Changes In Free Water Clearance Research Articles

Different diuretic properties between tolvaptan and furosemide in congestive heart failure patients with diuretic resistance and renal impairment: a subanalysis of the K-STAR.

We attempted to identify the difference in diuretic properties between tolvaptan (TLV) and furosemide (FUR) in congestive heart failure (CHF) patients with loop diuretic resistance and renal impairment. We investigated 81 CHF patients with loop diuretic treatment and renal impairment included in t he Kanagawa Aquaresis Investigators Trial of Tolvaptan on Heart Failure Patients with Renal Impairment (K-STAR). Predictive baseline factors and their changes during treatment periods were analyzed for correlation with percentage change in urine volume (%ΔUV) after additive introduction of TLV or increasing doses of FUR. Higher urine osmolality at baseline (β = 0.355; p = 0.033) in the TLV group and a lower ratio of blood urea nitrogen to serum creatinine (BUN/Cr, β = - 0.405; p = 0.020) in the FUR group were predictive of higher %ΔUV. Higher Δfree-water clearance (β = 0.667; p < 0.0001) in the TLV group, and higher %ΔBUN/Cr (β = 0.344; p = 0.030), higher %Δurine sodium concentration (β = 0.337; p = 0.037), and lower %Δstroke volume (β = - 0.390; p = 0.017) in the FUR group were correlated with %ΔUV. In conclusion, baseline urine osmolality and change in free-water clearance with additive introduction of TLV and a changing ratio of BUN/Cr with increasing doses of FUR were identified as key clinical parameters related to diuretic response.Trial registration UMIN000009201.

Effect of Preexercise Soup Ingestion on Water Intake and Fluid Balance During Exercise in the Heat

To determine whether chicken noodle soup before exercise increases ad libitum water intake, fluid balance, and physical and cognitive performance compared with water. Nine trained men (age 25 ± 3 yr, VO2peak 54.2 ± 5.1 ml · kg-1 · min-1; M ± SD) performed cycle exercise in the heat (wet bulb globe temperature = 25.9 ± 0.4 °C) for 90 min at 50% VO2peak, 45 min after ingesting 355 ml of either commercially available bottled water (WATER) or chicken noodle soup (SOUP). The same bottled water was allowed ad libitum throughout both trials. Participants then completed a time trial to finish a given amount of work (10 min at 90% VO2peak; n = 8). Cognitive performance was evaluated by the Stroop color-word task before, every 30 min during, and immediately after the time trial. Ad libitum water intake throughout steady-state exercise was greater in SOUP than with WATER (1,435 ± 593 vs. 1,163 ± 427 g, respectively; p < .03). Total urine volume was similar in both trials (p = .13), resulting in a trend for greater water retention in SOUP than in WATER (87.7% ± 7.6% vs. 74.9% ± 21.7%, respectively; p = .09), possibly due to a change in free water clearance (-0.32 ± 1.22 vs. 0.51 ± 1.06 ml/min, respectively; p = .07). Fluid balance tended to be improved with SOUP (-106 ± 603 vs. -478 ± 594 g, p = .05). Likewise, change in plasma volume tended to be reduced in SOUP compared with WATER (p = .06). Only mild dehydration was achieved (<1%), and physical performance was not different between treatments (p = .77). The number of errors in the Stroop color-word task was lower in SOUP throughout the entire trial (treatment effect; p = .04). SOUP before exercise increased ad libitum water intake and may alter kidney function.

Genetic deletion of the angiotensin-(1–7) receptor Mas leads to glomerular hyperfiltration and microalbuminuria

Angiotensin-(1-7), an active fragment of both angiotensins I and II, generally opposes the vascular and proliferative actions of angiotensin II. Here we evaluated effects of the angiotensin-(1-7) receptor Mas on renal physiology and morphology using Mas-knockout mice. Compared to the wild-type animals, Mas knockout mice had significant reductions in urine volume and fractional sodium excretion without any significant change in free-water clearance. A significantly higher inulin clearance and microalbuminuria concomitant with a reduced renal blood flow suggest that glomerular hyperfiltration occurs in the knockout mice. Histological analysis found reduced glomerular tuft diameter and increased expression of collagen IV and fibronectin in the both the mesangium and interstitium, along with increased collagen III in the interstitium. These fibrogenic changes and the renal dysfunction of the knockout mice were associated with an upregulation of angiotensin II AT1 receptor and transforming growth factor-beta mRNA. Our study suggests that Mas acts as a critical regulator of renal fibrogenesis by controlling effects transduced through angiotensin II AT1 receptors in the kidney.

Diuretic Effects, Pharmacokinetics, and Safety of a New Centrally Acting Kappa‐Opioid Agonist (CI‐977) in Humans

The diuretic effects, pharmacokinetics, and safety of CI-977, a new centrally acting selective kappa-opioid agonist, were determined in 16 healthy subjects. Subjects received single intramuscular doses of CI-977 (5, 15, or 25 micrograms) or placebo 1 week apart according to a randomized, double-blind, placebo-controlled, four-period, crossover design. Serial blood and urine specimens were collected after each dose. Significant dose-related decreases in negative free water clearance and urine osmolality and increases in urine volume were observed after administration of 15- and 25-micrograms doses of CI-977. CI-977 had no effect on urine electrolyte excretion or serum antidiuretic hormone. Absorption of CI-977 was rapid with individual tmax values ranging from 0.17 to 1.5 hours. Cmax and AUC(0-infinity) increased proportionally with dose. Individual elimination half-life values ranged from 0.6 to 3.3 hours and were independent of dose. Changes in free water clearance were related to CI-977 Cmax (r2 = 0.29, P = 0.0001) and AUC(0-4 hr) (r2 = 0.32, P = 0.0001) values. The most frequently reported adverse events after CI-977 administration were dizziness, fatigue, paresthesia, headache, vasodilatation (facial flushing), emotional lability, high feeling, and abnormal thinking. The frequency and intensity of adverse events increased with increasing CI-977 dose. In conclusion, CI-977 Cmax and AUC(0-infinity) increased in proportion to dose over the range of 5 to 25 micrograms; decreases in negative free water clearance were related to CI-977 dose and Cmax and AUC(0-4 hr) values; and the frequency and intensity of adverse events increased with increasing CI-977 dose.

Alpha 2-adrenoceptor antagonism attenuates the diuretic response to acute cold exposure

Renal alpha 2-adrenoreceptors modulate the hydrosmotic action of arginine vasopressin (AVP) through suppression of AVP-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) accumulation. Circulating catecholamines, likely candidates for the endogenous ligand, are elevated during cold exposure (CE). These studies therefore tested the hypothesis that the diuresis observed with acute CE in rats is due in part to modulation of AVP's tubular action via alpha 2-adrenoceptor activation. Subjects were five male Brattleboro homozygous diabetes insipidus (DI) rats (358 +/- 8 g) receiving chronic AVP replacement (1 microgram.kg-1 x day-1) and seven Long-Evans (LE) normal rats (395 +/- 5 g). In a CE protocol, baseline measurements at room temperature (RT, 24 +/- 0.3 degrees C) were followed by 60-min exposure to 5 +/- 0.5 degrees C. Results were compared with those from a RT time control protocol. The selective alpha 2-antagonist yohimbine (YOH; 10 micrograms.kg-1 x min-1) or vehicle (VEH) was infused throughout the CE and RT protocols. In VEH-infused rats, CE increased urine flow by 63 +/- 12 (DI rats) and 31 +/- 4 microliters.min-1 x 100 g body wt-1 (LE rats), and mean arterial pressure by 36 +/- 1 (DI rats) and 32 +/- 2 mmHg (LE rats). The increased flow was largely a water diuresis, with changes in free water clearance averaging 45 +/- 11 (DI rats) and 28 +/- 3 microliters.min-1 x 100 g body wt-1 (LE rats). YOH treatment completely blunted the cold-induced diuresis in both strains but did not alter the CE-induced hypertension. Glomerular filtration rate was not affected by either CE or YOH infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhancement of Renal Function by a Long-acting Somatostatin Analogue in Patients with Decompensated Cirrhosis

The effect of the long-acting somatostatin analogue SMS 201-995 on renal function was investigated in nine cirrhotic patients with ascites, low urine output, low serum sodium, and normal serum creatinine. SMS 201-995, infused at 40 micrograms/h for 2 h, produced a significant increase in urine volume, a significant decrease in urine osmolality, and a significant increase in creatinine clearance. These changes, although less pronounced, persisted 24 h after the infusion of the analogue. No significant changes in free water clearance, urinary sodium excretion or serum sodium were noted. The effects of SMS 201-995 might be attributed to an improvement of renal haemodynamics through inhibition of vasoconstrictor systems acting in cirrhosis. It is concluded that SMS 201-995 may have a role in the treatment of the renal abnormalities complicating liver disease.

INFLUENCE OF NIFEDIPINE AND ENALAPRIL ON OSMOREGULATION OF VASOPRESSIN

To determine whether calcium fluxes and angiotensin II influence osmoregulation of vasopressin (AVP) secretion, the effects of the calcium antagonist nifedipine and of the converting enzyme inhibitor enalapril on the AVP response to an osmotic load were compared to those of a placebo in seven normal female subjects. Plasma and urinary AVP were measured before and during a 3-h infusion of 2.5% hypertonic saline. Nifedipine (10 mg orally 2 h before and 10 mg at the start of the infusion) increased heart rate but did not change blood pressure. The changes in free water clearance and in urinary AVP induced by hypertonic saline under nifedipine were greater than in the control test, but the slope and the intercept of the regression line of plasma AVP upon plasma osmolality were not significantly different. Enalapril (10 mg 3 h before the infusion) did not change heart rate or blood pressure. Free water clearance and urinary AVP did not differ from the control test, but the slope of the regression line was less steep. These slight modifications of the response to an osmotic load suggest that calcium fluxes and angiotensin II only exert a limited influence on AVP osmoregulation in normal females.

Signals from the oropharynx may contribute to the diuresis which occurs in man to drinking isotonic fluids.

The drinking of a variety of isotonic salt solutions provoked a short load-dependent diuretic response in man, similar in latency to that of a water diuresis and reaching its maximum 40-60 min from the start of drinking. Subjects differed in the threshold load at which the response became evident, and also in the magnitude of their responses. Changes in free water clearance matched the increases in urinary minute volume, with no significant change in either urinary sodium or potassium excretion. Changes in urinary pH and in ammonium excretion were similar to those described for a water diuresis. Drinking an isotonic solution of mannitol provoked a diuresis similar to that of the salt solutions. All subjects had diarrhoea after drinking the mannitol. Signals arising from the oropharynx might be partly responsible for eliciting the diuresis. The significantly smaller urinary responses to infusions of isotonic salt solutions directly into the stomach support this view. The absence of a significant response to 'sham drinking' appears inconsistent with this, but oropharyngeal signals may only have a priming role in man and interact with other signals to give the full response.

Mineralocorticoid modulation of prolactin effect on renal solute excretion in the rat.

The effects of ovine PRL (oPRL) on renal solute and water handling were examined in 1) intact, 2) salt-loaded (6 meq NaCl ip X 8 days), 3) adrenalectomized (adx), 4) adx plus corticosterone-treated (133 micrograms/100 g BW im), and 5) adx plus dexamethasone-treated (10 micrograms/100 g BW im) male rats. After 7 days treatment rats received a water load (3% BW ip) before a 4-h urine collection. Rats also received 0.9% NaCl im (controls) or 1.0 mg oPRL on days 4-7. Treatments were continued to day 8 for inulin clearance determination. The effects of arginine vasopressin (AVP) (173 microU im, days 4-7) on renal solute and water excretion were also examined in salt-loaded rats to see if renal effects of oPRL treatment were due to AVP contamination of the oPRL preparation. In intact rats drinking tap water, oPRL decreased sodium clearance (CNa) and potassium clearance (CK) (P less than 0.05) vs. controls, with no change in free water clearance (CH2O). In intact rats receiving 1.0% NaCl and 1.0% glucose as a replacement for drinking water, oPRL decreased CNa (P less than 0.05) and increased CK (P less than 0.05) vs. controls, with no change in osmolar clearance or CH2O. In salt-loaded rats oPRL increased CNa and CK (P less than 0.05) vs. controls, with no change in CH2O. AVP administration to salt-loaded rats, however, had no effect on CNa and decreased CK vs. controls. oPRL increased CK (P less than 0.05) in adx rats, with no effect on CNa. In adx plus corticosterone-treated rats oPRL decreased CNa and CK (P less than 0.005), similar to its effect in intact animals. oPRL had no effect on renal solute or water excretion as compared to control animals in dexamethasone-treated adx rats. oPRL did not alter glomerular filtration rate at any time. These data suggest that 1) oPRL requires the presence of mineralocorticoids for an effect on sodium, but not potassium, excretion, 2) elevated sodium intake reverses the effect of oPRL on potassium excretion, 3) oPRL potentiates the effects of corticosterone on sodium reabsorption, and 4) glucocorticoids may block the effects of oPRL on the kidney.

Effect of vasopressin on renal kallikrein excretion.

In an attempt to investigate a possible interaction between vasopressin and the renal kallikrein-kinin system, renal function and urinary kallikrein excretion were monitored in trained conscious dogs and in anesthetized rats in water diuresis and in vasopressin-induced antidiuresis. Vasopressin elevated urinary kallikrein excretion in a dose-dependent way in both species, with concomitant increases in urinary osmolality and electrolyte excretion. A significant increase in kallikrein excretion was observed with a dose of vasopressin as low as 2 mU . kg-1 . h-1 in the dog and 3 mU . kg-1 . h-1 in the rat without a change in renal hemodynamics. In the rat vasopressin-induced changes in kallikrein excretion were positively correlated with changes in sodium and potassium excretion and negatively correlated with changes in free water clearance. It is concluded that vasopressin over its normal physiological range of concentration stimulates renal kallikrein secretion.

Effect of norepinephrine on plasma vasopressin concentration and renal water metabolism.

In the anesthetized, normally hydrated dog, the i. v. infusion of norepinephrine (NE; 0.5 microgram/kg/min) resulted in an increased blood pressure and a marked reduction in the plasma vasopressin (ADH) concentration (2.6 +/- 0.2 to 1.1 +/- 0.2 muU/ml). Urine flow and osmolar clearance, and urine osmolality fell. However, the negative free water clearance (TcH2O) increased, despite the reduction in plasma ADH levels. Thus, the NE-induced diuresis appeared to be due largely to the increased solute excretion, but the reduction in plasma ADH levels may also have been a factor. These data show that change in free water clearance is not a satisfactory index of change in the plasma ADH levels may also have been a factor. These data show that change in free water clearance is not a satisfactory index of change in the plasma ADH concentration when there are acute changes in renal hemodynamics and solute excretion. The norepinephrine-induced reduction in ADH secretion appeared to be due largely to increased activity of the arterial baroreceptors, but a central action cannot be ruled out.

Effect of bradykinin on the renal medullary osmotic gradient in water diuresis.

The effect of bradykinin on the renal medullary osmotic gradient was evaluated in anesthetized dogs which were undergoing water diuresis and which received a unilateral renal arterial infusion of bradykinin. The effect of the peptide on the medullary osmotic gradient was determined by analysis of medullary tissue electrolyte and urea concentrations and by analysis of changes in urine osmolality induced by vasopressin. Bradykinin decreased the total osmolality per kg H2O in tissue from inner medulla and papilla (-18.7 +/- 6% and -19.3 +/- 8%) and increased fractional water excretion (3.8 +/- 1.3%). Furthermore, a direct relationship between changes in free water clearance and changes in papillary tissue, osmolality was found. Finally, the increase in urine osmolality after ADH was significantly less in vasodilated than in control kidneys. These results indicate that bradykinin can diminish the medullary osmotic gradient during water diuresis in the dog. Thus, a bradykinin-induced increase in free water clearance may be accounted for by other than an inhibition of proximal tubular sodium reabsorption.

Mechanisms of portal hypertension-induced alterations in renal hemodynamics, renal water excretion, and renin secretion.

Clinical states with portal venous hypertension are frequently associated with impairment in renal hemodynamics and water excretion, as well as increased renin secretion. In the present investigation, portal venous pressure (PVP) was increased in anesthetized dogs undergoing a water diuresis. Renal arterial pressure was maintained constant in all studies. As PVP was increased from 6 to 20 mm Hg, decreases in cardiac output (2.5-2.0 liter/min, P less than 0.05) and mean arterial pressure (140-131 mm Hg, P less than 0.05) were observed. Increases in PVP were also associated with decreases in glomerular filtration rate (GFR, 40-31 ml/min, P less than 0.001), renal blood flow (RBF, 276-193 ml/min, P less than 0.001), and increases in renin secretion (232-939 U/min, P less than 0.025) in innervated kidneys. No significant change in either GFR or RBF and a decrease in renin secretion occurred with increases in PVP in denervated kidneys. To dissociate the changes in cardiac output and mean arterial pressure induced by increase PVP from the observed decreases in GFR and RBF, studies were performed on animals undergoing constriction of the thoracic inferior vena cava. In these studies, similar decreases in cardiac output and mean arterial pressure were not associated with significant changes in GFR or RBF. Increases in PVP also were associated with an antidiuresis as urine osmolality increased from 101 to 446 mosmol/kg H2O (P less than 0.001). This antidiuresis was significantly blunted but not abolished by acute hypophysectomy. In hypophysectomized animals, changes in free water clearance and urine flow were linearly correlated as PVP was increased. These studies indicate that increases in PVP result in decreases in GFR and RBF and increases in renin secretion mediated by increased renal adrenergic tone. Increased PVP is also associated with antidiuresis; this antidiuresis is mediated both by vasopressin release and by diminished tubular fluid delivery to the distal nephron.

The effects of vasopressin on the diuretic response to left atrial distension.

1. The diuretic response to left atrial distension was studied during infusion of saline or during infusion of vasopressin at four different dose rates.2. During infusion of saline left atrial distension caused an increase in free water clearance and an increase in osmolal clearance.3. During infusion of vasopressin at a rate of 0.025 m-u./kg.min and 0.1 m-u./kg.min there was no statistically significant increase in free water clearance during left atrial distension but there were variations in free water clearance in individual experiments.4. During infusion of vasopressin in doses of 0.4 m-u./kg.min and 1.0 m-u./kg.min changes in free water clearance were dependent upon changes in osmolal clearance indicating that these doses of vasopressin provided a maximum antidiuretic effect.5. Infusion of vasopressin had no effect on the increase in osmolal clearance which occurred in response to left atrial distension.6. The results allow the view that a part of the diuretic response to left atrial distension could depend upon a decrease in the concentration of antidiuretic hormone in the circulating blood.

Effects of increased sodium delivery on distal tubular sodium reabsorption with and without volume expansion in man.

The separate effects of volume expansion and of increased delivery of sodium on sodium reabsorption in the diluting segment of the distal nephron were studied in man. In six normal subjects during a sustained water diuresis, sodium delivery to the distal nephron was increased without volume expansion by the administration of acetazolamide. In these subjects, free water clearance rose linearly as a function of urine flow. In five patients with complete, central diabetes insipidus, distal sodium delivery was increased by the infusion of hypertonic saline during a sustained water diuresis. In four of these five patients, changes in free water clearance were also observed during hypertonic saline diuresis in the presence of distal blockade of sodium reabsorption with chlorothiazide. At high rates of distal delivery the following observations were made: (a) free water clearance was lower and fractional sodium excretion higher during saline diuresis compared to acetazolamide diuresis; (b) although free water clearance was moderately reduced by chlorothiazide at low rates of urine flow, there was no difference in free water clearance between saline loading alone and saline plus chlorothiazide at high rates of urine flow; and (c) during saline loading free water clearance rose without evidence of a limit when increased distal delivery was accompanied by spontaneous increases in glomerular filtration rate, but tended toward a limit when glomerular filtration rate remained constant. The data indicate that during acute volume expansion with saline, there is a decrease in the fraction of delivered sodium reabsorbed in the distal nephron when compared to the response of the distal nephron to comparable increases in distal sodium delivery in the absence of volume expansion.

Mechanism of exaggerated natriuresis in hypertensive man: impaired sodium transport in the loop of Henle.

To evaluate the effects of saline loading on distal sodium reabsorption in hypertensive man, studies were performed during both water deprivation and water diuresis in eight hypertensive subjects, and the results were compared to data obtained from similar studies in normal subjects. All hypertensive patients exhibited an enhanced excretion of filtered sodium (C(Na)/C(In)) at any level of distal delivery of sodium compared to normal controls. Free water reabsorption (T(c) (H2O)) during hypertonic saline loading was quantitatively abnormal in the hypertensives at high levels of osmolar clearance (C(Osm)), and also the curve of T(c) (H2O) vs. C(Osm) leveled off above a C(Osm) of 18 ml/min per 1.73 m(2) in the hypertensive group in contrast to the normal controls in whom T(c) (H2O) showed no evidence of achieving an upper limit. Sodium depletion exaggerated the abnormality in T(c) (H2O) in hypertensives, and resulted in a positive free water clearance (C(H2O)) during hydropenia. During hypotonic saline loading in water diuresis, changes in free water clearance per 100 ml of glomerular filtrate (C(H2O)/C(In)) were less at any given increment in urine flow per 100 ml of glomerular filtrate (V/C(In)) in the hypertensives compared to normal controls (P < 0.001). This abnormality in C(H2O)/C(In) in the hypertensives in conjunction with the defect in T(c) (H2O) observed during hydropenia indicates that sodium reabsorption in the loop of Henle was abnormal at any given rate of distal delivery of sodium in hypertension. Furthermore, these abnormalities in T(c) (H2O) and C(H2O) coincided temporally with the development of the exaggerated natriuresis. Although the distal defect in sodium transport, in large part, accounted for the augmented natriuresis in hypertension, evidence was present also for enhanced rejection of sodium in the proximal tubule during saline loading in the hypertensives. Additional studies utilizing acetazolamide which increases distal delivery of sodium without extracellular fluid volume expansion showed only minimal abnormalities in C(H2O) in the hypertensive group, indicating that the defect in sodium transport in the loop of Henle in hypertensives is mainly an abnormal response to extracellular fluid expansion rather than an intrinsic defect in the loop to handle increased tubular loads of sodium. It is possible that the abnormality in sodium reabsorption in the loop of Henle is due to the transmission of the abnormally elevated blood pressure of the hypertensives to the medullary vasa recta during saline loading.

DIURESIS INDUCED BY WATER INFUSION INTO THE CAROTID LOOP AND ITS INHIBITION BY SMALL HEMORRHAGE. THE COMPETITION OF VOLUME- AND OSMOCONTROL.

In five unanesthetized trained dogs the effect on urine flow of the osmotic stimulus of a slow intracarotid water infusion alone and combined with a mild hemorrhage of 8% of the estimated blood volume was investigated. The blood loss was too small to cause any change in blood pressure or heart rate. In contrast to the effect of intracarotid infusion of 3 ml water/min over a 30 min period no diuresis occurred when this infusion was combined with a slow hemorrhage of 150 ml applied during the first 10 min of the infusion period. In the majority of cases restoration of blood volume by retransfusion of the hemorrhaged blood was promptly followed by water diuresis. In all maneuvers the diuresis was entirely due to a change in free water clearance. The excretion of osmotically active material was unchanged. It is concluded that during a competition of the control systems of osmotic pressure and fluid volume the former is acutely overruled if the homeostasis of fluid volume is jeopardized.

ANTIDIURETIC RESPONSE TO ELECTRICAL STIMULATION IN BRAIN STEM OF THE MONKEY.

Antidiuretic hormone release was produced in conscious monkeys by electrical excitation of certain regions in the brain stem. The experimental design allowed repeated control and test observations in the same animal over a period of months. Alterations in free water clearance and urine osmolality resulted from electrical stimulation of the hypothalamus, the mesencephalic reticular formation, the ventral tegmental area of Tsai, and the periaqueductal gray substance. A similar drop in free water clearance and a rise in urine osmolality without a change in glomerular filtration rate was observed in the same animals after intravenous infusion of vasopressin. No significant changes in free water clearance or in urine osmolality were observed during the taking of blood samples, the infusion of isotonic saline or of 5% dextrose, or as a result of stimulation of the dorsolateral hypothalamus, thalamus, red nucleus, tectum, pons, and the optic chiasm.

Factors influencing the diuretic response to ingested water.

Abstract Water diuresis in normal humans was studied during changes in posture, infusion of hypotonic solutions of sodium salts, infusion of mannitol, and the ingestion of urea in order to determine whether urinary dilution might be affected by changes in sodium excretion more than by equal changes in the excretion of other solutes. It was found that changes in sodium excretion were accompanied by changes in free water clearance in the same direction, even though total solute excretion remained unchanged, or changed in the opposite direction. Thus, the increase in free water clearance which accompanies natriuresis cannot be explained by the osmotic effect of the excreted sodium. It is concluded that during natriuresis under these conditions delivery of isotonic sodium-containing fluid to the distal tubule is augmented because of increased glomerular filtration rate or decreased reabsorption in the proximal tubule. As a result, there is not only increased sodium excretion but also increased distal hypertonic reabsorption of sodium salts, which causes the observed increase in free water clearance.

Metabolic and renal effects of acute hypercalcemia in dogs.

The acute metabolic and renal effects of exogenously produced hypercalcemia were studied in hydrated dogs ingesting high- and low-calcium diets, in parathyroidectomized dogs and in dogs receiving vitamin D2. Under all these conditions, elevation of the plasma calcium concentration to 18 mg/100 ml resulted in solute diureses containing all major cations and in hyperphosphatemia. No change in free water clearance or net tubular transport of phosphorus occurred. Further elevation of levels of the plasma calcium caused marked reductions of glomerular filtration, renal plasma flow, and solute excretion and an increase in free water clearance. The increment in cation excretion exceeded the quantity of calcium retained. Less than 50% of the calcium load could be located in the extracellular space and urine at the end of the infusions. Erythrocyte calcium content increased two- to fourfold but erythrocyte concentrations of magnesium and acid-soluble phosphorus did not change. These data suggest that the solute diuresis of hypercalcemia is primarily renal in origin. Displacement of cations from osseous and intracellular sites by calcium may also occur and contribute to the solute diuresis. The hyperphosphatemia is independent of changes in parathyroid function, glomerular filtration and tubular transport of phosphorus and constitutes an unexplained consequence of induced hypercalcemia.