Potassium-depletion alkalosis in the rat.

Studies were performed to investigate the role of concomitant chloride depletion in potassium-depletion alkalosis in the rat and the relationship between potassium depletion, plasma bicarbonate (PHCO3), and net acid excretion. 1) Selective potassium depletion (K-DEPL), potassium plus chloride depletion (KCl-DEPL), or selective chloride depletion (Cl-DEPL) was produced by administering a selectively potassium-, potassium and chloride-, or selectively chloride-deficient diet. In K-DEPL and KCl-DEPL rat, PHCO3 increased progressively and similarly during a 38-day period of restriction, whereas net acid excretion was similar and not elevated in either group. Cl-DEPL did not result in alkalosis. Chloride administration without potassium in alkalotic KCl-DEPL rats did not result in a sustained significant decrease in PHCO3. Potassium administration without chloride in alkalotic KCl-DEPL rats decreased PHCO3. Thus concomitant chloride depletion plays a minimal role in the alkalosis produced by dietary-induced potassium depletion. 2) Administration of a chronic acid load to alkalotic K-DEPL rats did not decrease PHCO3, and net acid excretion increased similarly as in normals. In K-DEPL rats after PHCO3 was reduced toward normal levels with acetazolamide, net acid excretion increased sharply above base-line values and PHCO3 increased markedly. Thus the alkalotic K-DEPL rat maintains the ability to excrete a chronic acid load, and a reduction in PHCO3 elicits an increase in acid excretion to restore the initial acid-base condition. These studies suggest that potassium depletion alters the set-point at which the kidney maintains PHCO3.

Suppressed humoral immunity in chicks fed diets deficient in sodium, chloride, or both sodium and chloride.

Four experiments were conducted to determine the effect of Na and Cl on the antibody response to sheep red blood cells (SRBC). In the first two experiments, Na and Cl were supplemented in the diet together as NaCl at levels from 0 to .75%. In two additional experiments, Na and Cl were supplemented independently; levels varied from .04 to .24% total dietary Na and from .07 to .36% total dietary Cl. Results of the first two experiments indicated that dietary Na and Cl levels above that found in a corn-soybean diet improved the antibody response to SRBC. Additional studies showed that the humoral immunity was significantly suppressed when chicks consumed diets with less than .14% Na and .17% Cl. Increasing dietary Cl from .17 to .27% when dietary Na was .04% suppressed the antibody response. Also, increasing dietary Cl from .21 to .36% when dietary Na was .14 or .24% suppressed the antibody response. The immunosuppression of the humoral response of chicks was determined to be not related to the decreased feed intake resulting from inadequate Na and Cl in the diet.

Effects of chloride and extracellular fluid volume on bicarbonate reabsorption along the nephron in metabolic alkalosis in the rat. Reassessment of the classical hypothesis of the pathogenesis of metabolic alkalosis.

Volume expansion has been considered essential for the correction of chloride-depletion metabolic alkalosis (CDA). To examine the predictions of this hypothesis, rats dialyzed against 0.15 M NaHCO3 to produce CDA and controls, CON, dialyzed against Ringer-HCO3 were infused with either 6% albumin (VE) or 80 mM non-sodium chloride salts (CC) added to 5% dextrose (DX) and studied by micropuncture. CDA was maintained in rats infused with DX. VE expanded plasma volume (25%), maintained glomerular filtration rate (GFR), but did not correct CDA despite increased fractional delivery of total CO2 (tCO2) out of the proximal tubule (36 +/- 2%) as compared with VE/CON (24 +/- 4%; P less than 0.05). In contrast, CC corrected CDA despite volume contraction (-16%) and lower GFR than CC/CON; proximal tCO2 delivery in CC/CDA (29 +/- 4%) did not differ from VE/CDA. CC was associated with an increment in tCO2 excretion. The data strongly suggest that maintenance and correction of CDA are primarily dependent upon total body chloride and its influences on intrarenal mechanisms and not on the demands of sodium or fluid homeostasis.

Severe chloride deficiency in the neonate: the canine puppy as an animal model.

Studies were designed to develop an animal model for the syndrome of hypochloremic, hypokalemic metabolic alkalosis (HMA), and failure to thrive in infants due to intake of chloride-deficient formula. Littermate canine puppies, 2 wk old, were fed soy formula containing normal chloride, 20 mEq/liter (NC, n = 5), or low chloride, 1 mEq/liter (LC, n = 5) for 4 wk, first by gavage and ad libitum thereafter. After 1 wk of LC formula, HMA developed in LC puppies although both NC and LC puppies had similar fluid and caloric intake and gain in weight and forelimb length. Two wk of LC formula also resulted in a higher serum creatinine and calcium but lower phosphate level in LC than NC puppies. After 4 wk of LC, weight and forelimb length were much less in LC than NC puppies. Plasma renin activity decreased with age in NC but remained elevated in LC. In a separate group of puppies (n = 6) with HMA, chloride supplementation of LC formula as NaCl to NC levels corrected HMA despite continued citrate intake. We conclude that the canine puppy is an appropriate model to study HMA due to decreased chloride intake. Low chloride intake independent of citrate caused the HMA.

Neuroendocrine factors mediating polydipsia induced by dietary Na, Cl, and K depletion.

We investigated whether the increased intake of water during dietary electrolyte depletion is related to activation of the renin-angiotensin system. Young adult male rats were fed a low Na-, Cl-, K-free (low-salt) diet for 2 wk during which measurements were made of daily water intake and urine volume, plasma osmolality (Posm) and electrolytes, and plasma renin activity (PRA) and angiotensin I (ANG I) concentration. Water intake and urine output increased on day 3 of the low-salt diet, reached a maximum on day 4, and remained elevated, paralleling the time course of increases in PRA and ANG I plasma concentrations. Posm was normal after 2 days on the low-salt, although it was significantly lower by day 11. Renal concentrating ability was not different from controls after 6 days, but was significantly reduced after 11 days of treatment. Electrolytic lesions of the subfornical organ (SFO) abolished the low-salt diet-induced polydipsia, but had no effect on the diet-induced increases in PRA and plasma ANG I concentration. These data demonstrate that polydipsia induced by feeding a low-salt diet can develop in the presence of a normal or reduced Posm and precedes the development of a renal concentrating defect. The primary polydipsia is associated with elevated PRA and ANG I and appears to be mediated by angiotensin receptors in the SFO.

Enhancement of fluoride retention by low dietary chloride without manifestation of chloride deficiency in the rat.

Weanling male albino rats were fed a purified diet containing 10 ppm fluoride as sodium fluoride and 0.02, 0.04, 0.06, 0.08, or 0.10% chloride as sodium chloride for 6 wk. Food intake was unaffected by the level of dietary chloride. Rats fed diets containing either 0.02 or 0.04% chloride had significantly higher fluoride retention and skeletal uptake of fluoride than did rats fed higher chloride levels. Diets, however, had to contain 0.04% chloride or more to support normal weight gain, femur ash weight and plasma chloride concentration. The ability to enhance fluoride content of bone on a low chloride diet without undesirable effects of chloride deficiency may have important implications, since fluoride is thought to play a role in strengthening the mineral apatite structure of bone.

Is chloride depletion an important contributing cause of death in infants with bronchopulmonary dysplasia?

A retrospective analysis of infants with bronchopulmonary dysplasia requiring prolonged hospitalization (greater than 100 days) was carried out to determine those factors associated with fatal outcome. Twenty-three infants made up the study population. Eleven infants died and 12 survived (survivors). No differences were noted between the groups regarding ventilator requirement, radiographic changes, and medication use (digoxin, aldactazide), except for furosemide which was used twice as frequently in the group of infants who died v the group of infants who survived (P less than .001). Differences noted between the groups included moderate hypochloremia (chloride less than 80 mEq/L) in all 11 infants who died v six of 12 survivors, severe hypochloremia (chloride less than 70 mEq/L) in the nine of 11 infants who died v two of 12 survivors, metabolic alkalosis (pH greater than 7.45) in nine of 11 infants who died v three of 12 survivors, hypertension (systolic BP greater than 113 mm Hg) in eight of 11 infants who died v one of 12 survivors, decrease in head growth in ten of the 11 infants who died v one of the 12 survivors; these differences were all significant (P less than .001). The metabolic alkalosis and head growth changes appear to be related to the hypochloremia. The data suggest that chloride deficiency may be an important contributing factor in the genesis of poor outcome in infants with bronchopulmonary dysplasia and that close attention to chloride supplementation might influence outcome.

Importance of the kidney in the correction of chloride-depletion alkalosis in the rat.

Correction of chloride-depletion alkalosis (CDA) may involve renal as well as extrarenal mechanisms. To determine the relative contribution of these mechanisms in a rat model of CDA produced by peritoneal dialysis (PD), we studied six groups of anesthetized Sprague-Dawley rats after PD. Groups II-IV and IIa were subjected to functional bilateral nephrectomy, and groups I and Ia were sham-operated. Groups I, Ia, II, and IIa were infused with isotonic fluid containing 70 mM Cl- and 40 mM HCO3-; the infusate in group III was 140 mM Cl- and in group IV, 70 mM neutral PO4 was substituted for Cl-. Groups I and Ia were infused at 0.5 ml . h-1 X 100 g body wt-1 and groups II, IIa, III, and IV at 0.25 ml . h-1 X 100 g-1. After 3 h of infusion, early partial correction with reciprocal changes in plasma Cl (+6.1 +/- 1.9 mmHg) and total CO2 (-6.0 +/- 0.8 meq/liter) occurred (P less than 0.01) only in group I. Hypokalemia (3.1 +/- 0.1 meq/liter) also occurred only in group I. The responses of groups Ia and IIa studied at 5 h were similar to those of groups I and II. These data suggest that the kidney, and not extrarenal mechanisms, is primarily responsible for the correction of CDA during infusion of chloride.

Cerebral dysfunction following infantile dietary chloride deficiency.

Twenty-two children who were chloride-depleted in infancy due to a chloride-deficient diet and who had resultant hypochloremic alkalosis were analyzed in regard to their signs and symptoms, metabolic studies, and growth parameters. Deceleration of weight, linear growth, and head growth occurred in most, and persistent growth failure occurred in some. The majority had cognitive deficits at follow-up. Comparison with growth parameters in a chronically malnourished group of children who had a variety of disorders revealed a similar degree of deceleration of weight (p = 0.50) and height (p = 0.70), but more severe deceleration of head growth (p = 0.01). Comparison with follow-up cognitive deficits reported in the United States medical literature in children with similar severity of nutritional deprivation indicates that the chloride-depleted infants had more frequent and more severe cognitive deficits (p = 0.09). Cognitive deficits have been documented in U. S. children who are nutritionally deprived only when disorders causing concomitant chloride depletion are responsible for the malnutrition.

Effects of dietary potassium depletion and mineralocorticoid excess on renal Cl-conservation in the dog.

Preexisting dietary K+ depletion (KD) in dogs exaggerates the renal acid excretory response to mineralocorticoid hormone (MCH) and attenuates the renal Cl- reabsorptive response without altering the Na+ reabsorptive response. The exaggerated acid excretory response has been postulated to be an electrophysiological consequence of a defect in renal Cl- reabsorption caused by KD. To investigate the specific effects of KD on renal Cl- transport in dogs, we assessed renal Cl- conservation during dietary Cl- restriction in KD adrenalectomized dogs maintained on physiological replacement doses of MCH. After a 16-day period of dietary K+ restriction and physiological MCH replacement, reduction of dietary NaCl from 5.0 to 0.25 mmol X kg-1 X 24 h-1 was attended by reduction in urinary Cl- excretion to values less than intake and to significantly lower values than in K+ -replete controls. In a subsequent experimental period of continued Cl- restriction and administration of DOC (15 mg/24 h, i.m.), urinary Cl- excretion decreased further in both groups to stable values, but the values were significantly greater in KD (2.7 +/- 0.4 vs. 1.1 +/- 0.1 meq/24 h, P less than 0.05) and the cumulative retention of urinary Cl- was significantly less (10.3 +/- 1.4 vs. 29.5 +/- 6.7 meq, P less than 0.05). These findings demonstrate that preexisting dietary KD accelerates chronic renal Cl- conservation in response to dietary Cl- restriction under conditions in which MCH supply is normal and fixed but that it impairs maximal renal Cl- -conserving ability in response to MCH excess.

Nutritional chloride deficiency in early lactation Holstein cows.

Beginning 1 wk postpartum, weekly changes of feed and water intake, body weight, milk production, and electrolyte concentrations in serum, saliva, urine, milk, and feces were observed for 8 to 11 wk. Three dietary treatments differing in sodium chloride and sodium bicarbonate supplementation but containing equal sodium concentrations were used. Dietary chloride percents were low .10%, medium .27%, and high .45%. Consistently changes were significant for feed and water intake, body weight, milk production, and electrolyte concentrations in serum, urine, milk, and feces of cows fed the low chloride diet. By wk 8, body weight had declined from 575.0 +/- 56.7 to 476.7 +/- 54.3 kg, and daily milk production decreased from a peak of 27.7 +/- 2.4 to 19.2 +/- 3.9 kg for cows fed the low chloride diet. Serum chloride decreased from 106.0 +/- 2.8 to 75.5 +/- 6.7 meq/liter during the same time. Cows on the low chloride diet developed clinical signs of a deficiency characterized by depraved appetite, lethargy, hypophagia, emaciation, hypogalactiae, constipation, and cardiovascular depression. Metabolic alterations could be summarized as a severe primary hypochloremic, secondary hypokalemic, metabolic alkalosis.

Clinical aspects of experimentally induced chloride deficiency in Holstein calves.

A severe total body chloride deficit was induced in Holstein calves by feeding a low-chloride ration (0.063% Cl) and removing digesta daily from the abomasum through a surgically implanted cannula. Clinical signs of the deficit observed included polydipsia, polyuria, dehydration, anorexia, scleral injection, decreased respiratory rate, and blood and mucus in the feces. Necropsy findings included dehydration, blood in the lumen of the small intestine, and renal lesions. The most extensive histopathologic changes occurred in the renal tubular epithelium of the outer medulla where mineralization of the tubular epithelium and basement membranes was frequently seen.

Effects of dietary chloride restriction in lactating dairy cows.

Early-lactation Holstein cows fed a corn silage-based diet low in chloride and supplemented with sodium bicarbonate were observed for clinical, metabolic, and production alterations over the course of 8 to 11 weeks. In 3 of the more severely affected cows, metabolic derangements included a rapidly developing primary hypochloremic, secondary hypokalemic and hyponatremic metabolic alkalosis, and hemoconcentration. Clinical signs included severe hypophagia, weight loss, muscle weakness, hypogalactia, dehydration, constipation, cardiopulmonary depression, and a depraved appetite. It was concluded that the rapid progression of these derangements, apart from any anatomic abnormalities or infectious causes, emphasizes the need for rapid assessment and therapeutic intervention in primary imbalance associated with body chloride depletion and metabolic alkalosis.

Effect of adrenalectomy on the renal response to chloride depletion in the rat.

These experiments were aimed at investigating renal behavior towards chloride, as distinct from sodium, during dietary deprivation of these ions in adrenalectomized rats. Adrenalectomized and shamoperated control rats were maintained on saline for 3 wk, then chloride conservation during a very low chloride intake was assessed both with an abundant sodium intake (as buffered sodium phosphate in the drinking water) and after subsequent withdrawal of sodium. When sodium intake was high, there was no difference in chloride conservation between adrenalectomized and control animals, and sodium balance and weight were maintained similarly in both groups. At the same time, both experimental and control rats developed significant hypokalemia and elevation of the plasma bicarbonate levels as compared to other control rats ingesting a normal diet. In another group of adrenalectomized rats sodium phosphate was withdrawn, after normal chloride conservation was observed, and the low-salt diet continued. Negative sodium balance developed and was associated with a negative chloride balance, whereas sham-operated rats continued to conserve sodium and chloride. In further studies during polyuria, both adrenalectomized and control rats developed urinary chloride concentrations of less than 1 meq/liter. Thus adrenalectomized rats can maintain chloride balance on a low chloride, high sodium intake, in contrast to their inability to conserve sodium on a low-sodium intake. It is concluded that renal tubular reabsorption of chloride in adrenalectomized rats is adequate to establish and maintain very low urinary chloride concentrations, which may imply active chloride transport in the papillary collecting duct despite the absence of adrenocortical hormone. In addition, the typical renal response to chloride deprivation, enhanced loss of potassium and accelerated reabsorption of bicarbonate, is not dependent on adrenocortical hormones.