Adrenocorticotropic hormone in the control of renal tubular hydrogen ion secretion. Balance of non-metabolizable base in ACTH-stimulated weanling rats subject to acid or base loading

Groups of weanling rats subject to ACTH-stimulation (tetracosactrin, 1 mg kg-1 day-1) were exposed to heavy oral loads of ammonium chloride (approx. 21 mmol kg-1 day-1) or sodium bicarbonate (approx. 40 mmol kg-1 day-1) for 8 days. During loading with sodium bicarbonate, the animals maintained a normal positive external (whole body) balance of non-metabolizable base (NB), excess NB being excreted quantitatively in the urine, whereas loading with ammonium chloride caused a fall in the mean balance of NB from a reference value of 12.1 mmol per 8 days to about zero. However, in the two groups the concentration in plasma of NB rose from the reference value (41 mmol l-1) to the same level (57 and 59 mmol l-1, respectively; P greater than 0.5) despite extreme differences in rates of gastrointestinal NB absorption, despite a significant rise in the rate of endogenous sulphuric acid production and despite the presence of ample chloride in diet and urine. These results indicate that ACTH determines the extracellular concentration of NB at which exchange of NB takes place by influencing, directly or indirectly, the relative rates of renal tubular H- secretion and Cl- reabsorption at any given rate of tubular reabsorption of Na-. Some cybernetic considerations of the disturbance are presented.     

Parathormone as a mediator of inorganic phosphate diuresis during saline infusion in the rat

Summary Normal rats were infused with isotonic saline at 0.50 ml/min for 2 hours in order to expand their extracellular fluid volume. Under these conditions fractional excretion of inorganic phosphate was found to be as high as 38.8±3.0% of filtered phosphate, while fractional sodium excretion was 12.9±0.7% of filtered sodium. The combined addition of calcium and magnesium to the infusion solution decreased inorganic phosphate excretion significantly (P<0.001) to 11.2±3.6% (presumably by inhibiting parathyroid gland activity), while sodium excretion was unchanged (13.5±1.1%). Parathyroidectomized rats were infused with isotonic saline at 0.50 ml/min to achieve a similar extent of extracellular fluid volume expansion as in the normal rats. In these animals inorganic phosphate excretion was as low as 0.9±0.9% of filtered phosphate, while sodium excretion was 11.8±2.2% of filtered sodium. Administration of parathormone to volume expanded parathyroidectomized rats resulted in marked increases or inorganic phosphate excretion to 41.5±3.1% of filtered phosphate (P<0.001), while sodium excretion remained unaltered (12.0±2.8% of filtered sodium), thus resembling very closely the results in normal volume expanded rats.From these results it is concluded, that saline induced phosphaturia in normal rats is mediated primarily by parathormone. Furthermore, sodium excretion during volume expansion of extracellular fluid appears to be independent of inorganic phosphate excretion and independent of changes in parathyroid activity.This work was supported in part by a grant from the Deutsche Forschungsgemeinschaft.     

Renal tubular transport and metabolism of carboxyamidated and glycine-extended gastrins in pigs

Renal handling of postprandial and intravenously administered gastrin was investigated in anaesthetised pigs. The fractional extraction of postprandial carboxyamidated and glycine-extended gastrin in the kidneys was 0.21 ± 0.01 and 0.16 ± 0.02, but the respective urinary clearance comprised only 0.57 ± 0.03 and 0.44 ± 0.05% of the GFR (P < 0.02). The respective total body clearance of carboxyamidated and glycine-extended gastrin-17 (gastrin-17 and gastrin-17Gly) during continuous infusion was 22.9 ± 1.5 and 19.6 ± 1.4 mL kg^?1 min^?1 (NS), and the renal fractional extraction of the peptides was 0.31 ± 0.03 and 0.29 ± 0.05, respectively. The kidneys accounted for 8% of total body clearance of gastrin-17. Renal filtration rate of gastrin-17 exceeded renal extraction rate (9.739 ± 0.487 vs. 6.407 ± 0.321 pmol min^?1). Urinary clearance of gastrin-17 and gastrin-17Gly amounted only 0.91 ± 0.16 and 0.13 ± 0.03%, respectively, of the GFR (P < 0.01), but urinary excretion rate correlated with the filtered amount of the peptides (r = 0.93, P < 0.01). Neither was a renal plasma threshold recorded nor was a T_m value for tubular uptake or degradation of gastrin achieved in spite of supraphysiological plasma levels of the peptides. The results indicate that filtered gastrin is almost completely removed in the renal tubules, primary by metabolism although part of the absorbed peptides may be returned to the circulation in intact form. The process for uptake or metabolism has a high capacity but varies with the molecular form of gastrin.     

Acidosis,hypoxia and stress hormone release in response to one-minute inhalation of 80% CO2 in swine

The study pertains to a series of investigations on the effects of CO₂ inhalation as used for pre-slaughter anaesthesia in swine. Acid/base parameters, blood oxygen tension, plasma Na, K, Ca and stress hormone concentrations were monitored in Yorkshire swine before, during, and for 10 min after the animals were descended for 1 min into 80% CO₂ in air. Severe respiratory acidosis (P_aco2? 50 kPa, arterial pH ? 6.6) and hypoxia (P_ao2? 4 kPa) had developed after 45 s of the CO₂ inhalation. The corresponding changes in venous blood were less drastic (P_vCO2? 17 kPa, pH 7.1, P_vo2? 4 kPa). Readjustment to P_aCO2? 11 kPa, arterial pH 7.2, and P_ao2? 13 kPa had occurred at 1 min post CO₂. Four minutes later the respiratory acidosis had become converted into metabolic acidosis subjected to partial respiratory compensation (arterial pH 7.3 in the presence of moderate hypocapnia and hyperoxaemia). The cause of this metabolic acidosis (present also at 10 min post CO₂) was apparently hypoxia-induced anaerobic metabolism (= lactic acid production). Apparently due to hydrogen ion transport into the cells in exchange for other cations, hyperkalaemia (K? 6.6 mmol 1^-l), and a 7 mmol 1^-1 increase in plasma Na had developed at 1.5 min later. The CO₂ inhalation did not change the total plasma Ca significantly. The transport of the swine from the stable to the immediate pre-experimental situation induced a 3-fold increase in plasma Cortisol concentration (PC, to ? 130 mmol 1^-1). No further increase in PC occurred in response to the CO₂ inhalation. It indicates that no additional emotional strain was imposed upon the animals during the CO₂ exposure. Another possibility is that a maximal secretion of Cortisol was here reached already before the descent into the CO₂. The transport procedure caused only minor increases in plasma adrenalin (A) and noradrenaline (NA). However, during the CO₂ exposure plasma A and NA exhibited 15- and 50-fold rises, respectively (to 3.5 and 22 mmol l^-1, respectively). The main cause of the A/NA elevation seems to have been the severe respiratory acidosis.     

Impaired urinary acidification in the hypothyroid rat

Summary Since abnormalities in the renal handling of sodium and water in both the proximal and distal tubule have been described in primary hypothyroidism, this study was undertaken to examine renal tubular hydrogen secretion in this disorder. Metabolic acidosis was induced in hypothyroid rats (H) and their age matched controls (C) by the administration of an oral ammonium chloride load of 0.15 g/24 h/kg for three days. On day 3 animals were prepared for clearance and acid-base studies, receiving an infusion of Ringer's solution of 0.6 ml/hr/100 g during surgery and the experimental procedure. A 26% decrease in GFR (P<0.005) and a doubling in fractional excretion of sodium (P<0.02) were observed in H rats. The lowest blood pH and average bicarbonate concentration and the excretion of chloride were similar in the two groups, indicating that the acid load was reabsorbed and led to similar degrees of systemic acidification. Urine flow also was comparable in the two groups. Minimal urine pH after NH₄Cl was 6.21±0.06 in H and 5.68±0.09 in C (P<0.001). Ammonium excretion was 28% (P<0.05) lower in H than in C. The defect in urine acidification in H was only partially corrected after 5 days on a low sodium diet and DOCA administration for 2 days. Fractional bicarbonate excretion at normal blood pH and bicarbonate concentration was not different in the two groups. These data indicate that hypothyroid rats have a mild defect in urine acidification and that it is localized predominantly in the distal tubule.     

Comparison of acid/base status in conscious and anaesthetized rats during acute hypothermia

Acute hypothermia was surface-induced in unrestrained conscious rats at two different levels, moderate (30°C T _B) and severe (20°C T _B). Data reflecting the acid/base status were determined. The values obtained for moderate hypothermia were compared with the acid/base pattern observed during hypothermia induced by two different anaesthetics, sodium pentobarbital and urethane, at room temperature. Conscious, hypothermic animals developed an apparent respiratory alkalosis, with an increase in pH_a (from 7.476 to 7.546 in moderate hypothermia and from 7.484 to 7.563 in severe hypothermia) correlated with a decrease in arterial bicarbonate levels (from 22.9 to 16.8 mmol 1^–1 and from 20.7 to 14.9 mmol 1^–1 respectively). Lactate increased slightly in conscious, severely hypothermic rats (1.02 mmol 1^–1). This acid/base pattern was clearly different from that seen in sodium pentobarbital (mild respiratory acidosis) and urethane-induced hypothermia (metabolic acidosis). These results suggest that conscious rats follow a pattern closer to that underlying the relative alkalinity shown by many poikilotherms than to that underlying the constant pH shown in hibernating mammals. This latter pattern, nevertheless, approaches that observed during moderate pentobarbital hypothermia and the acid/base pattern during shallow hypothermia in birds. Anaesthesia may interfere with the development of the processes that lead to the acid/base pattern observed in conscious animals.     

Effect of Na−K-ATPase inhibition on hydrogen ion and potassium secretion

The purpose of the present study was to examine whether in vivo inhibition of renal Na–K-ATPase affects renal H⁺ and potassium (K) secretion. Infusion of digoxin, furosemide, or ethacrynic acid into one renal artery of HCO₃ loaded dogs caused similar increases in urine flow, fractional Na and Cl excretion, and fractional water excretion. Glomerular filtration rate and urinary HCO₃ concentration fell comparably in all experiments. Maximal HCO₃ reabsorption was not depressed by any of the drugs infused, however only digoxin inhibited renal Na–K-ATPase activity. Furthermore, unilateral digoxin infusion resulted in a marked depression in the urine to bloodpCO₂ gradient (U-BpCO₂) and prevented the rise in fractional K excretion secondary to HCO₃ infusion observed in the contralateral control kidney. At all urinary HCO₃ concentrations, U-BpCO₂ was significantly higher in urine obtained from furosemide or ethacrynic acid infused kidneys than in urine obtained from digoxin infused kidneys. In addition, furosemide or ethacrynic acid administration markedly enhanced fractional K excretion in both kidneys. The systemic infusion of tris(hydroxymethyl)aminomethane (THAM; pK 8.0) failed to return U-BpCO₂ in the digoxin infused experimental kidneys to control levels, whereas THAM caused a marked rise in U-BpCO₂ in the control kidney. These data demonstrate that the in vivo inhibition of renal Na–K-ATPase by digoxin causes a defect in the secretion of both H⁺ and K. This defect likely results from the dissipation of the Na dependent lumen negative potential difference (PD) by digoxin, since a lumen negative PD favors both H⁺ and K secretion in the collecting duct. Furthermore, these data do not support the notion that furosemide or ethacrynic acid affect tubular transport through the inhibition of renal Na–K-ATPase activity.     

Mutual inhibition ofl-cystine/l-cysteine and other neutral amino acids during tubular reabsorption

In microperfusion experiments renal tubular reabsorption of³⁵S- and¹⁴C-labelledl-cysteine (=cys),l-cystine (= cys-cys), andl-cystathionine was measured in vivo et situ at different initial concentrations. The interactions of cys and cys-cys with several neutral amino acids were investigated. The cys reabsorption mechanism was found to be saturable and has a high capacity and a low affinity for cys. AnJ _max-value of 3.22±0.88 nmol · m^–1 · s^–1 and aK _m-value of 7.5±0.7 mmol · l^–1 were estimated. A saturation of cys-cys reabsorption could not be demonstrated. The fractional reabsorption rate (=FRR) of cys-cys was about 85% at initial concentrations of 0.01, 0.08, and 0.4 mmol · l^–1 after a perfusion distance of 2 mm. The FRR ofl-cystathionine at an initial concentration of 0.115 mmol · l^–1 was only 30% under the same conditions. After perfusion of tubule segments between late proximal and early distal loops the recovery of cys, cys-cys, and cystathionine was smaller than 10%. The FRR of cys was decreased only byl-methionine. Six other neutral amino acids had no effect. On the other hand the FRR of cys-cys was reduced significantly by any of the tested neutral amino acids. The inhibitory effect increased in the orderl-alanine <l-methionine <l-citrulline < -aminoisobutyric acid <l-phenylalanine < cycloleucine. The FRR ofl-methionine andl-phenylalanine was slightly reduced in the presence of cys.It is concluded from these results that cys-cys shares a transport system with other neutral amino acids which is not identical with the reabsorption mechanism for cys. Reabsorption of cys, cys-cys, and cystathionine occurs also in a tubular section between late proximal and early distal sites.Parts of this study were reported at the International Conference on Renal Transport of Organic Substances at Innsbruck/Austria, July 1980 [24] and at the XIV. Symposion of the German Society for Nephrology at Würzburg/FRG, October 1980 [25].     

Acidosis and hypercalciuria: renal mechanisms affecting calcium, magnesium and sodium excretion in the sheep

1. Observations were made on the excretion of calcium and magnesium by the sheep's kidney following manipulation of the acid-base status.2. Intravascular administration of a synthetic solution resembling saliva abolished the naturally occurring acidosis in sheep during feeding, and it also prevented the normal onset of post-prandial hypercalciuria and hypermagnesiuria.3. Non-respiratory acidosis (induced by infusion of hydrochloric acid) and respiratory acidosis arising from inhalation of 6% (v/v) CO(2) in air both caused an acute increase in calcium excretion.4. Measurement of filtered loads showed that feeding exerted an effect on the functional characteristics of the sheep's kidney. The renal clearances of calcium and magnesium increased, whereas sodium clearance decreased.5. Experimental conditions were arranged so that variations in acid-base status could be imposed at a time when the filtered load of calcium was declining.6. With hydrochloric acid-acidosis the renal excretion of calcium increased, despite a steady fall in the filtered load. With sodium bicarbonate alkalosis, the filtered load and the renal excretion of calcium decreased in unison.7. These variations in calcium excretion were not accompanied by corresponding changes in the excretion of sodium.8. It is concluded that the renal tubules in the sheep are sensitive to acid-base status and that they respond to a lowering of the blood pH by decreasing the tubular reabsorption of filtered calcium.     

Proximal tubule specific knockout of the Na+/H+ exchanger NHE3: effects on bicarbonate absorption and ammonium excretion

The existing NHE3 knockout mouse has significant intestinal electrolyte absorption defects, making this model unsuitable for the examination of the role of proximal tubule NHE3 in pathophysiologic states in vivo. To overcome this problem, we generated proximal convoluted tubule-specific KO mice (NHE3-PT KO) by generating and crossing NHE3 floxed mice with the sodium-glucose transporter 2 Cre transgenic mice. The NHE3-PT KO mice have >80 % ablation of NHE3 as determined by immunofluorescence microscopy, western blot, and northern analyses, and show mild metabolic acidosis (serum bicarbonate of 21.2 mEq/l in KO vs. 23.7 mEq/l in WT, p?<?0.05). In vitro microperfusion studies in the isolated proximal convoluted tubules demonstrated a ～36 % reduction in bicarbonate reabsorption (J _HCO3?=?53.52?±?4.61 pmol/min/mm in KO vs. 83.09?±?9.73 in WT) and a ～27 % reduction in volume reabsorption (J _v ?=?0.67?±?0.07 nl/min/mm in KO vs. 0.92?±?0.06 nl/min/mm in WT) in mutant mice. The NHE3-PT KO mice tolerated NH₄Cl acid load well (added to the drinking water) and showed NH₄ excretion rates comparable to WT mice at 2 and 5 days after NH₄Cl loading without disproportionate metabolic acidosis after 5 days of acid load. Our results suggest that the Na⁺/H⁺ exchanger NHE3 plays an important role in fluid and bicarbonate reabsorption in the proximal convoluted tubule but does not play an important role in NH₄ excretion.     

Substrate specificity of the luminal Na+-dependent sulphate transport system in the proximal renal tubule as compared to the contraluminal sulphate exchange system

The efflux of [³⁵S]sulphate from the lumen of the proximal renal tubule into tubular cells of rats was measured by the stop-flow tubular-lumen microperfusion technique. The transport parameters obtained and the apparent K _i values of competing substrates were compared with those of the contraluminal influx of [³⁵-S]sulphate from the interstitium into tubular cells. For the luminal sulphate efflux a K _m(l, SO ₄ ^2– ) of 0.8 mmol/l and a J _max(l, SO ₄ ^2– ) of 0.2 pmol s^–1 cm^–1 were found. The corresponding contraluminal values were K _m(cl,SO ₄ ^2– ) 1.4 mmol/l and J _max(cl, SO ₄ ^2– ) 1.2 pmol s^–1 cm^–1. Omission of Na⁺ from the perfusates reduced the luminal efflux of sulphate by 83%, while the contraluminal influx of sulphate was not changed. Increase in HCO ₃ ^– concentration inhibited both luminal efflux and contraluminal influx of sulphate, while a change of pH from 6.0 to 8.0 was without effect. Comparing the apparent K _i(SO ₄ ^2– ) values for luminal and contraluminal sulphate transport, a relationship close to 11 was seen for some inorganic substrates with tetrahedral molecular structure (thio-sulphate, sulphate, molybdate and selenate). The same holds for phosphate, while for oxalate the contraluminal K _i(SO ₄ ^2– ) value was lower than the luminal one (1.2 and 4.5 mmol/l). Some of the dicarboxylates and disulphonates tested show the same affinity to the luminal Na⁺-dependent sulphate transporter and the contraluminal sulphate exchange system, whereas most of the benzene carboxylate and benzenesulphonate derivatives tested exhibit higher luminal than contraluminal k _i values. The inhibitory potency increased with rising numbers of substituents on the benzene ring. This effect was more pronounced for the contraluminal sulphate transporter. In general, only disulphonates and analogues as well as similarly structured compounds (5-sulphosalicylate, 2-hydroxy-5-nitrobenzenesulphonate, eosine-5-isothiocyanate) have a good inhibitory potency toward the luminal sulphate transporter [apparent K _i 0.9–3.1 mmol/l]. All the tested sulphamoyl and phenoxy diuretics, and fluorescein and phenolphthalein dyes showed no or a smaller inhibitory potency to the luminal sulphate transport system than to the contraluminal. The most effective inhibitors of both sulphate transport systems are 8-anilino-1-naphthalenesulphonate, orange G, and H₂-DIDS. The data indicate that the Na⁺-dependent luminal and the Na⁺-independent contraluminal sulphate transport systems accommodate a similar spectrum of anionic substrates, whereby the inhibitory potency against the luminal Na⁺-dependent sulphate transport system is identical or smaller than against the contraluminal transporter.     

Regulation of the renal transport of inorganic sulfate: Effects of metabolic changes in arterial blood pH

The present experiments were designed to examine the effects of mild metabolic changes of blood pH on the reabsorption of inorganic sulfate (SO₄) in the rat. Female adult Sprague Dawley rats (which were kept on a standard diet) were used. In order to produce either a metabolic alkalosis (Alk) or a metabolic acidosis (Ac), 130 mmol/l NaHCO₃ or a mixture of 130 mmol/l NH₄Cl and 130 mmol/l NaCl was infused. The blood pH values were 7.49±0.02 and 7.29±0.02, respectively. The fractional excretion (FE) of SO₄ was 28.6±5.7 (Alk) and 9.5±2.7 (Ac), respectively. These changes were significant (P<0.001). It is concluded, that physiological metabolic changes of blood pH may be important in the renal regulation of the transport of SO₄.This work was supported by a grant from the Deutsche Forschungsgemeinschaft (Fr 239/9-2)     

Untersuchungen zur Wirkung eines Allopurinol/Benzbromaron-Präparates auf die Harnzusammensetzung im zirkadianen Verlauf

Summary In 13 patients suffering from recurrent calcium-oxalate urolithiasis the circadian course in the excretion of urinary components was investigated before and during treatment with a combination of allopurinol and benzbromarone. The patients were given a diet standardized in food and liquid intake. Urine was collected for 3 days every 3 h from the 7th day of standard diet. On days 8 and 9 each patient received one tablet of the combination. On all 3 days of urine collection a constant circadian course of urine volume was observed; pH values also showed a nearly identical course on all 3 days with increased daytime and low night values. Maximum excretion of uric acid under dietary conditions was discovered between 11 a.m. and 5 p.m. (day 7). After the first application of the compound (day 8, 8 a.m.) a transient increase in uric acid excretion was observed in the third collection period (2–5 p.m.), followed by a sharp decrease. Following the second application (day 9) the transient increase of the uric acid excretion was clearly diminished. Uric acid excretion in the 24-h urine also decreased steadily from 3.46 mmol/day (control) to 3.25 and 3.06 mmol/day (treatment). Serum uric acid decreased significantly from 324.5 to 275.6 µmol/l.After the first application of the compound (day 8) moderate changes of the urinary components — oxalic acid, Na, K, and chloride — significant changes of Ca were observed, whereas after the second application of the compound (day 9) the values no longer differed from control values.During treatment, uric acid concentration in every urinary collection period did not exceed the maximum concentration value without treatment (2.22 mmol/l). At no time during therapy with the combination of allopurinol and benzbromarone, were concentrations reached in the circadian course of uric acid excretion which could lead to a precipitation of uric acid.

     

In situ characterization of oxalate transport across the basolateral membrane of the proximal tubule

 Oxalate transport across the contraluminal membrane of the proximal tubule was studied in vivo using the ”capillary stopped flow microperfusion method” (Pflügers Arch 400:250–256, 1984). Cellular uptake of oxalate was characteristic of a carrier-mediated transport process (J _max = 1.6 ± 0.6 pmol/s per cm proximal tubular length, K _m = 2.03 ± 0.77 mmol/l). Sulphate inhibited oxalate transport in a dose-dependent manner (K _i-value = 1.53 ± 0.38 mmol/l). Sulphate transport across the basolateral membrane was also characteristic of a carrier- mediated transport process (J_max = 1.83 ± 0.56 pmol/s per cm proximal tubular length, K _m = 1.37 ± 0.57 mmol/l). Oxalate inhibited the sulphate transport in a dose-dependent manner (K _i = 2.06 ± 0.82 mmol/l). No significant differences were found between the K _i values and the K _m values of the two substances, indicating that oxalate and sulphate are transported by the same carrier across the basolateral membrane of the proximal tubule. Oxalate transport was not dependent on the extracellular sodium or potassium concentration. Bicarbonate competitively inhibited the oxalate transport. Chloride significantly inhibited the oxalate transport, but not dose dependently. It is, therefore, suggested that oxalate is transported into the cell of the proximal tubule in exchange for sulphate or bicarbonate. The dose-independent inhibition by chloride is suggested to be mediated by the coupling of the sulphate (bicarbonate)/oxalate exchanger with the chloride/bicarbonate exchanger at the basolateral membrane of the proximal tubule. This, furthermore, suggests that the transport of oxalate or sulphate across the basolateral membrane might be indirectly coupled with the reabsorption of chloride at this membrane side. Received: 5 August 1997 / Accepted: 8 January 1998     

Dependency of renal potassium excretion on Na,K-ATPase transport rate

Potassium secretion may depend on the transport rate of Na, K-ATPase in basolateral cell membranes of distal tubular cells. To examine this hypothesis experiments were performed in anaesthetized dogs during inhibition of proximal potassium reabsorption by acetazolamide or mannitol (fractional potassium excretion 1.2-1.4) or additional stimulation of potassium secretion by ethacrynic acid (fractional potassium excretion 2.1). Ouabain in a dose which inhibits 70–80% of the Na, K-ATPase activity reduced fractional potassium excretion to 0.8-0.9 by an effect on distal tubular secretion since potassium transport in the proximal tubules was not affected. Ouabain-sensitive potassium excretion varied in proportion to ouabain-sensitive sodium reabsorption during variation in glomerular nitration rate, even at urinary sodium concentrations exceeding 80 mmol 1^-1. In experiments without ouabain, saline infusion raised potassium excretion and sodium reabsorption until maximal Na, K-ATPase transport rate was reached, as judged from heat production measurements, but not during further increments in urine flow. After inhibition of Na, K-ATPase activity by hypokalaemia, potassium excretion and cortical heat production remained constant over a wide range of urine flow and sodium excretion. We conclude that potassium secretion is dependent on intact Na, K-ATPase activity and is stimulated by sodium delivery to the distal nephron until maximal transport rate of the enzyme is reached.     

Potassium substitution via the oral route: Does its efficacy depend on the anion of the potassium salt?

Summary In an open, randomized study, we investigated the effect of oral potassium chloride (KCl) and of potassium citrate/bicarbonate (K-cit/bic) in 42 patients with hypokalemia (3.5 mmol/l). In both groups 80 mmol K⁺ were administered daily. The parameters examined were serum potassium concentration, acid-base status, and urinary electrolyte excretion. Parameters were evaluated on days 0, 2, 4, and 6. With KCl, [K⁺] increased from 3.2± 0.2 (mean± SD) on day 0 to 3.8± 0.4 mmol/l on day 2 (p<0.005) and 4.0± 0.5 mmol/l on day 4 (p< 0.005). On day 6 [K⁺] was also 4.0±0.4 mmol/l (p< 0.005 vs day 0). With K-cit/bic, [K⁺] increased from 3.2± 0.2 to 3.7± 0.4 on day 2, 3.9± 0.5 on day 4, and 4.1± 0.6 mmol/l on day 6 (allp< 0.005 vs day 0). The increase of [K⁺] was not different between the two groups. Blood pH on day 0 was in the normal range in both groups and did not change significantly during the study. There was a decrease of carbon dioxide partial pressure (pCO₂) with KCl from 38.7± 4.9 on day 0 to 36.4± 3.6 on day 2 (p<0.05). On days 4 and 6, pCO₂ was back up to the basal level. In contrast, with K-cit/bic, pCO₂ rose from 35.0±5.8 mmHg on day 0 to 39.9± 5.8 mmHg on day 2 (p< 0.05). On days 4 and 6, pCO₂ was not different from day 0. The increase in urinary potassium excretion was equal in both groups. These results indicate that oral substitution with either KCl or K-citrate/bicarbonate may have only minor effects on the acid-base status under the conditions of the present study. Both potassium salts appeared to be equally effective in correcting hypokalemia via the oral route.Abbreviations GFR glomerular filtration rate - K-bic potassium bicarbonate - K-cit potassium citrate - KCl oral potassium chloride - pCO₂ carbon dioxide partial pressure - t.i.d. three times a day     

Renal, cardiovascular and endocrine responses of fetal sheep at 0.8 of gestation to an infusion of amino acids

Amino acid infusions increase renal blood flow (RBF) and glomerular filtration rate (GFR) and stimulate tubular reabsorption in adults. To characterize the effects of amino acids on fetal renal haemodynamics, tubular sodium reabsorption, acid-base homeostasis and plasma renin levels, 11 chronically catheterized fetal sheep aged 121 ± 1 days (term ∼150 days) were infused i.v for 4 h with alanine, glycine, proline and serine (0.1, 0.1, 0.06 and 0.06 mmol min⁻¹, respectively) in 0.15 m saline at 0.165 ml min⁻¹. Eight control fetuses were given saline. During amino acid infusion, plasma amino acid levels increased up to 20-fold (   P < 0.005  ). GFR increased by 50 ± 8 % (   P < 0.001  ); there was only a small transient increase in RBF. Proximal fractional sodium reabsorption fell from 74.6 ± 2.9 to 55.5 ± 5.4 % (   P < 0.005  ). Distal sodium delivery increased, but a smaller percentage of this distal sodium load was reabsorbed (   P < 0.005  ). Thus fractional sodium reabsorption fell from 95.5 ± 0.9 to 81.4 ± 2.0 % (   P < 0.005  ). There was a large diuresis, natriuresis, kaliuresis and increase in osmolar excretion (   P < 0.005  ). Plasma sodium and chloride concentrations fell (   P < 0.005  ). Plasma osmolality did not change. Plasma renin levels fell (   P < 0.05  ), cortisol levels increased (   P < 0.05  ), and there was a compensated metabolic acidosis. Thus the fetal sheep kidney demonstrated a remarkable functional capacity to respond to amino acid infusion. The increase in filtration fraction and the lack of an increase in RBF suggest that efferent arteriolar vasoconstriction occurred, a very different response from the renal vasodilatation seen in adult animals.     

Unchanged expression of the sodium-dependent phosphate cotransporter NaPi-IIa despite diurnal changes in renal phosphate excretion

Renal phosphate excretion is subjected to circadian rhythmicity. The bulk of filtered inorganic phosphate (P_i) is reabsorbed by the sodium-dependent phosphate cotransporter NaPi-IIa. The regulation of proximal tubular phosphate reabsorptive capacity is largely attributed to the altered abundance of NaPi-IIa residing in the brush border membrane (BBM) of proximal tubular cells. Therefore, we examined if the diurnal rise in renal phosphate excretion is accompanied by a corresponding change in NaPi-IIa expression. Renal phosphate excretion, creatinine clearance, and serum phosphate were determined at consecutive time points in rats, starting from 8 a.m. until 5 p.m. During this period, renal phosphate excretion (fractional P_i excretion) increased more than eightfold until 5 p.m. compared to the morning values at 8 a.m. In addition, serum phosphate and creatinine clearance as well as the calculated tubular phosphate threshold increased. Neither immunoblot analysis of BBMs nor immunohistochemical staining for NaPi-IIa yielded evidence for a lower abundance of NaPi-IIa in kidneys collected in the afternoon compared to those in the morning. However, kidneys sampled in the afternoon showed a small decrease (14%) in ³²P uptakes into BBM vesicles (BBMVs). Thus, the diurnal rise in renal phosphate excretion was associated with a mild reduction in the sodium-dependent phosphate transport rate in proximal tubular BBMs. There was no apparent downregulation of NaPi-IIa abundance and only a small reduction in Na⁺-dependent Pi-transport activity. Thus, the diurnal changes in urinary phosphate excretion appear to be mainly related to changes in serum phosphate and tubular threshold but not to NaPi-IIa expression.     

Effect of metabolic alkalosis and metabolic acidosis on urinary kallikrein excretion of anaesthetized rats: evidence for a role of blood pH as regulator of renal kallikrein secretion

The effect of altering the acid-base status on urinary kallikrein excretion of barbiturate-anaesthetized rats was investigated. Alkalosis was induced in a group of rats by intravenous (i.v.) infusion of NaOH at 0.45 mmol ⋅h⁻¹ for 30 min. Acidosis was induced in two groups of rats by i.v. infusion of HCl at 1.5 mmol⋅h⁻¹ for 30 min (uncompensated acidosis) or 0.15 mmol⋅h⁻¹ for 3 h (compensated acidosis), respectively. Time controls received 0.45 mmol⋅h⁻¹ NaCl. Rats with alkalosis excreted less kallikrein than their controls (P < 0.05). Rats with uncompensated acidosis excreted more active kallikrein (P < 0.05), whereas rats with compensated acidosis excreted similar amounts when compared with their respective controls. In rats with uncompensated acid-base derangements, the urinary kallikrein excreted per millilitre of glomerular filtrate was correlated with blood H⁺ activity (r = 0.99, P < 0.01). Arterial blood pressure, haematocrit, glomerular filtration rate, urine flow rate and Na⁺ and K⁺ excretions of experimental and control animals did not differ. Thus, renal kallikrein secretion into the tubular fluid appears to be regulated by blood proton activity. This, along with our previous demonstration that kallikrein inhibits HCO₃ ⁻ secretion into the tubular lumen (Renal Physiol 17:301–306, 1994; J Physiol (Lond) 488:163–170, 1995), indicates that this enzyme is part of a feedback loop regulating acid-base balance. Received: 26 June 1995/Received after revision: 27 December 1995/Accepted: 8 January 1996