Salt Depletion Research Articles

Double knockout of pendrin and Na-Cl cotransporter (NCC) causes severe salt wasting, volume depletion, and renal failure.

The Na-Cl cotransporter (NCC), which is the target of inhibition by thiazides, is located in close proximity to the chloride-absorbing transporter pendrin in the kidney distal nephron. Single deletion of pendrin or NCC does not cause salt wasting or excessive diuresis under basal conditions, raising the possibility that these transporters are predominantly active during salt depletion or in response to excess aldosterone. We hypothesized that pendrin and NCC compensate for loss of function of the other under basal conditions, thereby masking the role that each plays in salt absorption. To test our hypothesis, we generated pendrin/NCC double knockout (KO) mice by crossing pendrin KO mice with NCC KO mice. Pendrin/NCC double KO mice displayed severe salt wasting and sharp increase in urine output under basal conditions. As a result, animals developed profound volume depletion, renal failure, and metabolic alkalosis without hypokalemia, which were all corrected with salt replacement. We propose that the combined inhibition of pendrin and NCC can provide a strong diuretic regimen without causing hypokalemia for patients with fluid overload, including patients with congestive heart failure, nephrotic syndrome, diuretic resistance, or generalized edema.

242 Are we missing salt depletion in cystic fibrosis?

242 Are we missing salt depletion in cystic fibrosis?

Lack of Validation of a Same-Day Outpatient Protocol for Determination of Salt Sensitivity of Blood Pressure

Salt sensitivity of blood pressure has been studied in humans with a 48-hour inpatient protocol of salt loading and depletion or with longer outpatient protocols using high- and low-salt diets. Results have been reproducible, but both methods are laborious and costly. A 6-hour protocol of intravenous salt loading and furosemide has been reported but never validated. We studied 14 normal volunteers (39±2 years old; 86% women and 21% black) with the inpatient and 6-hour protocols, separated by 30 days. Four subjects (29%) were salt sensitive in the inpatient protocol. They had higher systolic blood pressure, higher body mass index, and somewhat lower plasma renin activity than salt-resistant subjects. Baseline systolic blood pressure before both protocols was highly reproducible (r=0.90; P<0.0001; limits of agreement: +6.2 to -8.0 mm Hg), whereas the response to salt depletion was not (r=0.09). Three salt-sensitive and 4 salt-resistant subjects were misclassified by the short protocol. Three-hour natriuresis by furosemide in the short protocol (344±15 mmol) was not different from the 12-hour natriuresis in the inpatient protocol (357±19). However, stimulation of plasma renin activity and aldosterone was significantly less in the short (+0.10±0.07 ngA(I)/L/sec and -61±44 pmol/L) than in the inpatient protocol (+1.80±0.60 ngA(I)/L/sec and +256±88 pmol/L; P<0.03 for both). Activation of hormonal changes that regulate depressor responses to salt depletion may not have occurred with the 3-hour natriuresis of the short protocol. This methodology cannot be used to study salt sensitivity of blood pressure, because the phenotype, mechanisms, and prognosis of the latter have been defined with the inpatient protocol.

Diffuse-charge dynamics of ionic liquids in electrochemical systems

We employ a continuum theory of solvent-free ionic liquids accounting for both short-range electrostatic correlations and steric effects (finite ion size) [Bazant et al., Phys. Rev. Lett. 106, 046102 (2011)] to study the response of a model microelectrochemical cell to a step voltage. The model problem consists of a 1-1 symmetric ionic liquid between two parallel blocking electrodes, neglecting any transverse transport phenomena. Matched asymptotic expansions in the limit of thin double layers are applied to analyze the resulting one-dimensional equations and study the overall charge-time relation in the weakly nonlinear regime. One important conclusion is that our simple scaling analysis suggests that the length scale √(λ*(D)l*(c)) accurately characterizes the double-layer structure of ionic liquids with strong electrostatic correlations where l*(c) is the electrostatic correlation length (in contrast, the Debye screening length λ*(D) is the primary double-layer length for electrolytes) and the response time of λ(D)(*3/2)L*/(D*l(c)(1/2)) (not λ*(D)L*/D* that is the primary charging time of electrolytes) is the correct charging time scale of ionic liquids with strong electrostatic correlations where D* is the diffusivity and L* is the separation length of the cell. With these two new scales, data of both electric potential versus distance from the electrode and the total diffuse charge versus time collapse onto each individual master curve in the presence of strong electrostatic correlations. In addition, the dependance of the total diffuse charge on steric effects, short-range correlations, and driving voltages is thoroughly examined. The results from the asymptotic analysis are compared favorably with those from full numerical simulations. Finally, the absorption of excess salt by the double layer creates a depletion region outside the double layer. Such salt depletion may bring a correction to the leading order terms and break down the weakly nonlinear analysis. A criterion which justifies the weakly nonlinear analysis is verified with numerical simulations.

Gitelman's syndrome with persistent hypokalemia - don't forget licorice, alcohol, lemon juice, iced tea and salt depletion: a case report

IntroductionChronic hypokalemia is the main finding in patients with Gitelman's syndrome. Exogenous factors can trigger deterioration of the patient's condition and provoke clinical symptoms. We discuss the pathophysiology of and therapy for Gitelman's syndrome, with a focus on dietary factors which may aggravate the disease.Case presentationWe describe the case of a 31-year-old, previously apparently healthy Caucasian Swiss man who presented to our hospital with gait disturbance of subacute onset and a potassium level of 1.5 mmol/L. A detailed medical history revealed that he had been consuming large amounts of licorice (in the form of Fisherman's Friend menthol eucalyptus lozenges). Despite discontinuing the intake of glycyrrhizinic acid, his potassium level remained low. Biochemical investigations showed refractory hypokalemia and secondary hyperaldosteronism, suggestive of Gitelman's syndrome. Despite treatment with supplementation of potassium and magnesium in combination with an aldosterone antagonist, further clinically symptomatic episodes occurred. Triggers could be identified only by repeated detailed history taking. In response to the patient's dietary excesses (ingestion of relevant amounts of alcohol, lemon juice and iced tea), his hypokalemia was aggravated and provoked clinical symptoms. Finally, vomiting and failure to replace salt led to volume depletion and hypokalemic crisis, with a plasma potassium level of 1.0 mmol/L and paralysis with respiratory failure necessitating not only infusion of saline and potassium but also temporary mechanical ventilation.ConclusionDietary preferences may have a much larger impact than any drug treatment on the symptoms of this chronic syndrome. Individual (mainly dietary) preferences must be monitored closely, and patients should be given dietary advice to avoid recurrent aggravation of hypokalemia with muscular weakness.

A comparison between sphygmomanometer-based and ambulatory blood pressure monitoring in acute salt loading and depletion protocol

INTRODUCTION:Ambulatory blood pressure monitors have been used in salt loading and depletion protocols. However, the agreement between measurements made using ambulatory blood pressure monitors and those made with the sphygmomanometer has not been evaluated.OBJECTIVE:The objective of this study was to compare the concordance of the two methods of blood pressure measurements in protocols of acute salt loading and depletion.METHOD:Systolic blood pressure was measured using a sphygmomanometer at the completion of salt infusion (2 L NaCl 0.9%, 4 h) and salt depletion (furosemide, 120mg/day, p.o.) in 18 volunteers. Using the Pearson correlation coefficient (ρ), these readings were compared with the mean systolic blood pressure measured using the ambulatory blood pressure monitoring device during the following periods: 4 h of saline infusion and 12 h of salt depletion; 4 h of saline infusion and the last 6 h of salt depletion; 12 h of salt loading and the last 6 h of depletion; 12 h of salt loading and 12 h of depletion. Salt sensitivity was defined by a difference in the systolic blood pressure between salt loading and salt depletion greater than 10 mmHg when measured with the sphygmomanometer, and the Kappa analysis of concordance (K) was used with a significance level of P<0.05.RESULTS:Only the blood pressure readings obtained using the ambulatory blood pressure device during 4 h of intravenous NaCl and during 12 h of salt depletion showed a high correlation with the variation in the systolic blood pressure measured by the sphygmomanometer, with a full agreement with the salt sensitivity classification (ρ = 0.71; P = 0.001 and K = 1).CONCLUSION:In acute salt loading and depletion protocols, an ambulatory blood pressure monitoring device should be used to record the blood pressure during the 4-h interval of salt infusion and 12-h interval of salt depletion.

Functionally induced changes in water transport in the proximal tubule segment of rat kidneys.

To eliminate freezing artifacts in the proximal tubule cells, two cryotechniques were applied to normal rat kidneys, ie, freeze substitution and special freeze drying. In addition, salt depletion and salt loading were applied to groups of rats to evaluate whether the segmental structure of the proximal tubule could be altered. In the superficial part of the renal cortex of normal kidneys, the typical first segment structure in the proximal tubule was generally present in the early postglomerular fraction of the tubule. However, in the second segment, a special cellular phenomenon was constantly present, comprising a significant intercellular space that was easily identified using a light microscope. In the third segment, in which the presence of basolateral interdigitations is minimal, the small lateral space, which was found to be present in cryopreparations between neighboring cells from the normal kidney, was found to be enlarged by heavy salt loading of short duration. It is concluded that these cryotechniques demonstrate quantitative structural variations between superficial and deep nephrons, as well as the presence of extracellular areas between the cells of the second and the third segment, representing a structural background for the essential transport of water from the proximal tubules to the peritubular capillaries.

New angiotensin-receptor blocker approved by FDA

FDA and Takeda Pharmaceuticals North America Inc. on February 25 announced the agency’s approval of azilsartan medoxomil, an angiotensin-receptor blocker, for the treatment of hypertension. The product’s brand name is Edarbi. Azilsartan medoxomil administered at a dosage of 80 mg/day was “statistically superior” to placebo and the angiotensin-receptor blockers olmesartan and valsartan during six-week clinical studies, according to the new product’s FDA-approved labeling. The 80-mg/day dosage of azilsartan medoxomil, which is the dosage the labeling recommends for adults, lowered patients’ systolic blood pressure by a mean of 13.2–15.5 mm Hg and diastolic blood pressure by a mean of 7.5–9.4 mm Hg in six weeks. In patients who are volume or salt depleted, perhaps because of high-dosage diuretic therapy, the labeling suggests that clinicians consider starting azilsartan medoxomil therapy at a dosage of 40 mg/day. An alternative suggestion is to correct the patients’ volume or salt depletion before starting azilsartan therapy. The goal of these measures is to prevent symptomatic hypotension.

The Sustainable Development of Kuwaiti Sabkhas

Abstract“Sabkha” is an Arabic term commonly used in foreign languages to denote a salt flat, a shallow depression. Sabkhas normally occur near sea level or at the underground water level. They usually are encrusted with a salt crust layer, the thickness of which depends on the location of the sabkhas and the evaporation rate. Sabkhas are one of the prominent surface topographical features in the Kuwaiti coastal zone, occupying an area of about 769.4 km2, equivalent to 4.3 percent of the nation's total area. Due to their presence in the most important locations near the coastline, they are a most suitable setting for exploitative human activities. Sabkhas have attracted development proponents, particularly after the increased economic growth, and urgent need for homes and housing facilities. The most significant developments in the sabkha lands are urban development, agricultural forestation, and nature reserves. This study has revealed that there are environmental hazards related to the use of sabkha lands, including salt weathering, soil salinization, tree damage and depletion of natural reserves, the deterioration of nebakha (formation and growth around plants in the desert where groundwater is available for vegetation; the usual dune forms that occur in such instances are isolated mounds around individual plants) fields, and semikarstic (an area of irregular limestone in which erosion has produced fissures, sinkholes, underground streams, and caverns) solution holes. Therefore, use of such lands should take into account scientific investigation and selection among the different development fields. Such a fragile environment obliges us to consider nature conservation, a non‐disruption or depletion of sabkhas' limited natural resources, and their environmental components. The concept of the sustainable development should prevail in the use of such sabkhas.

Can Salt Sensitivity of Blood Pressure Be Assessed Without Changing Salt Diet?

See related article, pp 180–185 Blood pressure is responsive to sodium intake in many patients with essential hypertension. It seems that subjects of African-American ancestry and older subjects are most sensitive to salt.1 Yet, there is no agreement on how such salt sensitivity is determined: frequently, such measurements involve 2 different periods on high- and low-sodium diets; others involve intravenous sodium loading and then low-salt diet and furosemide depletion. In different studies, the definition of salt sensitivity and related procedures differ substantially and quite arbitrarily (or perhaps empirically).1,–,3 Regardless of definition, in research settings salt loading or depletion is short term, while in reality, it is the long-term exposure that counts, especially with the recent recognition that sodium can accumulate in the skin and perhaps other tissues.4 Hypertensive subjects with salt sensitivity retain salt. However, salt retention also exists in other conditions. In renal failure, it is likely to be associated with hypertension, while not necessarily so in heart failure or cirrhosis of the liver. Healthy subjects with normal blood pressure may also be salt sensitive and are then more likely to become hypertensive over time.1 In individuals with salt-sensitive hypertension, high sodium intake expands vascular volume, and arterial pressure rises along with cardiac output. Urinary sodium excretion increases in parallel to blood pressure elevation, but balance is maintained at increased vascular pressures compared …

Effects of N-Acetylcysteine on Renal Hemodynamics in Contrast Media-Induced Nephropathy

Background: N-acetylcysteine (NAC) has been proposed to prevent radiocontrast nephropathy in high-risk patients. Methods: The effect of single-dose and prolonged administration of NAC before application of either the ionic, high-osmolar radiocontrast agent diatrizoate sodium (DTZ) or the nonionic, low-osmolar radiocontrast agent iohexol (IOH) in a rat model combining uninephrectomy, salt depletion, and administration of indomethacin was explored. Arterial blood pressure and total, cortical, and medullary blood flow were continuously recorded in anesthetized Sprague-Dawley rats. Results: NAC had no effect on renal hemodynamics in control rats. Both DTZ and IOH induced biphasic changes in renal blood flow and cortical renal blood flux and persistently reduced medullary blood flux. Neither single-dose nor prolonged administration of NAC prevented the hemodynamic changes following administration of DTZ or IOH, respectively. Acute prophylactic administration of NAC prevented increased urinary ET excretion after injection of IOH and, to a smaller degree, of DTZ. Both an ionic, high-osmolar (DTZ) and a nonionic, low-osmolar (IOH) radiocontrast agent induce marked changes in renal hemodynamics in salt-depleted rats treated with indomethacin. Conclusions: Renal perfusion is not affected by NAC application in a model of experimental contrast nephropathy in rats. Other effects of NAC might thus account for the presumed renoprotective properties.

THE RELATION BETWEEN THE RENIN-ANGIOTENSIN SYSTEM AND FIBRINOLYTIC SYSTEM

Background: Several lines of evidence point to an interrelation of the renin angiotensin system (RAS) with the endogenous fibrinolytic system. Aim & Methods: this study was planned to examine the effect of salt depletion as a method of activation of the endogenous RAS on plasma fibrinolytic balance in 10 healthy human subjects in the presence and absence of Angiotensin converting enzyme inhibitor- ACEi (captopril). Activation of the RAS during low salt intake was documented by a significant increase in serum aldosterone concentration. Results: the data suggest that activation of the RAS results in increased plasminogen activator inhibitors (PAI-I) antigen and that interruption of the RAS with the ACE inhibitor captopril significantly lowers PAI-I antigen without lowering tissue-type plasminogen activator (t-PA) antigen. Conclusion: this data provides an evidence of a direct functional link between the RAS and the fibrinolytic system in humans and these findings may help to elucidate possible mechanisms by which ACE inhibitionexerts vasculoprotective effects and reduces the risk of atherothrombotic events.

Strongly nonlinear dynamics of electrolytes in large ac voltages

We study the response of a model microelectrochemical cell to a large ac voltage of frequency comparable to the inverse cell relaxation time. To bring out the basic physics, we consider the simplest possible model of a symmetric binary electrolyte confined between parallel-plate blocking electrodes, ignoring any transverse instability or fluid flow. We analyze the resulting one-dimensional problem by matched asymptotic expansions in the limit of thin double layers and extend previous work into the strongly nonlinear regime, which is characterized by two features--significant salt depletion in the electrolyte near the electrodes and, at very large voltage, the breakdown of the quasiequilibrium structure of the double layers. The former leads to the prediction of "ac capacitive desalination" since there is a time-averaged transfer of salt from the bulk to the double layers, via oscillating diffusion layers. The latter is associated with transient diffusion limitation, which drives the formation and collapse of space-charge layers, even in the absence of any net Faradaic current through the cell. We also predict that steric effects of finite ion sizes (going beyond dilute-solution theory) act to suppress the strongly nonlinear regime in the limit of concentrated electrolytes, ionic liquids, and molten salts. Beyond the model problem, our reduced equations for thin double layers, based on uniformly valid matched asymptotic expansions, provide a useful mathematical framework to describe additional nonlinear responses to large ac voltages, such as Faradaic reactions, electro-osmotic instabilities, and induced-charge electrokinetic phenomena.

Effect of Salt Depletion on Charging Dynamics in Nanoporous Electrodes

Electrochemical double-layer capacitors built from nanoporous electrodes can have such a high ratio of electrode surface area to pore volume that charging the capacitor can deplete the salt from the liquid volume. This can result in increased resistance, resulting in a slow, nonlinear charging rate of which quantitative understanding is limited. In some cases, this effect is masked by an external solution resistance or by the transport of salt into the pore from an external reservoir. However, in forms relevant to a compact energy storage device, the phenomenon can have an important effect on charging time and linearity, and understanding it is important for such design. We have observed salt depletion effects by using dealloyed gold, which has well-defined 10 nm pores and a chemically well-understood surface, and by minimizing the amount of external salt within range of diffusion. Good correspondence is observed with a modified de Levie model that accounts for reduced local conductivity due to salt depletion. The model’s assumption that the Stern layer (ions closely bound to the pore wall) makes a low contribution to conductance in the pore is validated by experimental data.

Protective Effect of Dietary Potassium against Cardiovascular Damage in Salt-Sensitive Hypertension: Possible Role of its Antioxidant Action

It is well known that high salt intake induces hypertension and cardiovascular damage, while dietary potassium supplementation counteracts these harmful effects. Actually, the protective effect of potassium is strengthened with excess salt as compared with salt depletion. Although the precise mechanisms have not been fully elucidated, in our previous reports, the antihypertensive effect of dietary potassium was accompanied by sympathetic nerve inhibition in salt-sensitive hypertension. Also, potassium supplement suppressed salt-induced insulin resistance. These effects of dietary potassium can explain its cardio- and vasculo-protective action in addition to the potassium supplementation induced decreased salt-induced rise in blood pressure. On the other hand, salt-sensitive hypertension is associated with reactive oxygen species (ROS) overproduction. Moreover, sympathoexcitation can be induced by central ROS upregulation and insulin resistance can be caused by ROS excess in the target organs of insulin, such as skeletal muscle. Conversely, the seemingly different actions of potassium can be explained by the antioxidant effect of dietary potassium; in our recent studies, potassium supplementation inhibits salt-induced progress of cardiac diastolic dysfunction and vascular neointima formation by cuff placement around arteries, associated with the inhibition of regional ROS overproduction, in salt-sensitive hypertension. Thus, it is possible that dietary potassium protects against salt-induced cardiovascular damage by the reduction of ROS generation and by central sympatholytic action and amelioration of insulin resistance induced through its antioxidant effect.

Dynamic Computation of Incentive Salience: “Wanting” What Was Never “Liked”

Pavlovian cues for rewards become endowed with incentive salience, guiding "wanting" to their learned reward. Usually, cues are "wanted" only if their rewards have ever been "liked," but here we show that mesocorticolimbic systems can recompute "wanting" de novo by integrating novel physiological signals with a cue's preexisting associations to an outcome that lacked hedonic value. That is, a cue's incentive salience can be recomputed adaptively. We demonstrate that this recomputation is encoded in neural signals coursing through the ventral pallidum. Ventral pallidum neurons do not ordinarily fire vigorously to a cue that predicts the previously "disliked" taste of intense salt, although they do fire to a cue that predicts the taste of previously "liked" sucrose. Yet we show that neural firing rises dramatically to the salt cue immediately and selectively when that cue is encountered in a never-before-experienced state of physiological salt depletion. Crucially, robust neural firing to the salt cue occurred the first time it was encountered in the new depletion state (in cue-only extinction trials), even before its associated intense saltiness has ever been tasted as positively "liked" (salt taste had always been "disliked" before). The amplification of incentive salience did not require additional learning about the cue or the newly positive salt taste. Thus dynamic recomputation of cue-triggered "wanting" signals can occur in real time at the moment of cue re-encounter by combining previously learned Pavlovian associations with novel physiological information about a current state of specific appetite.

Salt-driven interactions between Pistacia lentiscus and Salsola inermis

It can be learned from the Pistacia spp. germplasm collection (http://www.bgu.ac.il/pistacia) that the growth of Salsola inermis is inhibited in the vicinity of the evergreen Pistacia lentiscus, but not in the surroundings of the deciduous Pistacia atlantica and Pistacia chinensis. Irrigation of trees during the summer months increases soil salinity around the trees. It was therefore hypothesized that inhibition of S. inermis around P. lentiscus is related to depletion of salt in the vicinity of the latter species. A multi-approach experimental scheme was carried out which included soil edaphic characterization and germination tests. To test salt tolerance of P. lentiscus, plants were grown in a hydroponic system for a month in medium containing NaCl, while physiological and growth parameters were measured. Conductivity measurements in summer, during the growth season of S. inermis, indicated that soil salinity beneath deciduous Pistacia trees was significantly higher than that below P. lentiscus. Germination of S. inermis seeds on filter paper moistened with P. lentiscus low-conductivity soil filtrate was twice as high as that of the deciduous trees high-conductivity soil filtrates. Nevertheless, fresh and dry weights of mature S. inermis growing next to P. atlantica and P. chinensis were 2.9 to 4.8 times higher than those of plants growing in the vicinity of P. lentiscus. In a hydroponic system, no significant differences were found in growth parameters and stomatal conductance between P. lentiscus growing in control and salt treatments. It was therefore proposed that salt depletion in the vicinity of P. lentiscus inhibits the growth, but not germination, of S. inermis thus confirming the halophylic characteristics of this plant. The nature of Salsola-Pistacia interactions cannot be explained by allelopathic effects; hence, plausible salt-driven interactions were considered. Our data showed that S. inermis accumulated salt and has halophytic characteristics. Interestingly, germination of S. inermis was inhibited in medium containing salt, but the salt was obligatory for further growth, development, and fast biomass production. These results explained the observation of large biomass accumulation in the more saline soil around the deciduous P. atlantica and P. chinensis and the lack of development in the salt-depleted soil around the salt-tolerant accumulator P. lentiscus. Soil salinity around Pistacia trees critically affects the growth of S. inermis. Inhibition of S. inermis growth, but not germination, around the evergreen P. lentiscus, stems from the latter's ability to deplete salt from its surroundings. The results indicated that P. lentiscus is able to tolerate and accumulate salt, which we assume contributes to its wide distribution along the Mediterranean coast in Israel. Recommendations and perspectives While the phytoremediation potential of Salsola spp. has been explored to some extent, this of P. lentiscus has not been tested and proven before. The results suggest that the evergreen perennial salt-tolerant P. lentiscus can be recommended for horticulture purposes and soil stabilization in relatively saline environments.

Connexin 37 is dispensable for the control of the renin system and for positioning of renin-producing cells in the kidney

Within the juxtaglomerular apparatus, renin-producing cells and endothelial cells of the afferent arterioles express connexin (Cx)37 and Cx40, which form abundant gap junctions among these cells. Deletion of Cx40 leads to strong hyperreninemia and ectopic localization of renin-producing cells; however, the relevance of Cx37 for the renin system in the kidney has not been investigated. We therefore studied renin expression and renin secretion in kidneys from Cx37-deficient mice, both on normal salt diet and during chronic challenge of the renin system by pretreatment of mice with a low-salt diet in combination with an angiotensin I-converting enzyme inhibitor. This treatment procedure strongly enhances renin gene expression and renin secretion. We found that renal renin mRNA abundance and plasma renin concentration did not differ between wild-type and Cx37-/- mice under normal conditions. The stimulation of renin gene expression and renin secretion by salt depletion was even more pronounced in Cx37-/- as compared to wild-type mice. The regulation of renin secretion from isolated perfused kidneys by perfusion pressure and by angiotensin II was normal in Cx37-/- mice. In addition, the localization of renin-expressing cells was also regular in Cx37-/- kidneys. Finally, the expression pattern of other vascular Cxs such as Cx40, Cx43, and Cx45 was not altered in Cx37-/- kidneys. Our findings suggest that Cx37 is not essential for normal development and function of renin-producing cells. As a consequence, it appears unlikely that Cx40 exerts its important function in renin-producing cells via Cx37/Cx40 heteromeric gap junctions.

Methods to Evaluate Electrolyte and Water Turnover of Athletes

Fluid-electrolyte deficiencies may accumulate over several days in athletes whose diets contain nutrients (eg, water, sodium, potassium) in quantities that are smaller than the losses that occur in sweat and urine. Individualized assessment and personalized dietary recommendations are necessary, especially in cases of water or salt depletion, heat exhaustion, and heat cramps. Unfortunately, no composite source of these techniques exists. The purpose of this article is to describe methods that validly assess urine and sweat volumes, electrolyte concentrations, dietary fluid and electrolyte intake, and 24-hour water and electrolyte balance for athletes who train and compete in hot environments. Reference (ie, expected) values, sample data sheets, and a case report are presented. These techniques allow motivated professionals to validly characterize the fluid-electrolyte status of athletes and thereby suggest modifications of diet and train ing habits. Without these techniques, professionals must resort to inaccurate or indirect estimates of whole-body fluid and electrolyte balance.

Thiazide Effects and Adverse Effects

One of the longest-running debates in clinical medicine shows no sign of disappearing; just when it seems that thiazides have reassumed their role as front-line drugs to treat hypertension,1 new concerns emerge,2–4 leading some to question their role once again.5 Thiazides are effective antihypertensives with long track records and low cost. The major concerns about their use arise from their tendency to cause hypokalemia, impair glucose tolerance, increase serum cholesterol, and increase serum uric acid. Few medical controversies have generated as much heat, with well-established camps staking out positions that appear resistant to change.6–9 The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, the largest study of antihypertensive monotherapy ever performed,10 was intended to identify the best first-line treatment for high-risk hypertensive individuals; however, despite its size and the numerous resulting publications, its implications and authority continue to be disputed. The goal of this review is not take sides in this debate but rather to inject a distinct, and sometimes neglected, perspective; during the past 15 years, remarkable developments in molecular biology and human genetics have provided substantial insights into the pathogenesis of hypertension and mechanisms and adverse effects of diuretics. Diuretic proponents and antagonists alike often neglect these developments when addressing the topic; it is the purpose of this Brief Review to integrate these developments into the debate with the goal of generating questions that can be addressed scientifically. Thiazide diuretics were developed during the 1950s, when chemists and physiologists at Merck Sharpe and Dohme tested derivatives of sulfonamide-based carbonic anhydrase inhibitors, with the goal of discovering drugs that enhance the excretion of sodium with chloride rather than sodium bicarbonate.* Although these drugs lower arterial pressure effectively, the mechanisms have long perplexed investigators.11 Thiazides reduce cardiac output acutely by reducing extracellular …