Renal concentrating mechanism: possible role for sodium-potassium activated adenosine triphosphatase.

Sodium-potassium activated adenosine triphosphatase activity was found to be almost twice as high in renal medulla as in cortex. Infusion of digoxin, a specific inhibitor of the enzyme, into one renal artery of the dog resulted in unilateral natriuresis, impaired concentrating capacity, and reduction of the enzyme activity in both cortex and medulla. It is suggested that the sodium-potassium adenosine triphosphatase plays an important role in urine concentration mechanisms.

Effects of angiotensin-converting enzyme inhibition on altered renal hemodynamics induced by low protein diet in the rat.

We assessed the role of angiotensin II in mediating the alterations in renal hemodynamics known to result from low protein feeding to normal rats by examining the effect of the angiotensin-converting enzyme (ACE) inhibitor captopril. 2 wk of low protein (6% casein) diet resulted in decreased glomerular filtration rate (normal protein [NP], 1.82 +/- 0.17 vs. low protein [LP], 0.76 +/- 0.01 ml/min; P less than 0.05) and renal plasma flow (NP, 6.7 +/- 0.2 vs. LP, 3.3 +/- 0.3 ml/min; P less than 0.05); renal vascular resistance rose (NP, 8.7 +/- 0.4 vs. LP, 19.8 +/- 1.4 dyn . s per cm5; P less than 0.05). These changes were accompanied by a significant decrease in plasma renin activity (NP, 7.0 +/- 0.7 vs. LP, 4.4 +/- 0.8 ng A I/ml per h; P less than 0.05), plasma aldosterone concentration (NP, 7.0 +/- 0.6 vs. LP, 4.1 +/- 0.7 ng/dl; P less than 0.05), and urinary PGE2 excretion (NP, 3,120 +/- 511 vs. LP, 648 +/- 95 pg/mgCr; P less than 0.05); by contrast renal renin content was significantly increased (NP, 2,587 +/- 273 vs. LP, 7,032 +/- 654 ng A I/mg protein; P less than 0.05). Treatment with captopril (30 mg/kg per d) raised glomerular filtration rate (GFR; LP + capt, 1.6 +/- 0.2 ml/min) and renal plasma flow (RPF; LP + capt, 6.7 +/- 0.7 ml/min), and reduced renal vascular resistance (LP + capt, 9.2 +/- 0.5 dyn/s per cm5) in low protein-fed animals. These values were not different from those measured in untreated and captopril-treated rats fed a normal (23%) protein diet. There were no changes in systemic mean arterial pressure in any group of rats. These data provide evidence that intrarenal angiotensin II mediates the changes in intrarenal hemodynamics induced by protein deprivation. The effects of low protein feeding may be partly potentiated by the reduction in PGE2 synthesis. However, the normalization of GFR and RPF in view of only modest increases in PGE2 excretion after captopril (LP, 648 +/- 95 vs. LP + capt, 1,131 +/- 82 pg/mgCr; P less than 0.05) suggests that if PGE2 is involved in these changes, it plays a permissive but not essential role in the increased renovascular resistance.

The mechanism of suppression of proximal tubular reabsorption by saline infusions.

The mechanism by which expansion of extracellular fluid volume with isotonic saline suppresses reabsorption in the proximal tubule was studied in rats by examining the relations among glomerular filtration rate (GFR), absolute and fractional reabsorption of filtrate, intrinsic reabsorptive capacity (rate of reabsorption per unit tubular volume), transit time, and tubular volume. Saline infusions reduced the per cent of the glomerular filtrate reabsorbed in the proximal tubule from 50% during antidiuresis to 25% during saline diuresis. The suppression of proximal reabsorption was the result of two factors: 1) a 30% reduction of intrinsic reabsorptive capacity, and 2) a 26% reduction of tubular volume per unit GFR.GFR invariably rose during saline diuresis. However, prevention of the rise in GFR by aortic clamping had no effect on either the inhibition of intrinsic reabsorptive capacity or the reduction in tubular volume per unit GFR produced by saline infusions. Expansion of extracellular fluid volume with isotonic saline, therefore, depressed intrinsic reabsorptive capacity and tubular volume per unit GFR by some mechanism completely independent of GFR. The effects of furosemide administration were contrasted with those of saline infusions. Furosemide inhibited intrinsic reabsorptive capacity by 40% but had no significant effect on proximal fractional reabsorption. The failure to suppress fractional reabsorption was the consequence of a disproportionate rise in tubular volume (relative to GFR) that was sufficient to completely overcome the inhibition of intrinsic reabsorptive capacity. Inhibition of intrinsic reabsorptive capacity alone, therefore, will not result in a net suppression of reabsorption of filtrate in the proximal tubule. We concluded that, although intrinsic reabsorptive capacity was inhibited during saline diuresis, the critical factor responsible for translating this inhibition into effective net suppression of proximal reabsorption was the observed reduction in tubular volume per unit GFR.

Renal sodium-potassium-activated adenosine triphosphatase and sodium reabsorption.

The role of renal Na(+),K(+)-ATPase in sodium reabsorption was further examined in dogs in which digoxin, a specific inhibitor of the enzyme system, was infused into one renal artery in doses ranging from 0.4 to 0.9 mug/kg/min (low dose) and from 1.0 to 4.0 mug/kg/min (high dose). A significant natriuresis occurred with both dose ranges which was accompanied by inhibition of Na(+),K(+)-ATPase of cortex and medulla in the infused kidney. Despite over 90% enzyme inhibition in many experiments, at least 80% of the filtered sodium continued to be reabsorbed. The per cent change in enzyme activity correlated with the rate of digoxin administration and the total dose administered but not with changes in sodium excretion. Changes in medullary Na(+),K(+)-ATPase activity, however, bore a direct relationship to alterations in fractional solute free water reabsorption (T(c) (H2O)). Inhibition of cortical enzyme activity alone was not associated with natriuresis, suggesting that medullary enzyme activity must be depressed for increased sodium excretion to occur during digoxin infusion. In high-dose experiments, significant inhibition of cortical and medullary enzyme in the contralateral control kidney was also observed, but natriuresis did not occur. In these experiments the rate at which digoxin reached the control kidney rose progressively but never equaled the rates in the directly infused kidney with either dose. Nevertheless, it is clear that under certain circumstances enzyme inhibition of either cortex or medulla need not be accompanied by natriuresis. We conclude that the major role of renal Na(+),K(+)-ATPase is in sodium reabsorption in the medulla (ascending limb of Henle's loop) and that it has a relatively small role in proximal sodium reabsorption. The kidney can rely on other sodium reabsorptive mechanisms depending on the rate of enzyme inhibition, so that natriuresis may not occur at all if depression in activity occurs "slowly." The nature of these mechanisms is not clear.

Effects of volume expansion, purified parathyroid extract, and calcium on renal bicarbonate absorption in the dog.

The role of parathyroid hormone (PTH) and of Ca(++) in the regulation of bicarbonate absorption (RHCO(3)) and its response to extracellular volume expansion (VE) was studied in HCO(3) (-)-loaded dogs.VE lowered RHCO(3) in both intact (from 24.8 to 22.0 mmol/liter GFR, P < 0.01) and thyroparathyroid-ectomized (TPTX) (from 24.5 to 18.0 mmol/liter GFR, P < 0.001) dogs; glomerular filtration rate (GFR) and filtered HCO(3) (-) did not change. Both groups showed a significant increase in the fractional excretion of sodium (C(Na) x 100/GFR), calcium (C(Ca) x 100/GFR), and chloride (C(Cl) x 100/GFR) and a decrease in phosphorus reabsorption. Fractional clearance of phosphate (C(P) x 100/GFR) rose in both groups but did not achieve significance. Infusion of purified parathyroid extract (PTE) decreased RHCO(3) in intact dogs (from 24.6 to 22.5 mmol/liter GFR, P < 0.025) and in TPTX dogs (from 26.9 to 22.6 mmol/liter GFR, P < 0.05). No change was noted in GFR, renal blood flow (RBF), filtered HCO(3) (-), or fractional excretion of sodium, calcium, or chloride in either group. There was a significant increase in fractional phosphorus clearance and a decrease in phosphorus reabsorption in each group. Infusion of Ca(++) raised ultrafilterable Ca(++) from 5.7 to 7.9 mg/100 ml in intact and from 4.9 to 7.2 mg/100 ml in TPTX dogs; RHCO(3) increased in intact (from 22.9 to 26.9 mmol/liter GFR, P < 0.025) and in TPTX dogs (from 26.6 to 28.6 mmol/liter GFR, P < 0.05). The GFR, RBF, and the fractional excretion of sodium, chloride, and calcium did not change in either group. The reabsorbed phosphate increased in both groups, and fractional phosphorus clearance fell in the intact group but did not change significantly in the TPTX group. Superimposition of PTE on hypercalcemia in TPTX dogs resulted in a decrease in RHCO(3) (from 27.3 to 23.9 mmol/liter GFR, P < 0.001), which was accompanied by an increase in the fractional excretion of phosphate and a decrease in the reabsorbed phosphate. In this group of TPTX dogs hypercalcemia caused a drop in RBF from 135.6 to 105.8 ml/min with no change in GFR. The RBF returned to control value with PTE infusion. IT IS CONCLUDED THAT: (a) the lowering of RHCO(3) by VE is not dependent solely on stimulation of PTH by the lowered Ca(++), (b) PTE acts directly on the renal tubules to lower RHCO(3), (c) Ca(++) enhances RHCO(3) and this effect is exerted in the absence of PTH and calcitonin, (d) neither the effects of Ca(++) nor of PTH appear to be mediated by altered hemodynamics, although this cannot be excluded in Ca(++)-infused TPTX dogs, (e) Ca(++) enhanced phosphate reabsorption in the absence of PTH; this may be a specific effect of hypercalcemia on phosphate reabsorption or the nonspecific consequence of the rise in serum phosphorus.

Effect of expansion of extracellular fluid volume on renal phosphate handling.

To examine the specific effect of extracellular fluid (ECF) volume expansion on phosphate excretion studies were performed in thyroparathyroidectomized dogs receiving saline solution intravenously. The natriuresis resulting from ECF volume expansion was consistently accompanied by an increase in phosphate excretion. The possible role of increased filtered load of phosphate was eliminated in experiments in which the filtered load of phosphate was reduced by acute reduction in the glomerular filtration rate. Despite considerable reductions in filtered phosphate, ECF volume expansion resulted in a consistent increase in phosphate excretion. Furthermore, the possible contribution of alteration in blood composition was investigated in experiments in which saline was infused during thoracic inferior vena cava constriction. In these experiments saline infusion failed to increase sodium or phosphate excretion. Cessation of saline infusion and release of caval constriction resulted in a prompt natriuresis and increased phosphate excretion. It is concluded from these studies that extracellular fluid volume expansion results in an increased phosphate excretion in the parathyroidectomized dog. This effect is the specific consequence of ECF volume expansion and is not due to increase in the filtered load of phosphate or alterations in blood composition.

Mechanism of reduced glomerular filtration rate in chronic malnutrition.

To determine the physiological basis for the low glomerular filtration rate in chronic malnutrition, micropuncture studies were performed in Munich-Wistar rats chronically pair-fed isocaloric diets of either low (group 1, nine rats) or high protein content (group 2, nine rats). Despite the absence of hypoalbuminemia, average values for single nephron and total kidney glomerular filtration rate were nearly 35% lower in group 1 than in group 2. Mean values for glomerular capillary and Bowman's space hydraulic pressures were essentially identical in the two groups, thereby excluding glomerular transcapillary hydraulic pressure difference as the cause for the low filtration rates in group 1 animals. On the other hand, average glomerular capillary plasma flow rate and glomerular capillary ultrafiltration coefficient were significantly lower (by approximately 25 and approximately 50%, respectively) in group 1 than in group 2. The fall in glomerular capillary plasma flow rate was the consequence of increased afferent and efferent arteriolar resistances. Plasma and erythrocyte volumes were found to be equal in five additional pairs of group 1 and group 2 rats. Thus, the substantial alterations in the ultrafiltration coefficient, glomerular capillary plasma flow rate, and renal arteriolar resistances responsible for the low filtration rate in group 1 animals were not merely a consequence of decreased circulating blood or plasma volumes. Mean values for glomerular cross sectional area were significantly lower in group 1 than in group 2 despite similar values for kidney weight in the two groups. This reduction in glomerular cross sectional area in group 1 rats is presumed to reflect a decrease in effective filtration surface area and therefore likely accounts, at least in part, for the decline in ultrafiltration coefficient observed in this group.Finally, since the daily caloric intake of group 2 animals was restricted because of pair feeding requirements tied to the group 1 rats, we studied a third group of seven rats (group 3) allowed an ad lib. intake of the same high protein diet as given to group 2 rats. Average values for single nephron glomerular filtration rate and its determinants were found to be indistinguishable between groups 2 and 3. These results suggest that low protein intake, rather than calorie deficiency per se, is primarily responsible for the reduction in filtration rate seen in this experimental model of chronic malnutrition.

Demonstration of a hormonal inhibitor of proximal tubular reabsorption during expansion of extracellular volume with isotonic saline.

Evidence for the elaboration of a hormonal inhibitor of renal tubular reabsorption in response to expansion of extracellular fluid volume was obtained by examining the effects of plasma from rats and dogs undergoing saline diuresis on the rate of proximal tubular reabsorption measured both directly by micropuncture techniques and indirectly by clearance techniques. Intravenous infusion of plasma from salineloaded rats and dogs, but not plasma from control animals, inhibited the intrinsic reabsorptive capacity of the proximal tubule (as estimated from the shrinking-drop technique) by 35%, and reduced fractional reabsorption (as estimated from the tubular fluid-to-plasma ratio) by 20%. In addition the natriuretic plasma increased urine flow, solute-free water clearance, and potassium excretion in rats with hereditary diabetes insipidus, indicating an increase in the delivery of filtrate out of the proximal tubule to the more distal diluting segments of the nephron. The hormonal inhibition of proximal tubular reabsorption had an extremely rapid onset of action (within seconds after instillation into the tubular lumen) and a short duration of action (less than 30 min after cessation of an intravenous infusion). Inhibitory activity was lost from natriuretic plasma upon dialysis and could be recovered in the dialysate. Dialysates of natriuretic plasma, when injected directly into the tubular lumen, also inhibited proximal reabsorption, indicating an action on the luminal side of the cell.

Effects of glucose on bicarbonate reabsorption in the dog kidney.

The effects of glucose on renal bicarbonate reabsorption were investigated in the dog. The infusion of small amounts of glucose calculated to slightly exceed the renal threshold for glucose absorption increased bicarbonate reabsorption in bicarbonate loaded dogs. Galactose in similar doses also increased the reabsorption of filtered bicarbonate. This effect is not due to insulin secretion since insulin alone did not alter bicarbonate reabsorption and the infusion of glucose into alloxan-diabetic dogs given a steady infusion of insulin also enhanced bicarbonate reabsorption. It is more likely that the increased tubular reabsorption of glucose, secondary to an increased filtered load, resulted in the increase in bicarbonate reabsorption since phlorizin reversibly inhibits the effect of glucose.

The use of isosorbide in the treatment of severe, uncontrolled hypertension.

Isosorbide dinitrate was administered sublingually and compared with placebo in a double-blind, randomized fashion to determine its effectiveness and safety in the rapid control of severe arterial hypertension. In 11 patients who received 10 mg of isosorbide dinitrate, blood pressure (BP) dropped from 205 +/- 8/131 +/- 3 to 166 +/- 9/106 +/- 5 mm Hg at 120 minutes. In eight patients who received placebo, BP dropped from 203 +/- 8/130 +/- 3 to 193 +/- 11/122 +/- 5 mm Hg at 120 minutes. When 10 mg of isosorbide dinitrate was administered sublingually after 120 minutes to placebo-pretreated patients, their BP dropped to 161 +/- 7/105 +/- 6 mm Hg at 240 minutes. Our study group (19 patients) was compared with a "control" group (six patients) whose BP (203 +/- 12/132 +/- 8 mm Hg) was treated only with conventional antihypertensive medications and bed rest; five (83%) of the six controls achieved steady BP control at 24 hours vs nine (47%) of the 19 study patients pretreated with isosorbide. There were no side effects, including hypotension, orthostatic effect, and reflex tachycardia. Sublingual isosorbide safely and effectively lowers systolic and diastolic BP in patients with severe, uncontrolled arterial hypertension.

Pathophysiology of renovascular hypertension.

Renovascular hypertension has its experimental counterpart in the two-kidney, one clip model (Goldblatt hypertension). From the study of this model, a general pathophysiological scheme has evolved suggesting that temporal stages in the development and maintenance of hypertension are regulated by complicated hormonal and neural interrelations. The central roles played by the renin-angiotensin system and the renal nerves is discussed as they relate to other hormones. In addition, the possible contribution of converting enzyme inhibitors to understanding the pathophysiology of this condition is discussed.

Role of macula densa in diuretics-induced renin release.

Diuretic therapy may enhance renin release by various mechanisms, principally contraction of extracellular fluid volume and its effects, including a fall in arterial pressure. Awake hydropenic or volume-expanded rats received diuretics (amiloride and hydrochlorothiazide) that are known inhibitors of NaCl transport beyond the macula densa; also the well-known Na(+)-K(+)-2 Cl- transport system inhibitor furosemide was administered. We also evaluated the effect of a dose of ethacrynic acid (a drug that shares the same mechanism of action as furosemide but is not diuretic in the rat). The direct action of the diuretics on renin-producing cells was examined in isolated glomeruli; a rise in renin release was observed with the calmodulin inhibitor trifluoperazine (10(-5) M). Renin release in intact hydropenic rats was not altered by diuretic therapy, but furosemide increased plasma renin activity in hydropenic as well as in volume-expanded rats. This demonstrates the importance of furosemide inhibition of transport in the macula densa for its renin secretory action. None of the diuretics (amiloride, hydrochlorothiazide, ethacrynic acid, or furosemide) elicited changes in renin release from glomeruli (10(-6) to 10(-3) M); amiloride and hydrochlorothiazide (10(-4) to 10(-3) M) did not change renin release from slices, but 10(-3) M ethacrynic acid and furosemide increased renin secretion in this preparation. This suggests that an effect on the macula densa is essential in loop diuretic-mediated renin release.(ABSTRACT TRUNCATED AT 250 WORDS)

Cataracts and hypertension in salt-sensitive rats. A possible ion transport defect.

In previous unrelated studies, we observed a 35 to 50% incidence of cataract formation in several groups of Dahl salt-sensitive hypertensive rats (DS) over a 4-year period. In the present study we evaluated longitudinal changes in blood pressure in DS in which cataracts eventually developed and those in which cataracts did not develop when all animals were maintained on a high sodium diet. Lenses were evaluated by slit-lamp microscopy to determine if cataractous lesions were similar among rats, to classify lesion types, and to define the age at which cataracts were detectable in DS. The possible participation of several cataractogenic risk factors as major influences on cataract formation also was evaluated. Finally, aqueous humor concentrations and lenticular content of sodium and potassium were determined to evaluate the possibility that a defect in ion transport at the lens epithelium and ciliary body might play a role in cataractogenesis in DS, since ion transport defects have been shown to lead to lens opacification in other models of genetic and experimental cataracts. Parallel studies were performed in Dahl salt-resistant control rats (DR). A high incidence of cataract formation was found in DS. Although systolic blood pressure was not consistently greater in adult DS with cataracts compared with values in age-matched DS without cataracts, the initial pressor response to a high salt diet was greatest in weanling DS in which cataractous lesions later developed. Slit-lamp analysis revealed that cataracts in this genetic model were cortical, with one mixed cortical, nuclear lesion. Posterior subcapsular lesions were not observed, suggesting that lesions were not steroid-induced.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal Na+-K+-ATPase in Okamoto and Dahl hypertensive rats.

Plasma renin activity (PRA, ng AI/ml/hr), plasma aldosterone (PA, ng%) and renal Na+-K+-ATPase (micron m PO 4/mg protein/hr) were measured in tow groups of eight spontaneously hypertensive rats (SHR), two groups of eight Dahl salt hypertensive rats (SS), and their controls (16 normal Wistar and 16 salt-resistant rats). Measurements were made in one group after 2 weeks on a normal (0.48% sodium) and in the other group after 2 weeks on a low (0.01% sodium) sodium diet. After a normal sodium diet, PRA and PA were lower in both groups of hypertensive rats than in control normotensive animals. Renal NA+-K+-ATPase was lower in SS than in controls: in SHR it was not different from control. On a sodium-free diet, SHR exhibited a rise in renal Na+-K+-ATPase but PRA and PA remained low. In contrast, under similar conditions PRA, PA, and renal Na+-K-ATPase increased in SS rats, although to a lesser extent than in SR. These results suggest that under basal conditions and after low salt diet, renal Na+-K+-ATPase activity in SHR behaves as it does in normal rats. However, the changes are independent of PA in SHR. The reduction in PRA and PA in SS suggest volume expansion hypertension. IN SHR, volume expansion is not present, and renal Na+-K+-ATPase is not altered. Enzyme activity is lower in SS than in SHR and control. This suggests that some factor that results from volume expansion may be responsible for inhibition of renal Na+-K+-ATPase.

Deoxycorticosterone hypertension in the intact weanling rat without salt loading.

Deoxycorticosterone (DOC) hypertension in the rat is generally induced in rats at an age of approximately 3 months. Both uninephrectomy and a high sodium diet are necessary, however, to induce DOC hypertension. Considering the inability of the developing kidney to adequately excrete a sodium load, we studied the possibility that DOC alone might induce hypertension when treatment is initiated in rats at the age of 21 days. The contribution of volume expansion as a factor mediating the pressor response to DOC was assessed in rats given a high sodium diet instead of DOC. Systolic blood pressure increased in DOC-treated rats within 3 weeks. Although systolic blood pressure also increased in rats on a high sodium diet, the increase was transient and of a lesser magnitude than that observed in DOC-treated rats. The rise in blood pressure in both groups of rats was associated with suppression of plasma renin activity and aldosterone concentration. Furthermore, extracellular fluid volume was similarly increased in DOC-treated rats and rats given a high sodium diet. Consistent with these data, DOC-treated rats showed an exaggerated natriuretic response to acute saline loading as compared with a vehicle-treated control group. Discontinuation of DOC treatment after 5 weeks led to normalization of all variables studied including blood pressure. Yet, when DOC was continued for 8 weeks, stopping treatment did not lower blood pressure despite normalization of the renin-angiotensin-aldosterone system and the natriuretic response to saline loading. In contrast, discontinuation of the high sodium diet after 8 weeks normalized blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Lenticular rubidium uptake and plasma renin activity in weanling cataract-prone salt-sensitive rats.

Our earlier studies of cataracts in Dahl salt-sensitive (DS) rats suggested the possibility of altered lens ion transport as a contributing factor in cataractogenesis in this genetic model. We also observed that those weanling DS rats with the greatest pressor response to a high salt diet eventually developed cataracts, and that changes in salt intake modified cataract formation. In the present studies, we measured lens 86Rb uptake as an index of sodium-potassium adenosine triphosphatase [(Na+,K+)-ATPase] activity in weanling DS rats before the development of cataracts or sustained hypertension. Additionally, plasma renin activity was measured to indirectly assess our hypothesis that the difference between cataract-prone DS rats and DS rats unlikely to develop cataracts might be a difference in degree of salt sensitivity. At the age of 4 weeks, 50 DS and 25 salt-resistant (DR) rats were given a high sodium diet for 2 weeks, at which time the rats were divided into three groups based on the systolic blood pressure response, that is, cataract-prone DS rats with systolic blood pressure equal to or greater than 155 mm Hg, DS rats unlikely to develop cataracts with systolic blood pressure less than or equal to 125 mm Hg, and DR rats. Lens and aqueous humor Na+ and K+, lens dry weight, and water content were not significantly different among the three groups of weanling rats. Plasma renin activity was lowest in cataract-prone DS rats and low in DS rats unlikely to develop cataracts when compared with values in DR rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in calcium excretion after prolonged metolazone therapy in recurrent stone formers.

The handling of an acute oral calcium load in 22 men with recurrent calcium stone disease was studied before and after diuretic therapy. As a group, the patients had marginal hypercalciuria (150 mg calcium per gram of creatinine in a 24-hr urine collection). Metolazone, a diuretic with an action in the cortical thick ascending limb of Henle's loop, was given in oral daily doses of 5.0 mg for periods of 9 to 34 mo. An oral calcium load induced a rapid rise in urine calcium exeretion, which was blunted markedly by metolazone. Further analysis of the subjects revealed that one group (11 subjects) had higher baseline 24-hr calcium excretion levels and higher parathyroid hormone (PTH) than the others. The effect of metolazone in reducing the calciuric response was significant only in this group. Thus, while long-term treatment with metolazone inhibited the rise in urinary calcium excretion elicited by an oral calcium load, the effect was significant only in patients who had high baseline urinary calcium and PTH values. The reduction in calcium excretion in response to an acute calcium challenge may explain in part the beneficial effects of cortical diluting segment diuretics in recurrent stone formers.

Effect of triamterene on potassium excretion in cirrhotic patients receiving furosemide.

In a three-way crossover study, 23 patients with hepatic cirrhosis, ascites, and dependent edema received 40 mg/day of furosemide alone and combined with triamterene 50 mg/day and triamterine 100 mg/day. Baseline potassium excretion did not increase when furosemide was given alone, but potassium excretion fell when 50 mg or 100 mg of triamterene was also given. Both doses of triamterene augmented the natriuretic effect of furosemide.

Downbeat nystagmus. Long-term therapy with moderate-dose lithium carbonate.

Downbeat nystagmus developed in a 67-year-old hypomagnesemic woman while she was receiving lithium carbonate for depression. This nystagmus abated each time lithium carbonate therapy was withdrawn, and no alternative causes of nystagmus were demonstrated. However, this nystagmus occurred despite serum lithium carbonate levels in the nontoxic range. Total-body magnesium deficiency may have enhanced the toxic effect of lithium carbonate on cerebellomedullary connections.

Clinical and electroencephalographic changes in progressive uremic encephalopathy.

A study of nine patients, aged 23 to 67 years, showed a remarkable sequence of EEG findings in progressive uremic encephalopathy. The initial characteristics suggested a disorder of subcortical gray matter, followed by involvement of cortical gray matter and finally white matter. The same EEG findings tended to persist in the early stages of the disease and were present throughout the night and during dialysis. During dialysis, the EEG background and clinical picture between paroxysms sometimes showed deterioration. Seizures indicated a grave prognosis. Five of six patients with seizures died. In some patients, progressive uremic encephalopathy may develop without hemodialysis. Routine EEGs in dialysis units or in patients prior to admission can help uncover progressive uremic encephalopathy before the clinical emergence of this disorder.