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The distal convoluted tubule (DCT) plays an essential role in the reabsorption of NaCl by the kidney, a process that can be inhibited by thiazide diuretics. Parvalbumin (PV), a [Ca.sup.2+]-binding protein that plays a role in muscle fibers and neurons, is selectively expressed in the DCT, where its role remains unknown, We therefore investigated the renal phenotype of PV knockout mice ([Pvalb.sup.-/-]) vs. wild-type ([Pvalb.sup.+/+]) littermates. PV colocalized with the thiazidesensitive [Na.sup.+]-[Cl.sup.-] cotransporter (NCC) in the early DCT. The [Pvalb.sup.-/-] mice showed increased diuresis and kaliuresis at baseline with higher aldosterone levels and lower lithium clearance. Acute furosemide administration increased diuresis and natriuresis/kaliuresis, but, surprisingly, did not increase calciuria in [Pvalb.sup.-/-] mice. NaCl supplementation of [Pvalb.sup.-/-] mice increased calciuria at baseline and after furosemide. The [Pvalb.sup.-/-] mice showed no significant diuretic response to hydrochlorothiazide, but an accentuated hypocalciuria. A decreased expression of NCC was detected in the early DCT of [Pvalb.sup.-/-] kidneys in the absence of ultrastructural and apoptotic changes. The PV-deficient mice had a positive [Ca.sup.2+] balance and increased bone mineral density. Studies in mouse DCT cells showed that endogenous NCC expression is [Ca.sup.2+]-dependent and can be modulated by the levels of PV expression. These results suggest that PV regulates the expression of NCC by modulating intracellular [Ca.sup.2+] signaling in response to ATP in DCT cells. They also provide insights into the [Ca.sup.2+]-sparing action of thiazides and the pathophysiology of distal tubulopathies. distal convoluted tubule | kidney | salt-losing nephropathy | sodium-chloride cotransport

Although effective in relieving symptoms of edema in congestive heart failure (CHF), diuretic-induced natriuresis may be associated with reductions in glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), which subsequently may reduce the duration of natriuresis. Moreover, recent studies have reported that the preservation of GFR is an important predictor of survival in human CHF. We hypothesized that the acute detrimental renal hemodynamic and tubular responses to furosemide in symptomatic human CHF will be attenuated by A[T.sub.1] receptor blockade with losartan. We defined the renal hemodynamic and tubular actions and aldosterone responses to furosemide (40 mg, orally) in the presence of acute A[T.sub.1] receptor antagonism (losartan, MSD, 50 mg orally) vs. placebo in 10 subjects with CHF (New York Heart Association II-III) in a double-blind, placebo-controlled crossover study. Furosemide with placebo increased sodium excretion and reduced ERPF and GFR (P < 0.05 vs. baseline). After 4 h, sodium excretion compared with baseline was decreased (P < 0.05). In contrast, furosemide with losartan resulted in a greater increase in sodium excretion but without reductions in ERPF and GFR (P < 0.05 vs. placebo). After 4 h, sodium excretion was greater compared with the placebo group. Importantly, plasma aldosterone tended to increase in the placebo group, whereas it was decreased (P < 0.05 vs. baseline) only in the losartan group. These studies underscore the pathophysiological role of the A[T.sub.1] receptor in mediating detrimental renal and adrenal properties of diuretics in human CHF. A[T.sub.1] receptor antagonism preserves GFR and renal blood flow and enhances sodium excretion during acute diuretic therapy in addition to inhibiting aldosterone secretion. These findings support the use of A[T.sub.1] receptor blockade for human CHF requiring acute diuretics to improve renal hemodynamic and tubular function and to suppress aldosterone. kidney; congestive heart failure; aldosterone; glomerular filtration rate

Recent studies demonstrated that the influence of the macula densa on glomerular filtration is abolished in adenosine [A.sub.1] receptor ([A.sub.1]AR) knockout mice. Inasmuch as the macula densa not only regulates glomerular filtration but also controls the activity of the renin system, the present study aimed to determine the role of the [A.sub.1]AR in macula densa control of renin synthesis and secretion. Although a high-salt diet over 1 wk suppressed renin mRNA expression and renal renin content to similar degrees in [A.sub.1][AR.sup.+/+], [A.sub.1][AR.sup.+/-] , and [A.sub.1][AR.sup.-/-] mice, stimulation of Ren-1 mRNA expression and renal renin content by salt restriction was markedly enhanced in [A.sub.1][AR.sup.-/-] compared with wild-type mice. Pharmacological blockade of macula densa salt transport with loop diuretics stimulated renin expression in vivo (treatment with furosemide at 1.2 mg/day for 6 days) and renin secretion in isolated perfused mouse kidneys (treatment with 100 [mciro]M bumetanide) in all three genotypes to the same extent. Taken together, our data are consistent with the concept of a tonic inhibitory role of the [A.sub.1]AR in the renin system, whereas they indicate that the [A.sub.1]AR is not indispensable in macula densa control of the renin system. loop diuretics; low salt; high salt

The diuretic response to loop diuretics in various disease states has consistently been found to be subnormal. One of the key determinants of the degree of diuretic response is the functional integrity of the sodium-potassium-chloride transporter in the loop of Henle. Studies in animal models suggest that expression/activity of the transporter may be affected by factors such as altered natural splicing events of NKCC2 (the gene encoding for the renal transporter), renal prostanoids, vasopressin, and other autacoids. We have reviewed the pharmacokinetics and pharmacodynamics of loop diuretics in health and in edematous disorders for which they are used. On the basis of evidence reviewed in this paper, we propose that altered expression or activity of the sodium-potassium-chloride transporter in the loop of Henle, in conjunction with events occurring in other segments of the nephron, possibly accounts for the altered diuretic response to these agents. Thus the modulators of this altered expression/activity could serve as important therapeutic targets for alternative diuretic regimens in these conditions. edematous disorders; furosemide

This article discusses Australian jockeys' food habits, diuretics and sauna use to maintain and lose weight. Topics include eating disorder, dehydration, health attitude, and laxative abuse.

Plant secondary compounds are deterrents and toxins to a variety of herbivores. The effect of secondary compounds on water balance of herbivores is virtually unexplored, yet many secondary compounds are renowned for their diuretic effects in humans and laboratory rats. We review data from the ethnopharmocological literature on plants with diuretic effects. We also present our data from experiments on water intake of specialist (Neotoma stephensi) and generalist woodrats (N. albigula) consuming plant secondary compounds from their natural diet. We measured effects of dietary secondary compounds on voluntary water consumption, urine volume and urine osmolarity. Ingestion of secondary compounds increased water intake and urine output and decreased urine osmolarity in both species. However, the generalist was more impacted by dietary secondary compounds than the specialist. Our results combined with that from the literature suggest that diuresis may be a prevalent consequence of ingestion of secondary compounds. Many herbivores live in arid habitats with limited access to free-standing water, thus an increase in the desire for water may have profound consequences on foraging behavior and fitness.

A laboratory exercise about the physiology of potassium ion (K+) balance was described and may be used by physiology teachers as a teaching tool. The exercise focused on three major elements of the K+ balance physiology: a case presentation of a diuretic-induced hypokalemia, renal handling of K+ and the total body K+ balance. The effects of diuretics on the secretion of K+ was also discussed. After conducting the exercise, an interactive discussion was held among the students to determine the extent of their acquired knowledge regarding the just concluded experiment.

The water retention and vasoconstriction observed in congestive heart failure (CHF) is attributed in part to arginine vasopressin (AVP). Water retention is modulated via the V2 receptor of AVP. The effects of chronic blocking of this receptor is investigated using the infarction-induced CHF model in rats. Results reveal that selective blocking of V2 leads to an increase in the excretion of water. The implications of these findings on diuretic therapy are discussed.

Byline: Giorgio Vescovo, Francesco Serafini, Luciano Dalla Libera, Cristiana Leprotti, Luigi Facchin, Pierluigi Tenderini, Giovanni Battista Ambrosio Abstract: Background Patients with congestive heart failure (CHF) have a reduced exercise capacity because of the early appearance of fatigue and dyspnea. Qualitative changes in the skeletal muscle composition and metabolism can be responsible for the origin of symptoms Methods We correlated the myosin heavy chain (MHC) composition of the gastrocnemius in 20 patients with different degrees of CHF to NYHA class, diuretic consumption, echocardiographic parameters, and expiratory gases measured during cardiopulmonary exercise testing. MHC composition was determined electrophoretically in skeletal muscle needle microbiopsies and the percent distribution was calculated by densitometry. Maximal cardiopulmonary exercise testing was performed on a treadmill with a modified Naughton protocol. A capnograph was used. Results There was no correlation between ejection fraction, left ventricular end systolic diameter, left ventricular end diastolic diameter, and MHC composition. We found a significant positive correlation between the percentage of MHC1 (slow aerobic isoform) and NYHA class (r.sup.2 = 0.62, p < 0.0001), peak VO.sub.2 (r.sup.2 =0.5, p < 0.0004), ventilatory threshold (VT) (r.sup.2 =0.33, p = 0.008) and O.sub.2 pulse (peak VO2/HR) (r.sup.2 = 0.40, p = 0.003). There was a negative correlation between both MHC2a (fast oxidative) and MHC2b (fast glycolytic) with peak VO2 (r.sup.2 = 0.38, p = 0.004 and r.sup.2 = 0.37, p = 0.004, respectively), VT (r.sup.2 = 0.2, p = 0.046 and r.sup.2 = 0.34, p = 0.007, respectively), and O.sub.2 pulse (peak VO.sub.2/HR) (r.sup.2 = 0.39, p = 0.003 and r.sup.2 = 0.23, p = 0.03). NYHA class was also correlated positively with MHC2a and MHC2b (r.sup.2 = 0.46, p = 0.001 and r.sup.2 = 0.41, p< 0.006, respectively) and negatively with the same clinical and functional parameters. Conclusions The correlation between the magnitude of the MHC shift from the slow aerobic to the fast glycolytic and fast oxidative with both functional and objective measurements of exercise capacity (peak VO.sub.2, VT, O.sub.2 pulse) seem to suggest that changes in skeletal muscle composition may play a determining role in exercise tolerance in patients with CHF. (Am Heart J 1998;135:130-7.) Author Affiliation: Venice and Padua, Italy Article History: Received 19 March 1997; Accepted 24 May 1997 Article Note: (footnote) [star] From the aFirst Department of Internal Medicine, Venice City Hospital, the bCNR Unit for Muscle Biology and Pathophysiology, University of Padua, and the cDepartment of Cardiology, Venice City Hospital., [star][star] Reprint requests: Giorgio Vescovo, MD, PhD, Internal Medicine I, Ospedale Civile di Venezia, SS Giovanni e Paolo, 30100 Venice, Italy., a 4/1/83774

Drugs designed to increase urine production called diuretics do not appear to increase the production of a salt deposit called oxalate that may be potentially harmful to the kidneys of premature infants. Oxalate, sodium, and calcium production were measured in the urine of 32 premature infants receiving either thiazide, thiazide and furosemide, or no diuretic. Oxalate and calcium production were similar in all three groups. There was a close relationship between calcium and sodium production in all three groups., Objective. To study the effect of diuretic drugs on urinary oxalate excretion in premature infants, and to examine the relationship between urinary calcium and sodium excretion in premature infants. Methodology. We measured urinary oxalate, calcium, and sodium excretion in 32 premature infants at approximately 34 weeks gestational age. Seven infants were receiving furosemide, 5 infants were receiving thiazide, 8 infants were receiving furosemide plus thiazide, and 12 infants who were not receiving diuretics served as controls. Results. Urinary oxalate to creatinine ratios in infants receiving furosemide (0.48 [+ or -] .26), thiazide (0.54 [+ or -] .20), furosemide plus thiazide (0.44 [+ or -] .19), and control infants (0.51 [+ or -] .43) were similar by analysis of variance (ANOVA). Data expressed as oxalate concentration gave similar results. Urinary calcium to creatinine ratios in infants receiving furosemide (0.81 [+ or -] .30), thiazide (0.54 [+ or -] .25), furosemide plus thiazide (0.75 [+ or -] .49), and control infants (0.37 [+ or -] .25) were similar by ANOVA. The urinary calcium concentration in infants receiving furosemide plus thiazide (0.085 [+ or -] 0.042 mg/mL) was different from control infants (0.044 [+ or -] .023) by ANOVA and Student-Newman-Keuls test. Urinary calcium to creatinine ratio was correlated with sodium to creatinine ratio (r = .751). Conclusion. Urinary oxalate excretion in premature infants is not affected by diuretic drugs. Urinary sodium and calcium excretion are closely linked in sodium supplemented premature infants receiving diuretics. The calciuric effect of furosemide is not decreased by the addition of thiazide in premature infants receiving sodium supplements. Pediatrics 1997;99:814-818; nephrocalcinosis, oxalate, calcium, premature infant., ABBREVIATIONS. VLBW, very low birth weight; ANOVA, analysis of variance. Renal calcification is a relatively rare problem in children, although reports have called attention to the development of nephrocalcinosis in [...]

The potential effects of glucagon-like peptide (GLP)-1-(7-39) amide on feeding and drinking behavior were analyzed in rats under a food restriction diet schedule. A marked inhibition in eating and drinking behavior was detected in rats after the administration of GLP-1. Furthermore, the rats also exhibited natriuresis and diuresis indicating the regulatory activity of GLP-1 in ingestion and water homeostasis on localized brain receptors.

A study of renal cortical and medullary oxygen tensions (PO2) by introducing sensitive Clark-type O2 microelectrodes using micromanipulators in anaesthetized rat kidney cortex and medulla reveals that cortical PO2 is higher than medullary PO2 under basal conditions. Furosemide, a medullary thick ascending limb resorptive transport inhibitor, enhances medullar PO2, without affecting cortical PO2. This effect, resulting from reduced tubular O2 consumption, is specific for loop diuretics. Acetazolamide, a proximal tubule metabolism inhibitor, specifically enhances cortical PO2.

Protein feeding results in the elevation of glomerular filtration rate, effective renal plasma flow and blood alpha amino nitrogen levels in dogs. Diuretics that act on the distal tubule did not modify this response to protein intake. However, diuretics that act on the proximal tubule completely negated this response. This suggest that reabsorption in the proximal tubule isan important event in effecting responses to protein feeding. Further, this results lend credence to the tubuloglomerular feedback hypothesis in the modulation of renal vasodilatory effect of meals.

The diuretic effects of nitric oxide (NO) synthase inhibitors administered at subpressor dose in rats are controversial, and the tubular segments involved are not known. In the present study, we examined the effect of [N.sup.[Omega]]-nitro-L-arginine methyl ester (L-NAME) at a subpressor dose on renal interstitial NO and cGMP activity and on renal tubular segmental reabsorption of fluid in the rat. Intravenous infusion of L-NAME at 1 [micro]g [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1] in Sprague-Dawley rats (N = 8), which did not alter mean arterial pressure or glomerular filtration rate, significantly increased urine flow rate ([U.sub.v]; from 78.2 [+ or -] 12.7 to 117.1 [+ or -] 14.9 [micro]l/min, P [is less than] 0.05). Paradoxically, this effect of L-NAME was concomitant with significant increases in nitrite/nitrate (from 10.79 [+ or -] 1.20 to 16.50 [+ or -] 2.60 [micro]M, P [is less than] 0.05) and cGMP (from 0.65 [+ or -] 0.09 to 0.98 [+ or -] 0.18 nM, P [is less than] 0.05) concentrations in renal cortical microdialysate as well as the nitrite/nitrate concentration in the medullary microdialysate. Micropuncture studies in the superficial nephron revealed that L-NAME significantly increased the flow rate (from 8.3 [+ or -] 0.9 to 12.2 [+ or -] 1.2 nl/min, P [is less than] 0.05) and fractional delivery of fluid to the distal tubule, but not those in the late proximal tubule. In conclusion, L-NAME, at the subpressor dose used in this study, increased renal nitrate/nitrite and cGMP and inhibited fluid reabsorption in tubular segments between the late proximal tubule and the distal tubule of superficial nephrons. rat; nitric oxide; microdialysis; distal tubule; [N.sup.[Omega]]-nitro-L-arginine methyl ester

In the past decade a wide range of new drugs to treat hypertension have been developed. As a result, hypertensive patients are placed on β blockers or ACE inhibitors upon [...]

Roy, B. D., H. J. Green, and M. Burnett. Prolonged exercise after diuretic-induced hypohydration: effects on substrate turnover and oxidation. Am J Physiol Endocrinol Metab 279: E1383-E1390, 2000.--To determine the influence of a diuretic-induced reduction in plasma volume (PV) on substrate turnover and oxidation, 10 healthy young males were studied during 60 min of cycling exercise at 61% peak oxygen uptake on two separate occasions [is greater than or equal to] 1 wk apart Exercise was performed under control conditions (CON; placebo), and after 4 days of diuretic administration (DIU; Novotriamazide; 100 mg triamterene and 50 mg hydrochlorothiazide). DIU resulted in a calculated reduction of PV by 14.6 [+ or -] 3.3% (P [is less than] 0.05). Rates of glucose appearance ([R.sub.a]) and disappearance ([R.sub.d]) and glycerol [R.sub.a] were determined by using primed constant infusions of [6,6-[sup.2]H]glucose and [[sup.2][H.sub.5]]glycerol, respectively. No differences in oxygen uptake; during exercise were observed between trials. Main effects for condition (P [is less than] 0.05) were observed for plasma glucose and glycerol, such that the values observed for DIU were higher than for CON. No differences were observed in plasma lac.. tare and serum free fatty acid concentrations either at rest or during exercise. Hypohydration led to lower (P [is less than] 0.05) glucose [R.sub.a] and [R.sub.d] at rest and at 15 and 30 min of exercise, but by 60 rain, the effects were reversed (P [is less than] 0.05). Hypohydration had no effect on rates of whole body lipolysis or total carbohydrate or fat oxidation. A main effect for condition (P [is less than] 0.05) was observed for plasma glucagon concentrations such that larger values were observed for DIU than for CON A similar decline in plasma insulin occurred with exercise in both conditions. These results indicate that diuretic-induced reductions in PV decreases glucose kinetics during moderate-intensity dynamic exercise in the absence of changes in total carbohydrate and fat oxidation. The specific effect on glucose, kinetics depends on the duration of the exercise. glucose turnover; glycerol turnover; lipolysis; stable isotopes

Ellison, David H. Divalent cation transport by the distal nephron: insights from Bartter's and Gitelman's syndromes. Am J Physiol Renal Physiol 279: F616-F625, 2000.--Elucidation of the gene defects responsible for many disorders of renal fluid and electrolyte homeostasis has provided new insights into normal and abnormal physiology. Identifying the causes of Gitelman's and Bartter's syndromes has greatly enhanced our understanding of ion transport by thick ascending limb and distal convoluted tubule cells. Despite this information, several phenotypic features of these diseases remain confusing, even in the face of molecular insight. Paramount among these are disorders of divalent cation homeostasis. Bartter's syndrome is caused by dysfunction of thick ascending limb cells. It is associated with calcium wasting, but magnesium wasting is usually mild. Loop diuretics, which inhibit ion transport by thick ascending limb cells, markedly increase urinary excretion of both calcium and magnesium. In contrast, Gitelman's syndrome is caused by dysfunction of the distal convoluted tubule. Hypocalciuria and hypomagnesemia are universal parts of this disorder. Yet although thiazide diuretics, which inhibit ion transport by distal convoluted tubule cells, reduce urinary calcium excretion, they have minimal effects on urinary magnesium excretion, when given acutely. This review proposes mechanisms that may account for the differences between the effects of diuretic drugs and the phenotypic features of Gitelman's and Bartter's syndromes. These mechanisms are based on recent insights from another inherited disease of ion transport, inherited magnesium wasting, and from a review of the chronic effects of diuretic drugs in animals and people. kidney tubules; distal; loop of Henle; calcium; magnesium; thiazide; thiazide-sensitive sodium-chloride cotransporter; bumetanide-sensitive sodium-potassium-2 chloride cotransporter; diuretics; aldosterone; sodium; chloride; voltage; heart failure

Characterization of the thiazidesensitive [Na.sup.+]-[Cl.sup.-] cotransporter: a new model for ions and diuretics interaction. Am J Physiol Renal Physiol 279: F161-F169, 2000.--The thiazide-sensitive [Na.sup.+]-[Cl.sup.-] cotransporter (TSC) is the major pathway for salt reabsorption in the apical membrane of the mammalian distal convoluted tubule. When expressed in Xenopus laevis oocytes, rat TSC exhibits high affinity for both cotransported ions, with the Michaelis-Menten constant ([K.sub.m]) for [Na.sup.+] of 7.6 [+ or -] 1.6 mM and for [Cl.sup.-] of 6.3 [+ or -] 1.1 mM, and Hill coefficients for [Na.sup.+] and [Cl.sup.-] consistent with electroneutrality. The affinities of both [Na.sup.+] and [Cl.sup.-] were increased by increasing concentration of the counterion. The [IC.sub.50] values for thiazides were affected by both extracellular [Na.sup.+] and [Cl.sup.-]. The higher the [Na.sup.+] or [Cl.sup.-] concentration, the lower the inhibitory effect of thiazides. Finally, rTSC function is affected by extracellular osmolarity. We propose a transport model featuring a random order of binding in which the binding of each ion facilitates the binding of the counterion. Both ion binding sites alter thiazide-mediated inhibition of transport, indicating that the thiazide-binding site is either shared or modified by both [Na.sup.+] and [C1.sup.-]. metolazone; distal tubule; osmolarity; salt reabsorption