and through contacts with experts. The articles were reviewed, classified according to study design and graded according to level of evidence. In addition, a systematic review of all published randomized controlled trials relating to dietary salt intake and hypertension was conducted. VALUES: A high value was placed on the avoidance of cardiovascular morbidity and premature death caused by untreated hypertension. BENEFITS, HARMS AND COSTS: For normotensive people, a marked change in sodium intake is required to achieve a modest reduction in blood pressure (there is a decrease of 1 mm Hg in systolic blood pressure for every 100 mmol decrease in daily sodium intake). For hypertensive patients, the effects of dietary salt restriction are most pronounced if age is greater than 44 years. A decrease of 6.3 mm Hg in systolic blood pressure and 2.2 mm Hg in diastolic blood pressure per 100 mmol decrease in daily sodium intake was observed in people of this age group. For hypertensive patients 44 years of age and younger, the decreases were 2.4 mm Hg for systolic blood pressure and negligible for diastolic blood pressure. A diet in which salt is moderately restricted appears not to be associated with health risks. RECOMMENDATIONS: (1) Restriction of salt intake for the normotensive population is not recommended at present, because of insufficient evidence demonstrating that this would lead to a reduced incidence of hypertension. (2) To avoid excessive intake of salt, people should be counselled to choose foods low in salt (e.g., fresh fruits and vegetables), to avoid foods high in salt (e.g., pre-prepared foods), to refrain from adding salt at the table and minimize the amount of salt used in cooking, and to increase awareness of the salt content of food choices in restaurants. (3) For hypertensive patients, particularly those over the age of 44 years, it is recommended that the intake of dietary sodium be moderately restricted, to a target range of 90-130 mmol per day (which corresponds to 3-7 g of salt per day). (4) The salt consumption of hypertensive patients should be determined by interview. VALIDATION: These recommendations were reviewed by all of the sponsoring organizations and by participants in a satellite symposium of the fourth International Conference on Preventive Cardiology. They have not been clinically tested. SPONSORS: The Canadian Hypertension Society, the Canadian Coalition for High Blood Pressure Prevention and Control, the Laboratory Centre for Disease Control at Health Canada, and the Heart and Stroke Foundation of Canada.
PMCID: PMC1230337  PMID: 10333851
10.  Two barriers for sodium in vascular endothelium? 
Annals of Medicine  2012;44(Suppl 1):S143-S148.
Vascular endothelium plays a key role in blood pressure regulation. Recently, it has been shown that a 5% increase of plasma sodium concentration (sodium excess) stiffens endothelial cells by about 25%, leading to cellular dysfunction. Surface measurements demonstrated that the endothelial glycocalyx (eGC), an anionic biopolymer, deteriorates when sodium is elevated. In view of these results, a two-barrier model for sodium exiting the circulation across the endothelium is suggested. The first sodium barrier is the eGC which selectively buffers sodium ions with its negatively charged prote-oglycans.The second sodium barrier is the endothelial plasma membrane which contains sodium channels. Sodium excess, in the presence of aldosterone, leads to eGC break-down and, in parallel, to an up-regulation of plasma membrane sodium channels. The following hypothesis is postulated: Sodium excess increases vascular sodium permeability. Under such con-ditions (e.g. high-sodium diet), day-by-day ingested sodium, instead of being readily buffered by the eGC and then rapidly excreted by the kidneys, is distributed in the whole body before being finally excreted. Gradually, the sodium overload damages the organism.
doi:10.3109/07853890.2011.653397
PMCID: PMC3470790  PMID: 22471931
Aldosterone; atomic force microscopy; endothelial dysfunction; endothelial glycocalyx; epithelial sodium channel; hypertension; mechanical stiffness; salt intake; spironolactone; stiff endothelial cell syndrome
11.  Chronic angiotensin II infusion causes differential responses in regional sympathetic nerve activity in rats 
Hypertension  2010;55(3):644-651.
Angiotensin II (AngII) – induced hypertension in experimental animals has been proposed to be due in part to activation of the sympathetic nervous system. This sympathetic activation appears to be accentuated in animals consuming a high salt diet (AngII-salt hypertension). However, accurate quantification of sympathetic activity is difficult and controversy remains. A particularly important question is: What are the critical vascular beds targeted by increased sympathetic nerve activity (SNA) in AngII-salt hypertension? To address this issue, mean arterial pressure (MAP) and renal (RSNA) or lumbar SNA (LSNA) were continuously recorded during a 5 day control period, 11 days of AngII (150 ng/kg/min, sc) and a 5 day recovery period in conscious rats on a high salt (2% NaCl) diet. Whereas MAP reached a new steady-state level of 30-35 mmHg above control levels by the end of the AngII period, RSNA decreased by 40% during the first 7 days of AngII and then returned towards control levels by day 10 of AngII. In contrast, LSNA remained at control levels throughout the AngII period. In another experiment we measured hindlimb norepinephrine (NE) spillover in conscious rats on normal (0.4%) or high (2.0%) salt diets before and during 14 days of AngII administration. AngII had no significant affect on hindlimb NE spillover in either group. We conclude that chronic AngII modulates renal and lumbar SNA differentially in rats consuming a high salt diet and that AngII-salt hypertension in the rat is not caused by increased SNA to the renal or hindlimb vascular beds.
doi:10.1161/HYPERTENSIONAHA.109.145110
PMCID: PMC2856065  PMID: 20100996
hypertension; renal nerve activity; lumbar nerve activity; norepinephrine spillover; sympathetic
12.  Spatio-temporal development of the endothelial glycocalyx layer and its mechanical property in vitro 
The endothelial glycocalyx is a thin layer of polysaccharide matrix on the luminal surface of endothelial cells (ECs), which contains sulphated proteoglycans and glycoproteins. It is a mechanotransducer and functions as an amplifier of the shear stress on ECs. It controls the vessel permeability and mediates the blood–endothelium interaction. This study investigates the spatial distribution and temporal development of the glycocalyx on cultured ECs, and evaluates mechanical properties of the glycocalyx using atomic force microscopy (AFM) nano-indentation. The glycocalyx on human umbilical vein endothelial cells (HUVECs) is observed under a confocal microscope. Manipulation of the glycocalyx is achieved using heparanase or neuraminidase. The Young's modulus of the cell membrane is calculated from the force–distance curve during AFM indentation. Results show that the glycocalyx appears predominantly on the edge of cells in the early days in culture, e.g. up to day 5 after seeding. On day 7, the glycocalyx is also seen in the apical area of the cell membrane. The thickness of the glycocalyx is approximately 300 nm–1 μm. AFM indentation reveals the Young's modulus of the cell membrane decreases from day 3 (2.93 ± 1.16 kPa) to day 14 (0.35 ± 0.15 kPa) and remains unchanged to day 21 (0.33 ± 0.19 kPa). Significant difference in the Young's modulus is also seen between the apical (1.54 ± 0.58 kPa) and the edge (0.69 ± 0.55 kPa) of cells at day 7. By contrast, neuraminidase-treated cells (i.e. without the glycocalyx) have similar values between day 3 (3.18 ± 0.88 kPa), day 14 (2.12 ± 0.78 kPa) and day 21 (2.15 ± 0.48 kPa). The endothelial glycocalyx in vitro shows temporal development in the early days in culture. It covers predominantly the edge of cells initially and appears on the apical membrane of cells as time progresses. The Young's modulus of the glycocalyx is deduced from Young's moduli of cell membranes with and without the glycocalyx layer. Our results show the glycocalyx on cultured HUVECs has a Young's modulus of approximately 0.39 kPa.
doi:10.1098/rsif.2011.0901
PMCID: PMC3405740  PMID: 22417911
vascular endothelium; the glycocalyx; confocal microscopy; atomic force microscopy nano-indentation; Young's modulus
13.  High dietary salt does not significantly affect plasma 25-hydroxyvitamin D concentrations of Sprague Dawley rats 
BMC Research Notes  2010;3:332.
Background
The Dahl salt-sensitive rat, but not the Dahl salt-resistant rat, develops hypertension and hypovitaminosis D when fed a high salt diet. Since the salt-sensitive rat and salt-resistant rat were bred from the Sprague Dawley rat, the aim of this research was to test the hypothesis that salt-resistant and Sprague Dawley rats would be similar in their vitamin D endocrine system response to high salt intake.
Findings
Sprague Dawley, salt-sensitive, and salt-resistant rats were fed high (80 g/kg, 8%) or low (3 g/kg, 3%) salt diets for three weeks. The blood pressure of Sprague Dawley rats increased from baseline to week 3 during both high and low salt intake and the mean blood pressure at week 3 of high salt intake was higher than that at week 3 of low salt intake (P < 0.05). Mean plasma 25-hydroxyvitamin D concentrations (marker of vitamin D status) of Sprague Dawley, salt-sensitive, and salt-resistant rats were similar at week 3 of low salt intake. Mean plasma 25-hydroxyvitamin D concentrations of Sprague Dawley and salt-resistant rats were unaffected by high salt intake, whereas the mean plasma 25-hydroxyvitamin D concentration of salt-sensitive rats at week 3 of high salt intake was only 20% of that at week 3 of low salt intake.
Conclusions
These data indicate that the effect of high salt intake on the vitamin D endocrine system of Sprague Dawley rats at week 3 was similar to that of salt-resistant rats. The salt-sensitive rat, thus, appears to be a more appropriate model than the Sprague Dawley rat for assessing possible effects of salt-sensitivity on vitamin D status of humans.
doi:10.1186/1756-0500-3-332
PMCID: PMC3018403  PMID: 21143930
14.  Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus 
Diabetologia  2010;53(12):2646-2655.
Aims/hypothesis
Endothelial glycocalyx perturbation contributes to increased vascular permeability. In the present study we set out to evaluate whether: (1) glycocalyx is perturbed in individuals with type 2 diabetes mellitus, and (2) oral glycocalyx precursor treatment improves glycocalyx properties.
Methods
Male participants with type 2 diabetes (n = 10) and controls (n = 10) were evaluated before and after 2 months of sulodexide administration (200 mg/day). The glycocalyx dimension was estimated in two different vascular beds using sidestream dark field imaging and combined fluorescein/indocyanine green angiography for sublingual and retinal vessels, respectively. Transcapillary escape rate of albumin (TERalb) and hyaluronan catabolism were assessed as measures of vascular permeability.
Results
Both sublingual dimensions (0.64 [0.57–0.75] μm vs 0.78 [0.71–0.85] μm, p < 0.05, medians [interquartile range]) and retinal glycocalyx dimensions (5.38 [4.88–6.59] μm vs 8.89 [4.74–11.84] μm, p < 0.05) were reduced in the type 2 diabetes group compared with the controls whereas TERalb was increased (5.6 ± 2.3% vs 3.7 ± 1.7% in the controls, p < 0.05). In line with these findings, markers of hyaluronan catabolism were increased with diabetes (hyaluronan 137 ± 29 vs 81 ± 8 ng/ml and hyaluronidase 78 ± 4 vs 67 ± 2 U/ml, both p < 0.05). Sulodexide increased both the sublingual and retinal glycocalyx dimensions in participants with diabetes (to 0.93 [0.83–0.99] μm and to 5.88 [5.33–6.26] μm, respectively, p < 0.05). In line, a trend towards TERalb normalisation (to 4.0 ± 2.3%) and decreases in plasma hyaluronidase (to 72 ± 2 U/ml, p < 0.05) were observed in the diabetes group.
Conclusion/interpretation
Type 2 diabetes is associated with glycocalyx perturbation and increased vascular permeability, which are partially restored following sulodexide administration. Further studies are warranted to determine whether long-term treatment with sulodexide has a beneficial effect on cardiovascular risk.
Trial registration
www.trialregister.nl NTR780/http://isrctn.org ISRCTN82695186
Funding
An unrestricted Novartis Foundation for Cardiovascular Excellence grant (2006) to M. Nieuwdorp/E. S. G. Stroes, Dutch Heart Foundation (grant number 2005T037)
doi:10.1007/s00125-010-1910-x
PMCID: PMC2974920  PMID: 20865240
Diabetes mellitus type 2; Endothelial glycocalyx; Hyaluronan; Sulodexide; Vascular permeability
15.  Potassium Inhibits Dietary Salt-Induced Transforming Growth Factor-β Production 
Hypertension  2009;54(5):1159-1163.
Human and animal studies demonstrate an untoward effect of excess dietary NaCl (salt) intake on cardiovascular function and life span. The endothelium in particular augments the production of transforming growth factor (TGF)-β, a fibrogenic growth factor, in response to excess dietary salt intake. This study explored the initiating mechanism that regulates salt-induced endothelial cell production of TGF-β. Male Sprague-Dawley rats were given diets containing different amounts of NaCl and potassium for 4 days. A bioassay for TGF-β demonstrated increased (35.2%) amounts of active TGF-β in the medium of aortic ring segments from rats on the high-salt diet compared with rats maintained on a 0.3% NaCl diet. Inhibition of the large-conductance, calcium-activated potassium channel inhibited dietary salt-induced vascular production of TGF-β but did not affect production of TGF-β by ring segments from rats on the low-salt diet. Immunohistochemical and Western analyses demonstrated the α subunit of the calcium-activated potassium channel in endothelial cells. Increasing medium [K+] inhibited production of dietary salt-induced vascular production levels of total and active TGF-β but did not alter TGF-β production by aortic rings from rats on the 0.3% NaCl diet. Increasing dietary potassium content decreased urinary active TGF-β in animals receiving the high-salt diet but did not change urinary active TGF-β in animals receiving the low-salt diet. The findings demonstrated an interesting interaction between the dietary intake of potassium and excess NaCl and further showed the fundamental role of the endothelial calcium-activated potassium channel in the vascular response to excess salt intake.
doi:10.1161/HYPERTENSIONAHA.109.138255
PMCID: PMC2766016  PMID: 19738156
dietary sodium chloride; potassium channel; endothelium; aorta; iberiotoxin; physiology
16.  Whole-body recruitment of glycocalyx volume during intravenous adenosine infusion 
Physiological Reports  2013;1(5):e00102.
Adenosine-mediated recruitment of microvascular volume in heart and muscle has been suggested to include, in addition to vasodilation of resistance vessels, an increased accessibility of the endothelial glycocalyx for flowing plasma as a result of an impairment of its barrier properties. The aim of the current study was to investigate the effect of systemic intravenous administration of adenosine on the glycocalyx-dependent exclusion of circulating blood at a whole-body level. In anesthetized goats (N = 6), systemic blood-excluded glycocalyx volume was measured by comparing the intravascular distribution volume of the suggested glycocalyx accessible tracer dextrans with a molecular weight of 40 kDa (Dex-40) to that of circulating plasma, derived from the dilution of labeled red blood cells and large vessel hematocrit. Systemic glycocalyx volume was determined at baseline and during intravenous infusion of adenosine (157 ± 11.6 μg/kg min−1). Blood-inaccessible glycocalyx volume decreased from 458.1 ± 95.5 to 18.1 ± 62.2 mL (P < 0.01) during adenosine administration. While circulating plasma volume did not change significantly (617.1 ± 48.5 vs. 759.2 ± 47.9 mL, NS), the decrease in blood-excluded glycocalyx volume was associated with a decrease in Dex-40 distribution volume (from 1075.2 ± 71.0 to 777.3 ± 60.0 mL, P < 0.01). Intravenous administration of adenosine is associated with a robust impairment of whole-body glycocalyx barrier properties, reflected by a greatly reduced exclusion of circulating blood compared to small dextrans. The observed decrease in Dex-40 distribution volume suggests that the reduction in glycocalyx volume coincides with a reduction in tracer-accessible vascular volume.
doi:10.1002/phy2.102
PMCID: PMC3841038  PMID: 24303174
Adenosine; glycocalyx; indicator dilution; systemic
17.  Eplerenone prevents salt-induced vascular stiffness in Zucker diabetic fatty rats: a preliminary report 
Background
Aldosterone levels are elevated in a rat model of type 2 diabetes mellitus, the Zucker Diabetic fatty rat (ZDF). Moreover blood pressure in ZDF rats is salt-sensitive. The aim of this study was to examine the effect of the aldosterone antagonist eplerenone on structural and mechanical properties of resistance arteries of ZDF-rats on normal and high-salt diet.
Methods
After the development of diabetes, ZDF animals were fed either a normal salt diet (0.28%) or a high-salt diet (5.5%) starting at an age of 15 weeks. ZDF rats on high-salt diet were randomly assigned to eplerenone (100 mg/kg per day, in food) (ZDF+S+E), hydralazine (25 mg/kg per day) (ZDF+S+H), or no treatment (ZDF+S). Rats on normal salt-diet were assigned to eplerenone (ZDF+E) or no treatment (ZDF). Normoglycemic Zucker lean rats were also divided into two groups receiving normal (ZL) or high-salt diet (ZL+S) serving as controls. Systolic blood pressure was measured by tail cuff method. The experiment was terminated at an age of 25 weeks. Mesenteric resistance arteries were studied on a pressurized myograph. Specifically, vascular hypertrophy (media-to-lumen ratio) and vascular stiffness (strain and stress) were analyzed. After pressurized fixation histological analysis of collagen and elastin content was performed.
Results
Blood pressure was significantly higher in salt-loaded ZDF compared to ZDF. Eplerenone and hydralazine prevented this rise similarily, however, significance niveau was missed. Media-to-lumen ratio of mesenteric resistance arteries was significantly increased in ZDF+S when compared to ZDF and ZL. Both, eplerenone and hydralazine prevented salt-induced vascular hypertrophy. The strain curve of arteries of salt-loaded ZDF rats was significantly lower when compared to ZL and when compared to ZDF+S+E, but was not different compared to ZDF+S+H. Eplerenone, but not hydralazine shifted the strain-stress curve to the right indicating a vascular wall composition with less resistant components. This indicates increased vascular stiffness in salt-loaded ZDF rats, which could be prevented by eplerenone but not by hydralazine. Collagen content was increased in ZL and ZDF rats on high-salt diet. Eplerenone and hydralazine prevented the increase of collagen content. There was no difference in elastin content.
Conclusion
Eplerenone and hydralazine prevented increased media-to-lumen ratio in salt-loaded ZDF-rats, indicating a regression of vascular hypertrophy, which is likely mediated by the blood pressure lowering-effect. Eplerenone has additionally the potential to prevent increased vascular stiffness in salt-loaded ZDF-rats. This suggests an effect of the specific aldosterone antagonist on adverse vascular wall remodelling.
doi:10.1186/1475-2840-10-94
PMCID: PMC3217853  PMID: 22008236
18.  Knowledge and practices of people in Bia District, Ghana, with regard to iodine deficiency disorders and intake of iodized salt 
Background
Despite numerous educational programmes to create awareness about iodized salt and iodine deficiency disorders (IDD), a survey conducted in the Western Region of Ghana in 2007 revealed that the goitre rate stood at 18.8%; and 78.1% of households consumed iodized salt, which is below the goal of the IDD programme in Ghana which aimed at 90% household consumption of iodized salt by the end of 2005 and sustaining the gains by 2011. It was therefore, considered timely to investigate the knowledge levels and the extent of utilization of iodized salt among the people living in Bia District, the District with the lowest intake (77.4%) of iodized salt based on findings of the 2007 survey.
Methods
This was a descriptive cross-sectional study. It was conducted among a total of 280 household members, mainly in charge of meal preparation, who were interviewed using a structured interview guide. A combination of cluster and simple random sampling techniques was used to select the respondents from all the seven sub- districts in Bia District.
Results
The study revealed that 75.6% of households in the district consumed iodized salt (including households described as occasional users of iodized salt), and knowledge of iodized salt was quite high, as 72% of the respondents knew that not every salt contained iodine. In addition, 69.3% indicated that an inadequate intake of iodized salt can lead to the development of goitre. Despite the high awareness level, only 64.6% of respondents indicated that they exclusively used iodized salt for cooking. The main reason given by exclusive users of common salt was that the price of iodized salt is a little higher than that of common salt.
Conclusions
Although majority of the respondents are aware of the importance of iodized salt and iodine deficiency disorders, only 64.6% exclusively used iodized salt, suggesting that respondents' high knowledge levels did not necessarily translate into an increase in the number of households who used iodized salt. Existing laws and policies on universal salt iodization and quality assurance of iodized salt from the production stage to the distribution/selling stage should be enforced.
doi:10.1186/0778-7367-70-5
PMCID: PMC3415111  PMID: 22958618
Knowledge; Practices; Iodized salt; Iodine deficiency disorders; Ghana
19.  High Salt Intake Increases Copeptin but Salt Sensitivity Is Associated with Fluid Induced Reduction of Copeptin in Women 
This study investigated if copeptin is affected by high salt intake and whether any salt-induced changes in copeptin are related to the degree of salt sensitivity. The study was performed on 20 men and 19 women. In addition to meals containing 50 mmol NaCl daily, capsules containing 100 mmol NaCl and corresponding placebo capsules were administered during 4 weeks each, in random order. Measurements of 24 h blood pressure, body weight, 24 h urinary volume, and fasting plasma copeptin were performed at high and low salt consumption. Copeptin increased after a high compared to low dietary salt consumption in all subjects 3,59 ± 2,28 versus 3,12 ± 1,95 (P = 0,02). Copeptin correlated inversely with urinary volume, at both low (r = −0,42; P = 0,001) and high (r = −0,60; P < 0,001) salt consumption, as well as with the change in body weight (r = −0,53; P < 0,001). Systolic salt sensitivity was inversely correlated with salt-induced changes of copeptin, only in females (r = −0,58; P = 0,017). As suppression of copeptin on high versus low salt intake was associated with systolic salt sensitivity in women, our data suggest that high fluid intake and fluid retention may contribute to salt sensitivity.
doi:10.1155/2014/641587
PMCID: PMC4227450  PMID: 25405024
20.  A multi-component model of the dynamics of salt-induced hypertension in Dahl-S rats 
BMC Physiology  2009;9:20.
Background
In humans, salt intake has been suggested to influence blood pressure (BP) on a wide range of time scales ranging from several hours or days to many months or years. Detailed time course data collected in the Dahl salt-sensitive rat strain suggest that the development of salt-induced hypertension may consist of several distinct phases or components that differ in their timing and reversibility. To better understand these components, the present study sought to model the dynamics of salt-induced hypertension in the Dahl salt sensitive (Dahl-S) rat using 3 sets of time course data.
Results
The first component of the model ("Acute-Reversible") consisted of a linear transfer function to account for the rapid and reversible effects of salt on BP (ie. acute salt sensitivity, corresponding with a depressed slope of the chronic pressure natriuresis relationship). For the second component ("Progressive-Irreversible"), an integrator function was used to represent the relatively slow, progressive, and irreversible effect of high salt intake on BP (corresponding with a progressive salt-induced shift of the chronic pressure natriuresis relationship to higher BP levels). A third component ("Progressive-Reversible") consisted of an effect of high salt intake to progressively increase the acute salt-sensitivity of BP (ie. reduce the slope of the chronic pressure natriuresis relationship), amounting to a slow and progressive, yet reversible, component of salt-induced hypertension. While the 3 component model was limited in its ability to follow the BP response to rapid and/or brief transitions in salt intake, it was able to accurately follow the slower steady state components of salt-induced BP changes. This model exhibited low values of mean absolute error (1.92 ± 0.23, 2.13 ± 0.37, 2.03 ± 0.3 mmHg for data sets 1 - 3), and its overall performance was significantly improved over that of an initial model having only 2 components. The 3 component model performed well when applied to data from hybrids of Dahl salt sensitive and Dahl salt resistant rats in which salt sensitivity varied greatly in its extent and character (mean absolute error = 1.11 ± 0.08 mmHg).
Conclusion
Our results suggest that the slow process of development of salt-induced hypertension in Dahl-S rats over a period of many weeks can be well represented by a combination of three components that differ in their timing, reversibility, and their associated effect on the chronic pressure natriuresis relationship. These components are important to distinguish since each may represent a unique set of underlying mechanisms of salt-induced hypertension.
doi:10.1186/1472-6793-9-20
PMCID: PMC2785758  PMID: 19874603
21.  Salt content of school meals and comparison of perception related to sodium intake in elementary, middle, and high schools 
Excessive sodium intake leading to hypertension, stroke, and stomach cancer is mainly caused by excess use of salt in cooking. This study was performed to estimate the salt content in school meals and to compare differences in perceptions related to sodium intake between students and staffs working for school meal service. We collected 382 dishes for food from 24 schools (9 elementary, 7 middle, 8 high schools) in Gyeonggi-do and salt content was calculated from salinity and weight of individual food. The average salt content from elementary, middle, and high school meals were 2.44 g, 3.96 g, and 5.87 g, respectively. The amount of salt provided from the school lunch alone was over 80% of the recommended daily salt intake by WHO. Noodles, stews, sauces, and soups were major sources of salt intake at dish group level, while the most salty dishes were sauces, kimchies, and stir-fried foods. Dietary knowledge and attitude related to sodium intake and consumption frequency of the salty dishes were surveyed with questionnaire in 798 students and 256 staffs working for school meal service. Compared with the staffs, the students perceived school meals salty and the proportions of students who thought school meals were salty increased with going up from elementary to high schools (P < 0.001). Among the students, middle and high school students showed significant propensity for the preference to one-dish meal, processed foods, eating much broth and dipping sauce or seasoning compared with the elementary students, although they had higher nutrition knowledge scores. These results proposed that monitoring salt content of school meals and consideration on the contents and education methods in school are needed to lower sodium intake.
doi:10.4162/nrp.2013.7.1.59
PMCID: PMC3572227  PMID: 23424102
School meal; salt content; sodium intake; saltiness perception
22.  Region-specific changes in sympathetic nerve activity in angiotensin II–salt hypertension in the rat 
Experimental physiology  2009;95(1):61-68.
It is now well accepted that many forms of experimental hypertension and human essential hypertension are caused by increased activity of the sympathetic nervous system. However, the role of region-specific changes in sympathetic nerve activity (SNA) in the pathogenesis of hypertension has been difficult to determine because methods for chronic measurement of SNA in conscious animals have not been available. We have recently combined indirect, and continuous and chronic direct, assessment of region-specific SNA to characterize hypertension produced by administration of angiotensin II (Ang II) to rats consuming a high-salt diet (Ang II–salt hypertension). Angiotensin II increases whole-body noradrenaline (NA) spillover and depressor responses to ganglionic blockade in rats consuming a high-salt diet, but not in rats on a normal-salt diet. Despite this evidence for increased ‘whole-body SNA’ in Ang II–salt hypertensive rats, renal SNA is decreased in this model and renal denervation does not attenuate the steady-state level of arterial pressure. In addition, neither lumbar SNA, which largely targets skeletal muscle, nor hindlimb NA spillover is changed from control levels in Ang II–salt hypertensive rats. However, surgical denervation of the splanchnic vascular bed attenuates/abolishes the increase in arterial pressure and total peripheral resistance, as well as the decrease in vascular capacitance, observed in Ang II–salt hypertensive rats. We hypothesize that the ‘sympathetic signature’ of Ang II–salt hypertension is characterized by increased splanchnic SNA, no change in skeletal muscle SNA and decreased renal SNA, and this sympathetic signature creates unique haemodynamic changes capable of producing sustained hypertension.
doi:10.1113/expphysiol.2008.046326
PMCID: PMC2856071  PMID: 19717492
23.  Effects of spironolactone in spontaneously hypertensive adult rats subjected to high salt intake 
Clinics  2011;66(3):477-482.
OBJECTIVE:
To evaluate the effect of spironolactone on ventricular stiffness in spontaneously hypertensive adult rats subjected to high salt intake.
INTRODUCTION:
High salt intake leads to cardiac hypertrophy, collagen accumulation and diastolic dysfunction. These effects are partially mediated by cardiac activation of the renin-angiotensin-aldosterone system.
METHODS:
Male spontaneously hypertensive rats (SHRs, 32 weeks) received drinking water (SHR), a 1% NaCl solution (SHR-Salt), or a 1% NaCl solution with a daily subcutaneous injection of spironolactone (80 mg.kg-1) (SHR-Salt-S). Age-matched normotensive Wistar rats were used as a control. Eight weeks later, the animals were anesthetized and catheterized to evaluate left ventricular and arterial blood pressure. After cardiac arrest, a double-lumen catheter was inserted into the left ventricle through the aorta to obtain in situ left ventricular pressure-volume curves.
RESULTS:
The blood pressures of all the SHR groups were similar to each other but were different from the normotensive controls (Wistar  =  109±2; SHR  =  118±2; SHR-Salt  =  117±2; SHR-Salt-S  =  116±2 mmHg; P<0.05). The cardiac hypertrophy observed in the SHR was enhanced by salt overload and abated by spironolactone (Wistar  =  2.90±0.06; SHR  =  3.44±0.07; SHR-Salt  =  3.68±0.07; SHR-Salt-S  =  3.46±0.05 mg/g; P<0.05). Myocardial relaxation, as evaluated by left ventricular dP/dt, was impaired by salt overload and improved by spironolactone (Wistar  =  -3698±92; SHR  =  -3729±125; SHR-Salt  =  -3342±80; SHR-Salt-S  =  -3647±104 mmHg/s; P<0.05). Ventricular stiffness was not altered by salt overload, but spironolactone treatment reduced the ventricular stiffness to levels observed in the normotensive controls (Wistar  =  1.40±0.04; SHR  =  1.60±0.05; SHR-Salt  =  1.67±0.12; SHR-Salt-S  =  1.45±0.03 mmHg/ml; P<0.05).
CONCLUSION:
Spironolactone reduces left ventricular hypertrophy secondary to high salt intake and ventricular stiffness in adult SHRs.
doi:10.1590/S1807-59322011000300020
PMCID: PMC3072011  PMID: 21552676
Hypertension; Salt Intake; Cardiac Hypertrophy; Ventricular Stiffness; Aldosterone Antagonism
24.  The involvement of prostaglandins in the contractile function of the aorta by aldosterone 
BMC Research Notes  2011;4:125.
Background
Aldosterone, one of the major culprits associated with the renin-angiotensin-aldosterone system (RAAS), is significantly elevated following high salt administration in Dahl rats. Since we have previously demonstrated that aldosterone (ALDO) upregulates cyclooxygenase (COX) expression in the kidney, the present study was design to assess whether prostaglandin release is involved in the effects of chronic aldosterone treatment on vascular function of the aorta from nonhypertensive Dahl salt-sensitive rats.
Findings
The effects of aldosterone on arachidonic acid metabolism and on the expression of cyclooxygenase (COX)-2 were evaluated in the Dahl salt sensitive (DS) rat aorta, renal, femoral and carotid arteries. DS rats on a low salt (0.3% NaCl) diet were treated with or without ALDO for four weeks. Indirect blood pressure (BP), the release of prostacyclin (PGI2) and prostaglandin E2, and the expression of COX-2 were measured to assess the vascular remodelling by aldosterone. Vascular function was also assessed by contractile responsiveness in the aorta to phenylephrine. ALDO increased BP (17 ± 1%) and inhibited the basal release of PGE2. ALDO enhanced vascular reactivity to phenylephrine and up regulated the expression of COX-2 in both aorta and renal vessels but reduced COX-2 expression in the femoral artery.
Conclusions
These data reveal that the effect of ALDO in the vasculature is tissue specific and may involve the inhibition of PGE2 release. Thus, suggesting a role for prostaglandins in the vasculopathic aspects of aldosterone.
doi:10.1186/1756-0500-4-125
PMCID: PMC3094371  PMID: 21492462
25.  Reducing salt intake for prevention of cardiovascular diseases in high-risk patients by advanced health education intervention (RESIP-CVD study), Northern Thailand: study protocol for a cluster randomized trial 
Trials  2012;13:158.
Background
Decreasing salt consumption can prevent cardiovascular diseases (CVD). Practically, it is difficult to promote people’s awareness of daily salt intake and to change their eating habits in terms of reducing salt intake for better cardiovascular health. Health education programs visualizing daily dietary salt content and intake may promote lifestyle changes in patients at high risk of cardiovascular diseases.
Methods/Design
This is a cluster randomized trial. A total of 800 high-CVD-risk patients attending diabetes and hypertension clinics at health centers in Muang District, Chiang Rai province, Thailand, will be studied with informed consent. A health center recruiting 100 participants is a cluster, the unit of randomization. Eight clusters will be randomized into intervention and control arms and followed up for 1 year. Within the intervention clusters the following will be undertaken: (1) salt content in the daily diet will be measured and shown to study participants; (2) 24-hour salt intake will be estimated in overnight-collected urine and the results shown to the participants; (3) a dietician will assist small group health education classes in cooking meals with less salt. The primary outcome is blood pressure change at the 1-year follow-up. Secondary outcomes at the 1-year follow-up are estimated 24-hoursalt intake, incidence of CVD events and CVD death. The intention-to-treat analysis will be followed.
Blood pressure and estimated 24-hour salt intake will be compared between intervention and control groups at the cluster and individual level at the 1-year follow-up. Clinical CVD events and deaths will be analyzed by time-event analysis. Retinal blood vessel calibers of CVD-risk patients will be assessed cross-sectionally. Behavioral change to reduce salt intake and the influencing factors will be determined by structured equation model (SEM). Multilevel regression analyses will be applied. Finally, the cost effectiveness of the intervention will be analyzed.
Discussion
This study is unique as it will recruit the individuals most vulnerable to CVD morbidity and mortality by applying the general Framingham CVD risk scoring system. Dietary salt reduction will be applied as a prioritized, community level intervention for the prevention of CVD in a developing country.
Trial registration
ISRCTN39416277
doi:10.1186/1745-6215-13-158
PMCID: PMC3533738  PMID: 22947342
Salt; CVD; Thailand; Behavior; Intervention

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