Aldosterone in congestive heart failure: analysis of determinants and role in sodium retention.

In patients with congestive heart failure (CHF), the role of aldosterone in the abnormal sodium (Na+) retention and the determinants of plasma aldosterone (PA) including plasma atrial natriuretic factor (hANF), plasma renin activity (PRA), and plasma potassium (K+) have not been fully elucidated. We therefore studied the effect of the specific aldosterone antagonist, spironolactone, on urinary Na+ and K+ excretion and plasma hormone responses in 6 Na(+)-retaining CHF patients. After withdrawal of diuretics 4 days prior to the study, the CHF patients were placed on a Na+ intake of 100 mmol/day for 9 days. Spironolactone, 200 mg p.o. bid, was administered for the last 4 days of the 9-day study period. PRA and norepinephrine increased with spironolactone treatment (both p less than 0.05). Plasma hANF before spironolactone was significantly elevated and decreased during spironolactone therapy (p less than 0.05). Urinary Na+ excretion significantly increased during spironolactone administration and the positive Na+ balance was reversed in the CHF patients. Moreover, the urine Na+:K+ concentration ratio significantly increased during spironolactone administration. Analysis of the relationship between PA, plasma K+, PRA, and plasma hANF indicated that PRA is the primary determinant of PA in patients with CHF. Thus, the present results indicate that the renin-angiotensin-aldosterone system is an important mediator of Na+ retention in CHF, as evidenced by the reversal of the positive Na+ balance with a specific aldosterone antagonist. This natriuretic effect can be demonstrated in the presence of potential antinatriuretic influences including stimulation of the renin-angiotensin and sympathetic nervous systems and a decrease in plasma hANF.     

Is spironolactone safe for dialysis patients?

BACKGROUND: Spironolactone is useful in heart failure, but is not given to dialysis patients for fear of hyperkalaemia. This study evaluated the safety of spironolactone administration in haemodialysis patients. METHODS: Fifteen haemodialysis outpatients with mean serum potassium <5.6 mEq/l over the preceding 4 months were treated with spironolactone 25 mg daily for 28 days. Serum potassium was measured before every haemodialysis during the study. Aldosterone and renin were measured at the beginning and end of the study. Patients were monitored for side effects. Data were examined with a paired t-test, with patients serving as their own controls and P < 0.05 considered significant. A sample size of 14 was required to achieve a power of 0.8 and a P = 0.05 to detect a potassium difference of 0.5 +/- 0.6 mEq/l. All patients were analysed as intention-to-treat. RESULTS: The mean potassium level was 4.6 +/- 0.6 mEq/l at baseline and 4.9 +/- 0.9 mEq/l at study completion (P = 0.14). Thirteen patients completed the trial with no potassium levels >6.0 mEq/l. Four patients had potassium levels between 5.5 and 6.0 mEq/l. One patient was withdrawn at day 20 after developing hyperkalaemia (7.6 mEq/l). Another patient was withdrawn at day 25 after missing a dialysis treatment. There were no differences in either baseline or 28 day aldosterone or renin levels (16.8 +/- 28.8 vs 11.7 +/- 6.1 ng/dl and 3.5 +/- 3.9 vs 3.5 +/- 3.5 ng/ml/h, respectively). Infrequent side effects included dry mouth, nosebleed, pruritis, gynecomastia and diarrhoea. No significant leukopenia or anaemia was noted. CONCLUSIONS: Spironolactone may be considered as a treatment option for selected chronic haemodialysis patients with heart disease.     

Insulin and mineralocorticoids influence on extrarenal potassium metabolism in chronic hemodialysis patients.

Insulin-mineral corticoids effects on extrarenal K+ metabolism in dialysis patients. During the inter-dialytic interval in dialyzed patients, hydrogen and potassium ions are regulated by extrarenal mechanisms. We studied the hormonal and acidotic effects on the extrarenal potassium metabolism, in selected, anuric and stable, hemodialysis patients. Fifteen patients, were grouped according to the mean mid-week pre-dialysis K+ over the past 12 months: > 6.0 mEq/L (G1, n=5), = 5.1-6.0 mEq/L (G2, n=5), < or = 5.0 mEq/L (G3, n=5). After a mid-week hemodialysis session and 12 h fasting, they received 1 g/Kg glucose p.os (A). Insulin, aldosterone, renin, pH, HCO3-, glucose, body weight, blood pressure and heart rate were measured before and 60' after the meal. We recorded the same parameters, except insulin, in 15 patients, similarly grouped, before hemodialysis (T0) and on 3 consecutive off dialysis days (T1-T3); G1 received fluorohydrocortisone (FHC) 0.1 mg-0.3 mg/day, according to body weight and G3 spironolactone (SLT) 200 mg per day. G2 were controls (B). (A) A significant rise in glycemia (81 +/- 23 to 157 +/- 52 mg/dL, P<0.001) and insulin (11.8 +/- 6.2 to 46.8 +/- 19.5 microU/mL, P<0.001), with a drop in K+ (5.1 +/- 0.6 to 4.8 +/- 0.7 mEq/L, P=0.001) and aldosterone (453 +/- 373 to 383 +/- 364 pg/mL, P<0.01), were noted at T60 vs. T0, in all groups. Insulin levels correlated negatively (r=-0.54, P<0.04) to serum K+ at T60, in all patients. (B) No major pH, HCO3 and aldosterone changes were observed in the 3 groups. Despite that, K+ dropped in G1 by FHC (6.7 +/- 0.9 to 5.9 +/- 0.6 mEq/L, P<0.05), rose in G3 by SLT (4.4 +/- 0.4 to 5.4 +/- 0.3 mEq/L, P<0.05) and remained unchanged in controls (5.8 +/- 0.2 to 5.8 +/- 0.6 mEq/L), (T0 vs T3 pre-dialysis values). Glucose significantly lowered K+ by promoting adequate insulin secretion. Drugs affecting aldosterone action significantly influenced potassium metabolism. Acid-base balance was not important in K+ handling in steady state anuric dialysis patients.     

Effect of spironolactone on K(+) homeostasis and ENaC expression in lymphocytes from chronic hemodialysis patients

BACKGROUND: Cardiac disease is the major cause of death in hemodialysis patients (HD). It is now clear that aldosterone has deleterious effects in the cardiovascular system. In the present study, we evaluated the effects of an aldosterone-antagonist, spironolactone, on the extrarenal regulation of potassium in HD patients. Furthermore, to validate the effectiveness of the spironolactone dose-design, we measured the expression of Na(+)-channel (ENaC alpha subunit) in peripheral blood mononuclear cells (PBMC), before and after a two-week course of spironolactone. METHODS: The study design included a two-week baseline period, followed by spironolactone treatment (50 mg three times weekly for 15 days), and by a two-week washout period and then a two-week placebo period. An oral K(+) load (0.3 mEq/K(+) kg body weight plus carbohydrates) was administered at the end of each period, and time-course of plasma potassium was evaluated. ENaC expression in PBMC was assessed before and after spironolactone. RESULTS: The maximal increase in plasma potassium after the K(+) carbohydrate load was: control 5.33 +/- 0.88 mEq K(+)/L; spironolactone 5.23 +/- 0.68 mEq K(+)/L; placebo 5.38 +/- 0.61 mEq K(+)/L (N= 9). No patients developed hyperkalemia during the spironolactone treatment period. ENaC expression was significantly higher in all six HD patients studied, compared to control subjects (P < 0.05). Treatment with spironolactone in HD patients reduced alpha subunit mRNA expression to values similar to those of normal subjects. CONCLUSION: Spironolactone may be considered for the treatment of selected chronic HD patients. The effect of the drug on a known target of aldosterone, the ENaC, demonstrates the effectiveness of the drug to block aldosterone effects in nonepithelial tissues.     

Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease

Experimental evidence suggests that aldosterone contributes to progressive kidney disease. Angiotensin-converting enzyme inhibitors and angiotensin type 1 receptor antagonists suppress the renin-angiotensin system but they do not effectively reduce plasma aldosterone. Hence, administration of aldosterone receptor antagonists may provide additional renal protection. In the present prospective randomized open-label study, we evaluated the effects of spironolactone (25 mg/day for 1 year) on proteinuria and estimated glomerular filtration rate in 83 patients with chronic kidney disease already treated with angiotensin-converting enzyme inhibitors and/or angiotensin type 1 receptor antagonists. Eighty-two patients were treated with angiotensin-converting enzyme inhibitors and/or angiotensin type 1 receptor antagonists alone and served as controls. After 1 year of therapy, proteinuria decreased from 2.1+/-0.08 to 0.89+/-0.06 g/g creatinine (P<0.001) in patients treated with spironolactone, but it did not change in control patients. Baseline aldosterone levels were significantly correlated with proteinuria (r=0.76, P<0.0001), and predicted the degree of reduction in proteinuria with spironolactone (r=0.42, P<0.0002). Baseline estimated glomerular filtration rate was similar in patients treated with spironolactone and controls (62.4+/-2.4 and 62.2+/-2.1 ml/min/1.73 m(2), respectively). After 1 month of therapy with spironolactone, estimated glomerular filtration rate decreased more in patients treated with spironolactone than in controls. However, by the end of 1 year the monthly rate of decrease in estimated glomerular filtration rate from baseline was lower in patients treated with spironolactone than in controls (0.323+/-0.044 vs 0.474+/-0.037 ml/min/1.73 m(2), P<0.01). Spironolactone caused a significant rise in serum potassium levels (from 4.2+/-0.04 at baseline to 5.0+/-0.05 mEq/l after 12 months of treatment, P<0.001). In conclusion, this study has shown that spironolactone may reduce proteinuria and retard renal progression in chronic kidney disease patients.     

Influence of aldosterone vs. endothelin receptor antagonism on renovascular function in liquorice-induced hypertension.

BACKGROUND: The enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) provides mineralocorticoid receptor specificity for aldosterone by metabolizing glucocorticoids to their receptor inactive 11-dehydro derivatives. Inhibition of 11beta-HSD2 by liquorice-derived glycyrrhizic acid (GA) therefore results in sodium retention and hypertension. The present study investigated the effect of the aldosterone receptor antagonist spironolactone in comparison with the endothelin ET(A) receptor antagonist darusentan on renovascular endothelial function in liquorice-induced hypertension. METHODS: GA, a recognized inhibitor of 11beta-HSD2 was supplemented to the drinking water (3 g/l) of Wistar Kyoto rats over a period of 21 days. From day 8 to 21, spironolactone (5.8+/-0.6 mg/kg/day), darusentan (45.2+/-6.5 mg/kg/day), or placebo was added to chow (n=7 per group). After the animals were killed, vascular function of isolated renal artery segments was assessed by isometric tension recording. RESULTS: Relaxation of pre-constricted renal artery segments in response to acetylcholine (10(-10) to 10(-5) mol/l) was impaired by GA as compared with controls (12+/-4% vs 98+/-5% of norepinephrine 3x10(-7) mol/l), whereas endothelium independent relaxations were unaffected. Endothelin receptor antagonism improved renovascular endothelium-dependent relaxation (32+/-4%, P<0.05 vs placebo) whereas endothelium-dependent relaxation was completely normalized by aldosterone receptor antagonism (85+/-4%, P<0.01 vs placebo). CONCLUSIONS: In GA-induced hypertension, both aldosterone receptor antagonism and endothelin receptor antagonism normalize blood pressure and improve renovascular function and, thus, may represent a new therapeutic approach in cardiovascular disease associated with impaired 11beta-HSD2 activity.     

Sodium-lithium countertransport in children with nephrotic syndrome

The mechanisms of sodium retention in edema-forming minimal change nephrotic syndrome (MCNS) have not been completely evaluated. The aim of this study was to characterize the transmembrane sodium transport in nephrotic syndrome by measuring the erythrocyte sodium-lithium countertransport (SLC) in vitro. Eighteen children with MCNS were studied in the edema-forming state, and subsequently at the beginning of remission. Nephrotic children with edema retained sodium (10±12 μmol/day) and had a higher SLC [426±118 vs. 281±60 μmol/l red blood cells (RBC) per hour, P=0.003). The intracellular sodium concentration of nephrotics was 6.1±2.1 mmol/l RBC, which did not differ from that of controls (6.42±2.24, n=13). In remission sodium balance became negative (–30 ±21 mmol/day), and the SLC decreased but still differed significantly from control values (P=0.009). The intracellular sodium content decreased to 4.4±0.9 mmol/l RBC (P=0.002). There was a negative correlation between erythrocyte SLC and plasma albumin concentration (r=0.48, P=0.003), and urinary sodium excretion rate (r=0.66, P=0.001). In conclusion, erythrocyte SLC is high in the edema-forming state of childhood nephrotic syndrome and decreases with the onset of remission. A role for the SLC in the altered sodium homeostasis of nephrotic syndrome is suggested. Received: 6 April 1998 / Revised: 5 October 1998 / Accepted: 4 November 1998     

The sodium retaining effects of cyclosporine.

The effect of chronic cyclosporine administration on volume regulation was studied in mongrel dogs. Dogs received either cyclosporine (20 mg/kg/day p.o.; N = 7) or vehicle (N = 6) while being maintained on a constant sodium diet. Dogs had measurement of baseline vasoactive hormones. Daily sodium excretion was determined. Following eight days of drug administration, dogs were anesthetized, pre-volume expansion data was collected, and dogs underwent a one hour, 10% body weight 0.9% saline volume expansion. Daily sodium balance was +8.6 +/- 2.2 mEq in the cyclosporine group versus 0.4 +/- 1.8 mEq (P less than 0.05) in the control group after 8 days. Prior to acute volume expansion, aldosterone was 22.5 +/- 7.1 ng% in the cyclosporine group versus 4.7 +/- 0.7 ng% in controls (P less than 0.05). ANF was suppressed in the animals receiving cyclosporine. In response to volume expansion, the cyclosporine group demonstrated an attenuation of maximum urine flow by 56%, fractional excretion of sodium by 52%, and electrolyte free water clearance by 75% when compared to controls (P less than 0.05). We demonstrate that chronic cyclosporine administration activates the renin-angiotensin-aldosterone system, suppresses circulating ANF, and results in chronic sodium retention. Additionally, cyclosporine attenuates the natriuretic and diuretic response to acute volume expansion.     

Effects of uroguanylin on natriuresis in experimental nephrotic rats

Aim:   Uroguanylin, isolated from human and opossum urine, is a candidate intestinal natriuretic hormone that controls the sodium and water balance between the intestine and the kidneys. Levels of immunoreactive (ir)-uroguanylin in the plasma and urine are increased in rats and humans with nephrotic syndrome, which is physiologically characterized by sodium retention with massive proteinuria. The present study evaluates the effect of natriuresis induced by uroguanylin on nephrotic rats.
Methods:   Normal rats and rats rendered nephrotic by injections of puromycin aminonucleoside (PAN) were treated with uroguanylin (0.5 nmol/h, delivered by an osmotic pump) or with vehicle during the sodium retention phase. All rats consumed the same quantity of sodium.
Results:   Uroguanylin did not increase urinary excretion of sodium and water in normal rats, but significantly increased urinary sodium excretion during the sodium retention phase in nephrotic rats (untreated vs uroguanylin-treated nephrotic rats in mmol/mmol creatinine; 2.92 ± 0.65 vs 8.93 ± 2.53 on day 6, P  < 0.05; 3.55 ± 0.47 vs 10.37 ± 1.73 on day 7, P  < 0.01; 14.88 ± 2.32 vs 24.47 ± 2.86 on day 8, P  < 0.05). Plasma levels of ir-uroguanylin in uroguanylin-treated nephrotic rats on day 6 were significantly increased compared with those in uroguanylin-treated control and untreated nephrotic rats.
Conclusion:   Uroguanylin increased urinary sodium excretion in rats with PAN-induced nephrosis, and might be useful for treating sodium retention in patients with nephrotic syndrome.     

Acute respiratory distress syndrome is a serious complication of microwave coagulation therapy for liver tumors

BACKGROUND: Acute respiratory distress syndrome (ARDS), also known as noncardiogenic pulmonary edema, is a severe complication in cirrhotic patients undergoing microwave coagulation therapy (MCT) for liver tumor. In this study, cirrhotic patients with ARDS after MCT were compared with others without ARDS. METHODS: Four patients with ARDS after open MCT and 17 other patients without ARDS were compared in terms of preoperative status, intraoperative findings, and postoperative management. RESULTS: The preoperative Child-Pugh score and intraoperative amount of irradiation showed no significant differences were observed. The postoperative cumulative water balance until the third day was 1,692 +/- 1,315 mL for the ARDS group and 165 +/- 1,524 mL for the non-ARDS group (P = .079), and by the fourth day the respective values were 1,992 +/- 1,585 mL and 66 +/- 1,685 mL, showing a significant difference (P = .049). The postoperative cumulative sodium administration until the third day was 510 +/- 132 mEq for the ARDS group and 362 +/- 122 mEq for the non-ARDS group with a significant difference (P = .044), and by the fourth day the respective values were 642 +/- 141 mEq and 477 +/- 160 mEq (P = .073). Of the 17 patients in the non-ARDS group, 6 were given aldosterone antagonist until the fourth postoperative day, but it was not administered to any of the patients in the ARDS group. CONCLUSIONS: The water balance and sodium administration have to be closely monitored to prevent cirrhotic patients undergoing MCT from developing ARDS. Aldosterone antagonist appears to be useful for the prevention of ARDS.     

Effect of postoperative hypertonic sodium infusion in the patients with total gastrectomy for gastric cancer

In 17 patients with gastric cancer undergoing total gastrectomy, the effect of postoperative hypertonic sodium infusion were studied. The subjects were divided into 2 groups by concentration in the postoperative infusions. Group 1(Na group): over 5.0 mEq/Kg/day of sodium were infused in the postoperative days (POD). (End of operation to POD-4), Group 2 (Control group): 2.0-2.5 mEq/Kg/day of sodium (End of Op. to POD-1), 1.5-2.0 mEq/Kg/day (POD-2-4). 2.0-2.5 mEq/Kg/day were infused after POD-5 in both groups. In the Na group, NAG-Index, FENa and BUN were higher than those of control group. And cumulative primary Na balance (from end of operation to POD-5) indicated positive balance in Na group, and negative in control group. Furthermore, the cumulative infused sodium dose correlated with cumulated urinary sodium dose, potassium dose and cumulative NAG dose (from end of operation to POD-5). Significant difference was observed between two groups in urinary nitrogen. These findings suggest that the sodium dose in the postoperative infusion were suitable with 2.0-2.5 mEq/Kg/day.     

Hyponatremia and natriuresis following subarachnoid hemorrhage in a monkey model

A monkey model of subarachnoid hemorrhage (SAH) was used to study both the incidence of hyponatremia and natriuresis and the associated changes in antidiuretic hormone (ADH) secretion and salt and water balance. Following SAH, seven of nine monkeys became natriuretic and hyponatremic. The natriuretic period lasted an average of 4.4 +/- 0.4 days. The mean nadir of serum sodium content was 125.7 +/- 1.6 mEq/liter, and occurred on the average on the 5th day following SAH. The sodium balance after SAH was negative as compared to the preoperative positive sodium balance (p less than 0.001). The plasma vasopressin level was usually elevated for a day following surgery, but there was no significant difference in the levels during the preoperative period and during the period of natriuresis following SAH. The daily urine output and aldosterone levels were not significantly different, and the plasma volume was slightly, but not significantly, decreased after SAH. Four of the animals that had a hyponatremic and natriuretic response following SAH showed a normal regulation of vasopressin in response to both a water challenge and hypertonic saline challenge. The three monkeys that underwent sham procedures did not become hyponatremic and natriuretic postoperatively. The sham-operated monkeys did not show significant differences in their plasma vasopressin levels, urine volume, plasma volume, and aldosterone levels following surgery. These observations are more consistent with primary natriuresis as the cause of hyponatremia rather than the syndrome of inappropriate secretion of ADH. The cause of the renal loss of sodium is not known, but the possibility of a brain natriuretic factor or an alteration in the neural control of the kidney should be considered.     

Effect of indomethacin and adrenocorticotrophic hormone on renal function in man: an experimental model of inappropriate antidiuresis.

The effect of prostaglandin synthesis inhibition on basal and ACTH-stimulated adrenal and renal function was investigated in normal volunteers. Data were collected during control and experimental study periods (13 days each). Adrenocorticotrophic hormone (Cosyntropin, 80 U/day) was administered i.v. on days 8 and 9 of each period. Indomethacin (150 mg/day) was given on days 5 through 13 of the experimental period. The subjects ate a constant diet containing 9 mEq of sodium, 100 mEq of potassium, and 2,500 ml of fluid daily. Indomethacin markedly inhibited urinary PGE excretion and plasma PGE concentration. The effect of ACTH alone as compared to the effect of ACTH and indomethacin showed: plasma sodium concentration, 139 +/- 1 vs. 131 +/ 3 mEg/liter (P less than 0.01, mean +/- SEM); plasma osmolality, 287 +/- 3 vs. 270 +/- 3 mOsm/liter (P less than 0.01); free water clearance, 97 +/- 66 vs. -1100 +/- 380 ml/24hr (P less than 0.01); urine volume, 2,000 +/- 60 vs. 950 +/- 200 ml/day (P less than 0.01); and urine osmolality 282 +/- 12 vs. 720 +/- 144 mOsm/liter (P less than 0.01). We conclude that the effects of ACTH and prostaglandin synthesis inhibition interact to result in inappropriate antidiuresis.     

Trans-tubular potassium gradient in patients with drug-induced hyperkalemia

BACKGROUND: Trans-tubular potassium gradient (TTKG) is considered to reflect mainly aldosterone bioactivity with regard to its kaliuretic response. We determined both TTKG and aldosterone serum concentrations in patients with severe drug-induced hyperkalemia (DIH). METHODS: Ten hyperkalemic patients with serum potassium of more than 5.5 mEq/l, and serum creatinine of less than 2.5 mg/dl (221 micromol/l) were studied prospectively. Two control groups of 10 patients each were used. Control 1 group with normal renal function, and control 2 group with normokalemia and renal failure of the same magnitude as that of the hyperkalemic patients. Serum osmolarity, electrolytes, creatinine, aldosterone and urine electrolytes and osmolarity were measured and TTKG calculated. RESULTS: DIH patients had lower TTKG values than control 1 patients (2.58 +/- 0.36 vs. 6.68 +/- 0.55, p < 0.001), and also lower than that of the control 2 patients (2.58 +/- 0.36 vs. 5.51 +/- 0.87, p < 0.01). Serum aldosterone concentration in the DIH group was higher than that of the control 1 group [24.30 +/- 5.0 vs. 7.4 +/- 2.1 pg/ml (674 +/- 139 vs. 205 +/- 58 pmol/l), p < 0.006] but not different from that of the control 2 group [24.3 +/- 5.0 vs. 15.3 +/- 3.8 pg/ml (674 +/- 139 vs. 424 +/- 106 pmol/l), respectively, p = 0.18]. Although there was some overlap in TTKG between DIH and control groups, 6 of 10 DIH patients had TTKG of less than 2.5, while none of the control patients had such a low value. CONCLUSION: DIH is characterized by lower TTKG values than those observed in patients with normal or mild-to-moderate renal failure. Other factors in addition to aldosterone seem to be involved.     

Intrauterine tracheal obstruction, a new treatment for congenital diaphragmatic hernia, decreases amniotic fluid sodium and chloride concentrations in the fetal lamb.

OBJECTIVE: To evaluate the effect of fetal tracheal occlusion on sodium and chloride concentrations in amniotic and tracheal fluid. SUMMARY BACKGROUND DATA: Intrauterine tracheal occlusion has been proposed to reverse pulmonary hypoplasia, an important prognostic factor in congenital diaphragmatic hernia. In early human trials, technical failure of the obstructive device has been reported. METHODS: Eight fetal lambs (gestational age = 95 days) were subjected to fetal tracheoscopy, and amniotic and tracheal fluid samples were taken. In multiple pregnancies (n = 6), amniotic fluid was also sampled from the contralateral amniotic sac and used as a control. Subsequently, endotracheal obstruction, using a detachable balloon, was performed. After 14 days, all fetuses were delivered, and sodium and chloride concentrations in amniotic and tracheal fluid were measured again. Statistical analysis was done using a two-tailed Student's t test, paired or unpaired as appropriate. RESULTS: In controls, between 95 and 109 days gestational age, no significant changes occurred in sodium or chloride concentrations in amniotic or tracheal fluid. After 2 weeks of tracheal obstruction, however, chloride and sodium concentrations in amniotic fluid decreased (chloride = 76.7 mEq/L vs. 107.6 mEq/L, p = 0.0003; sodium = 109.6 mEq/L vs. 125.9 +/- 5.2 mEq/L, p = 0.019). A concomitant increase in chloride and sodium concentration was observed in tracheal fluid (chloride = 145.4 mEq/L vs. 130.0 mEq/L, p = 0.047; sodium = 153.1 mEq/L vs. 142.9 mEq/L, p = 0.051). When comparing groups at 109 days, chloride and sodium concentrations in amniotic fluid were markedly lower in the treated group versus controls (p = 0.0004 and p = 0.05 for chloride and sodium, respectively). CONCLUSION: Complete tracheal occlusion in ovine fetuses results in a significant decrease of amniotic fluid sodium and chloride concentrations.     

Studies on the sodium concentration of dialysate solution for continuous ambulatory peritoneal dialysis]

Overloaded sodium(Na) induces the expansion of extracellular volume in case with severe renal insufficiency. Accordingly, in patients undergoing CAPD, the Na balance via trans-peritoneum is the critical determinant of fluid state. This study was performed to clarify the trans-peritoneal Na kinetics in patients using standard dialysate (Na: 132mEq/1,2-1), and to explore the clinical effects of lower Na concentration solution. Peritoneal dialysis effluent obtained from 87 patients was analysed [1.5% dextrose dialysate (D): 33 bags, 2.5%D: 54 bags]. In terms of net-Na removal, no significant relation was found with serum Na level. Whereas, a significant positive relation was found with ultrafiltration (UF) volume (p < 0.01). Net-Na removal was 10.0 +/- 3.3mEq in 1.5%D and 30.2 +/- 1.8 mEq in 2.5%D (mean +/- SEM). On the other hand, ultra low sodium concentration dialysate (ULNaD, Na level: 98mEq/1, Osm:340mOsm/1, 2l) was effectively used for the purpose of increasing Na removal. Net-Na removal was 78.1 +/- 5. 6mEq after 4-hr dwelling (n = 18). ULNaD was applied to ten patients who showed signs of overhydration, using once a day consecutively instead of standard one. After 9 days (mean) in this regimen, signs of overhydration were disappeared. Significant reductions in their body weight and fall in blood pressure were found compared to the periods before commencement of ULNaD, showing remarkable increase in Na removal (p < 0.01, respectively). No significant changes were found in serum Na level or UF volume.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of sulfinpyrazone on renal function and prostaglandin formation in man

Sulfinpyrazone (800 mg/day for 6 days) significantly reduced the excretion of the main urinary prostaglandin E metabolite by 54% in 6 healthy female volunteers. While sulfinpyrazone did not affect inulin clearance, clearances of creatinine and PAH were significantly diminished by 18.0 and 44.7%, respectively. In the anaesthetized dog sulfinpyrazone decreased PAH clearance and PAH extraction concomitantly without affecting renal blood flow. These results show that clearances of creatinine and PAH do not reliably reflect glomerular filtration and renal perfusion, respectively, during sulfinpyrazone administration. Whereas sodium balance and body weight were not significantly different between the first control period and sulfinpyrazone administration, net sodium excretion significantly increased from 121.6 +/- 5.4 mEq/day during sulfinpyrazone treatment to 139.3 +/- 6.6 mEq/day during the following control period, while body weight significantly decreased indicating modest sodium retention during drug administration. Plasma renin activity, vascular sensitivity to angiotensin II, and urinary excretion of the enzymes N-acetylglucosaminidase and alanineaminopeptidase were not affected by sulfinpyrazone administration. In summary, sulfinpyrazone caused a decrease of total body prostaglandin E formation in healthy female volunteers together with a moderate sodium retention. Despite inhibition of prostaglandin synthesis, glomerular filtration rate, plasma renin activity, or pressor effects of angiotensin II were not altered.     

Dietary NaCl determines severity of potassium depletion-induced metabolic alkalosis

It is uncertain whether, in humans, potassium depletion can cause or sustain metabolic alkalosis of clinically important degree in the absence of coexisting known alkalosis-producing conditions. Previously we found, in normal humans ingesting abundant NaCl, that dietary K+ depletion alone can induce and sustain a small decrease in blood acidity and increase in plasma bicarbonate concentration; we hypothesized that more severe alkalosis was prevented by mitigating mechanisms initiated by renal retention of dietary NaCl that was induced by K+ depletion. To ascertain the acid-base response to dietary K+ depletion under conditions in which the availability of NaCl for retention is greatly limited, in the present study of six normal men we restricted dietary K+ as in the previous study except that intake of NaCl was maintained low (2 to 7 mEq/day, Low NaCl Group) instead of high (126 mEq/day, High NaCl Group). Plasma acid-base composition and renal net-acid excretion (NAE) did not differ significantly between groups during the control period. In the steady state of K+ depletion (days 11 to 15 of K+ restriction), neither plasma K+ concentration (2.9 +/- 0.9 mEq/liter vs. 3.0 +/- 0.1 mEq/liter) nor cumulative K+ deficit (399 +/- 59 mEq vs. 466 +/- 48 mEq) differed significantly between groups. During K+ restriction, persisting metabolic alkalosis developed in both groups, which was more severe in the Low NaCl Group: increment in [HCO3-]p, 7.5 +/- 1.0 mEq/liter versus 2.0 +/- 0.3 mEq/liter, P less than 0.001; decrement in [H+]p, 5.5 +/- 0.6 nEq/liter versus 2.9 +/- 0.4 nEq/liter, P less than 0.003. A significantly more severe alkalosis in the Low NaCl Group was evident at all degrees of K+ deficiency achieved during the course of the 15 days of K+ restriction, and the severity of alkalosis in the Low NaCl Group correlated with the degree of K+ deficiency. During the generation of alkalosis (days 1 to 7 of K+ restriction), NAE increased in the Low NaCl Group whereas it decreased in the High NaCl Group. During the maintenance of alkalosis (days 11 to 15), NAE stabilized in both groups after it returned to values approximating the control values. In both groups, urine Cl- excretion decreased during K+ restriction even though Cl- intake had not been changed, with the result that body Cl- content increased negligibly in the Low NaCl Group (28 +/- 6 mEq) and substantially in the High NaCl Group (355 +/- 64 mEq).(ABSTRACT TRUNCATED AT 400 WORDS)     

A double-blind randomized crossover trial of two loop diuretics in chronic kidney disease

BACKGROUND: Torsemide has predictable absorption compared to furosemide. Thereby, torsemide results in more constant exposure to active drug. Our hypothesis was that this pharmacokinetic difference between these commonly used loop diuretics may translate into disparate antihypertensive responses in patients with chronic kidney disease (CKD). METHODS: We conducted a randomized, double-blind, two-period, crossover trial to compare the pharmacodynamics of torsemide and furosemide, in 14 subjects with stage 2 or 3 CKD. We first performed an inpatient study, where after the subjects were brought into sodium balance on a 200 mEq per day diet, a single bioequivalent dose of oral loop diuretic was administered with an intervening washout period. Measurements of urinary electrolytes were made. Subjects then participated in an outpatient study, wherein they received daily therapy for 3 weeks with the loop diuretics in random order. Twenty four-hour ambulatory blood pressure monitoring was performed before and after each drug to assess the antihypertensive response. RESULTS: In the inpatient phase, furosemide increased urinary sodium excretion from average (+/-SD) 199 +/- 49 mEq/day to 357 +/- 96 mEq/day and torsemide increased urinary sodium excretion from 213 +/- 79 mEq/day to 398 +/- 142 mEq/day. These differences between the diuretics were not significant, confirming bioequivalence. In the outpatient phase, furosemide reduced 24-hour ambulatory blood pressure from 147 +/- 17/78 +/- 11 mm Hg to 138 +/- 21/74 +/- 12 mm Hg (P = 0.021) and torsemide reduced it from 143 +/- 18/75 +/- 10 mm Hg to 133 +/- 19/71 +/- 10 mm Hg (P = 0.007). Although each diuretic was effective in reducing ambulatory blood pressure, the differences between diuretics were not statistically significant. CONCLUSION: Bioequivalent doses of torsemide and furosemide given in a randomized, double-blind design fail to demonstrate superiority of torsemide with respect to natriuresis or 24-hour ambulatory blood pressure control in subjects with stages 2 and 3 CKD.     

The ability of the rat epididymis to concentrate spermatozoa. Responsiveness to aldosterone

Experiments have been performed to determine if aldosterone is involved in the control of water reabsorption from the epididymal lumen in vivo. Micropuncture samples of lumen content were collected from the epididymides of control rats and those receiving aldrenalectomy, adrenalectomy + 25 micrograms aldosterone/day, 10 mg spironolactone/kg body weight/day, 10 mg spironolactone + 1 mg testosterone/kg body weight/day, 5 mg desoxycorticosterone acetate (DOCA)/day, 50 micrograms aldosterone/day, or 0.1 ml vehicle alone. The treatment period was three days. Seminal vesicles weights and testis weights were obtained. Sperm concentrations (SEM) in the caput, corpus, and cauda epididymidis of normal rats were 0.75 +/- 0.05, 1.24 +/- 0.13, and 1.99 +/- 0.15 x 10(9) sperm/ml, respectively. Both inhibition and removal of aldosterone caused significant reduction (P less than .01) of intraluminal sperm concentrations. Sham treatment had no effect. Sperm concentrations were normal in animals receiving aldrenalectomy plus aldosterone replacement. It is concluded that water resorption in the rat epididymis is responsive to aldosterone.