Hepatic osmoreceptors?

1. The effects of 0.45% saline infusions into the portal vein of conscious and anaesthetized dogs have been compared with similar infusions through a systemic vein.2. Measurements were made of plasma and urinary osmolality, sodium, potassium and chloride concentrations and urine flows; osmolal clearances, free water clearances, the percentage of the infused loads excreted at given times, and rates of sodium and potassium excretion in the urine, were calculated.3. In the conscious and anaesthetized series of experiments no significant differences were found between the portal and systemic routes of infusion.4. For both the portal and systemic routes of infusion there was a significantly smaller diuretic response to the saline infusion in anaesthetized as compared with conscious animals.5. These results do not support the concept of hepatic osmoreceptors occurring in the dog.     

The influence of intracerebroventricular infusions on osmotically induced urine excretion in the pigeon (Columba livia)

This study deals with the influence of intracerebroventricular (ICV) infusions on urine volume and electrolyte excretion in response to a peripherally administered osmotic load in conscious behaving pigeons. The ICV infusions were intended to influence the cerebrospinal fluid (CSF) sodium (Na+) concentration that would have been increased by the hypertonic NaCl or sucrose solutions infused intravenously (IV). Urine and electrolyte excretion following IV infusion of 0.5 M NaCl were enhanced by simultaneous ICV infusion of 0.3 M NaCl and essentially unchanged by ICV infusions of 0.3 M or 0.9 M sucrose, or water. Infusions (ICV) of water, isotonic and hypertonic NaCl or sucrose did not significantly influence urine and electrolyte excretions following IV infusion of 1.0 M NaCl or sucrose (except K+ in the case of ICV/IV sucrose). Isotonic (0.3 M) or hypertonic (0.9 M) sucrose infused ICV enhanced urine and electrolyte excretion following IV infusion of 1.5 M sucrose. Similar amounts of sodium were excreted following IV infusion of 0.5 M NaCl, 1.0 M sucrose or 1.5 M sucrose plus the ICV infusions. The results suggest that the concentration of Na+ in the CSF is one of the factors that play a role in urine and electrolyte excretion following IV administration of osmotic stimuli in the pigeon.     

Concentration and dilution of the urine in partially hepatectomized,conscious rats

1. The influence of partial hepatectomy on urinary concentrating ability and renal tissue sodium was determined in conscious rats deprived of water for 24 h. In comparison with a sham operation, partial hepatectomy resulted in: a) a 50% reduction in free-water reabsorption, urinary osmolality, and osmolal urine-to-plasma ratio; b) depression of free-water reabsorption at similar levels of osmolal clearance above 200 microliter/min per ml of GFR during the infusion of hypertonic NaCl and vasopressin; and c) a 30% reduction in sodium content of the renal papilla and outer medulla. 2. The renal response to an intravenous water load (2.5% glucose infused to 2.5% of body wt at 0.4 ml/min) was determined in sham-operated and partially hepatectomized, conscious rats. By 60 min after the water load, both groups had excreted practically all of the load. However, during and for 30 min after the infusion in the partially hepatectomized group, the percent of the water load excreted, urine flow, and free-water clearance were significantly reduced while urinary osmolality and osmolal urine-to-plasma ratio were significantly elevated. 3. These experiments demonstrate that shortly after partial removal of the liver the renal concentrating ability is defective and the excretion of a water load is not grossly impaired.     

A comparison of sodium excretion in response to infusion of isotonic saline into the vena porta and vena cava of conscious rats

1. Indwelling non-occlusive catheters were placed in the vena porta and inferior vena cava of female rats several days before experimentation. Isotonic saline or isosmotic glucose (2% of body wt.) was infused into one vein followed one to several days later with an identical infusion into the other vein of each conscious animal. 2. Significantly higher urine flow and sodium excretion resulted from infusion of isotonic saline (0.5 ml/min) into the vena porta than into the vena cava. Modest prehydration or section of the hepatic branch of the right vagus did not affect the differential sodium response. Changes in endogenous creatinine clearance and potassium excretion were not significantly different for the two routes. Mean values for net peak sodium excretion and contemporaneous urine flow, urinary sodium concentration, and fractional sodium excretion were significantly higher for the portal than for the caval infusion while differences in glomerular filtration rate and filtered sodium load were insignificant. No significant difference in sodium excretion resulted from infusion of isosmotic glucose by the two routes. 3. Compared to the response promoted by the isotonic saline load infused at 0.5 ml/min, the differential response in sodium excretion was prolonged when the same load was infused at 0.375 ml/min. Sodium excretion was not significantly different for the two routes when the same isotonic saline load was infused at 0.75 ml/min. 4. These experiments provide evidence for participation of the liver in the control of sodium excretion and suggest release of a hepatic humoral factor which may be controlled by the duration of exposure of the hepatic circulation to an adequate load of isotonic saline.     

Role of afferent renal nerves in renal adaptation to sodium restriction in uninephrectomized rats

In the present study we examined the role of the afferent renal nerves in the control of ipsilateral renal adaptation to sodium restriction. Uninephrectomized rats were subjected to selective renal deafferentation or sham operation, instrumented with catheters and housed in metabolism cages to collect urine in 90 min fractions. Only sodium deficient food (0.03% Na⁺) was allowed. Water and sodium excretion were stabilized via a continuous 48 h infusion (1.25 ml h^-1) of a Ringer's solution. During this period water, sodium and potassium excretion were similar in renal deafferented and sham operated rats. Then, the infusion was exchanged for a modified Ringer's solution, in which the sodium ion was replaced by the choline ion. Measurements were performed over 24 h. During the choline Cl infusion, urine flow increased similarly in renal deafferented and sham-operated rats. In both groups of rats, sodium excretion decreased within 24 h by more than 95 %, whereas potassium excretion stayed constant. Sodium loss was higher in renal deafferented rats only in the first 90 min period after the exchange of the infusions. These results indicate that afferent renal nerves are not necessary in ipsilateral renal adaptation during 24 h sodium restriction, but may play a modulatory role in correcting transient changes in ipsilateral renal excretory function.     

Renal and hormonal responses to atrial natriuretic peptide infusions in goats on high and low sodium intake

Synthetic atrial natriuretic peptide (ANP) was infused intravenously (1 microgram min-1; 60 min) in five goats during two series of experiments. For at least 4 weeks before the ANP infusions the goats received either no salt supplementation (= low sodium diet), or were given 16 g NaCl mixed with the food each day (Na = 274 mmol day-1; high sodium intake). The goats were changed between the treatments at random. ANP infusions caused diuresis, natriuresis and haemoconcentration during both diets. The urinary Na excretion increased about four-fold during the high sodium intake, and about 10 times during the low sodium intake. The urinary K excretion increased significantly during the low sodium diet, but decreased slightly during the high sodium intake. During both diets the K excretion became significantly lowered after the infusions. The mean glomerular filtration rate (GFR) was generally lower during the low sodium diet, but increased significantly during ANP infusions on both diets. The GFR returned to baseline immediately after the infusions, in contrast to urine flow and urinary Na excretion. Renal free water clearance increased slightly at the end of the infusion during the low sodium diet, but did not change during the high salt diet. Plasma renin activity (PRA) and plasma aldosterone concentration fell during ANP infusions in goats on the low sodium intake, but did not change significantly during the high sodium diet. These results indicate that the diuresis and natriuresis observed during intravenous ANP infusions in goats are mainly due to increased GFR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of renal responses to 5% saline infusions into vena portae and vena cava in conscious dogs

Indwelling catheters were placed in conscious dogs into the vena portae via a jejunal mesenteric vein several weeks prior to actual experiments. To compare a possible different response to different pathways of administration, 5% saline solution was infused either into vena portae or into vena cava at a rate of 0.05 ml/min/kg BW for 40 min.

1. Infusion of 5% sodium chloride into the vena portae, as well as into the vena cava caused a significant increase in urine flow, serum osmolality, sodium excretion rate and heat rate. The increase in urine flow was always due to an increase in osmolal clearance whereas free water clearance decreased consistantly. In some experiments plasma renin activity (PRA) was measured by radioimmunoassay. For both routes of administration the hypertonic saline infusion caused a decrease in PRA. At no time did any of these parameters display significant differences depending on route of application.
2. This means that the calculated differences between infused and excreted amounts of water and of sodium did not depend on the route of infusions.
3. A close relationship was found between initial urine osmolality and the length of the periods during which peak values of urine flow were observed.

These results do neither provide evidence for a hepatic osmoreceptor mechanism in dogs nor for the hypothesis that in conscious dogs the liver might control sodium excretion.     

Lithium-induced diuretic effect of antidiuretic hormone in rats.

The effect of a low dose of lithium (1 meq/kg per day) on renal function and its response to antidiuretic hormone (ADH) was studied in unanesthetized rats. This dose of lithium itself had no influence on renal water and electrolyte excretion, but lithium-treated rats responded paradoxically to exogenous ADH by increases in urinary volume, excretion of total solutes, sodium, potassium, and phosphate. Administration of ADH in the presence of lithium led to a lowering of urine osmolality, but free water clearance was not significantly reduced. Adenylate cyclase from the renal medulla of animals treated with ADH and lithium had a lower response to synthetic vasopressin in vitro than in animals treated with lithium alone. The results suggest that exogenous ADHis diuretic in the presence of a low concentration of lithilm. The predominant mechanism for this diuresis is probably inhibition of electrolyte and isomotic water reabbsorption in various nephron segments, including those proximal to the collecting ducts. ADH also markedly increased urinary excretion of lithium and appears to promote accumulation of lithium in the renal medulla.     

Extracellular space and membrane changes in brain owing to different alkali metal buffers

Summary Various alkali metal buffers were used in combination with glutaraldehyde, formaldehyde and acrolein to fix rat visual cerebral cortex by perfusion. Standard procedures of post-fixation, dehydration, and embedding were followed so that the buffer became the experimental variable. The cacodylate buffer system proved most versatile, and caesium, rubidium, potassium, sodium, and lithium cacodylate were used. An unusual amount of extracellular space averaging 300 nm was present with caesium cacodylate which contrasted with the apposed plasma membranes prevalent when lithium or sodium cacodylate was used. Rubidium and potassium cacodylate produced similar results with variable and irregular extracellular space. The effects of the addition of dimethyl sulphoxide, magnesium chloride and calcium chloride to the various cacodylate buffers were explored. In the case of caesium cacodylate, these additives caused less extracellular space and the retention of more material in this space in an irregular manner; with potassium cacodylate there was no noticeable difference, but with sodium and lithium cacodylate extracellular space increased. We suggest that the observed differences in extracellular space are explanable in terms of changes occurring in the polysaccharide cell coat which are caused by the buffers and additives.     

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 filtration rate, even at urinary sodium concentrations exceeding 80 mmol X 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.     

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.     

Effects of water diuresis and osmotic (mannitol) diuresis on urinary solute excretion by the conscious rat

1. The time course and extent of changes in urinary flow and in the outputs of urea, Na(+), K(+), and NH(4) (+) over a period of 7(1/2) hr in conscious rats during water and osmotic (mannitol) diuresis were determined, and compared with spontaneous changes in non-diuretic animals.2. In non-diuretic rats, a morning rise and subsequent decline in urinary osmolal, sodium, potassium and ammonium outputs occurred, possibly attributable to circadian rhythms.3. Water diuresis was accompanied by (i) a rapid increase in urea excretion during the phase of increasing urine flow, followed by a fall in later periods to values similar to those in non-diuresis, (ii) a slower increase in sodium output, continuing after the establishment of the constant water load, (iii) unchanged potassium excretion, but slightly increased ammonium outputs.4. Mannitol diuresis was accompanied by (i) a rapid increase in urea outputs which subsequently fell but remained significantly higher, (ii) a steep rise in sodium and potassium outputs to values which remained far higher than those in non-diuretic and water diuretic animals.5. The changes in mannitol diuresis are considered to result mainly from decreased tubular reabsorption, due to the lowered intraluminal sodium, potassium and urea concentrations and increased intratubular fluid flow. Some of the acute increase in urea excretion may be due to washout of medullary urea into the tubular fluid.6. In water diuresis, some of the changes in solute excretion may similarly result from altered tubular reabsorption, perhaps influenced by suppression of anti-diuretic hormone (A.D.H.). In addition, the slower changes in sodium output may be related to several consequences of change in body fluid volume.     

A central osmosensitive receptor for renal sodium excretion.

1. The effect on renal Na and water excretion of increasing the NaCl concentration of blood supplying the brain was investigated in conscious water-loaded sheep. Intracarotid infusion ot 4 M-NACl at 0-8 ml./min for 60 min was compared with equivalent intrajugular infusion. 2. A more rapid increase in renal Na excretion and urine osmolality occurred with the intracarotid infusions than with intrajugular infusions. 3. Intracarotid infusions of 2 M sucrose or fructose at 1-6 ml./min for greater increase in renal Na excretion, urine osmolality and a decrease in urine flow rate. 4. The results suggest that there are receptors in the brain sensitive to changes in extracellular tonicity which influence renal Na excretion. It is possible that changes in ADH secretion alone mediate the early natriuresis seen with intracarotid hypertonic infusions although an alternative concurrent mechanism cannot be ruled out.     

Effects of sodium and potassium salts with anions other than chloride on renin secretion in the dog

Intrarenal arterial infusions of sodium and potassium salts with anions other than chloride were given to evaluate the role of the chloride ion in influencing renin secretion (RS). The studies were conducted in dogs with thoracic caval constriction. Sodium lactate increased renal venous plasma sodium concentration (RVPNa) from 142 to 166 meq/liter (n, 6); RS decreased from 3,070 to 1,510 ng angiotensin/min (P less than 0.005). Arterial blood pressure and renal blood flow were not changed appreciably. Sodium excretion (ENa) increased, whereas chloride excretion (EC1) fell during the first three 15-min infusion periods. Potassium lactate increased renal venous plasma potassium concentration from 4.1 to 6.2 meq/liter (N, b). RS decreased during the first three 15-min periods of infusion (from 3,470 to 2,180 ng angiotensin/min, P less than 0.01). ENa and EC1 increased during the infusion. Potassium sulfate also decreased RS, and EC1 was usually increased. The results with sodium lactate favor a role for sodium compared with chloride in mediating the decreased renin release, but there are other possible interpretations which have been discussed. Additional studies are needed to resolve the role of chloride during potassium infusion.     

Increased urinary kallikrein excretion during prostaglandin E1 infusion in anaesthetized dogs and its relation to natriuresis and diuresis.

. The effect of intra-arterial prostaglandin E1 (PGE1) infusion on urinary kallikrein, sodium, potassium and water excretion was studied in normal anaesthetized dogs. 2. Infusion of PGE1 caused a dose-related increase in urinary excretion of kallikrein, sodium, potassium and water as well as an increase in renal blood flow (R.B.F.) and a fall in urinary osmolality and renal vascular resistance. 3. The changes occurred in the absence of appreciable changes in inulin clearance (Cin), arterial blood pressure, haematocrit, and plasma sodium and potassium concentrations. 4. The increased urinary kallikrein excretion correlated positively with the natriuresis, diuresis and kaliuresis and the increase in renal blood flow, but negatively with the urinary osmolality and renal vascular resistance. 5. It is concluded that renal kallikrein is involved in the renal response to arterial infusion of PGE1.     

Angiotensin II in the renal excretory response to behavioral stress in conscious dogs

The effects of inhibition of the renin-angiotensin system on the decreased renal excretion of sodium and water resulting from behavioral stress (shock avoidance) were examined in conscious saline-infused (4-5 ml/min) dogs. During saline infusion alone in six dogs, avoidance decreased sodium excretion (64% from 329 mueq/min) and urine flow (63% from 1.9 ml/min). During converting enzyme inhibition with captopril in the same dogs, the decreases in sodium excretion (35% from 464 mueq/min) and urine flow (35% from 2.6 ml/min) during avoidance were attenuated. Similarly, in six other dogs, avoidance decreased sodium excretion (41% from 361 mueq/min) and urine flow (43% from 2.1 ml/min) with saline infusion alone. During angiotension II (ANG II) receptor antagonism with saralasin, decreases in sodium excretion (29% from 417 mueq/min) and urine flow (27% from 2.2 ml/min) were attenuated. These mean changes in excretion during inhibition of the renin-angiotensin system were significantly (P less than 0.05) less than during saline alone. Whereas decreases in fractional sodium and water excretion were attenuated by renin-angiotensin inhibition, decreases in glomerular filtration rate and effective renal blood flow and increases in mean arterial pressure were not affected. These results indicate that ANG II contributes to the renal excretory response to avoidance.     

Hormonal control of distal nephron function

Summary The distal tubule and collecting tubules are important control sites of fluid and electrolyte excretion. In our presentation we consider the cell mechanisms of transport of sodium and potassium ions and the effects of several hormones. Aldosterone and antidiuretics stimulate potassium secretion directly, and the available evidence strongly suggests that this effect involves the principal cell population. Epinephrine inhibits potassium secretion at sites beyond the distal tubule. In addition to such direct effects, secondary factors such as hormone-induced changes in flow rate along the distal tubule and changes in the plasma potassium level play an important modifying role. Several examples are presented to demonstrate that interaction of several control components uncouples potassium secretion from distal flow rate and tends to stabilize urinary potassium excretion during changes in sodium and water balance.Work in the authors laboratory was supported by NIH Grant No AM-17433     

Prostaglandin E2 in renal transplant recipients.

Prostaglandin E2 (PGE2), sodium, potassium and creatinine were determined in the blood and urine of 50 renal transplant recipients treated for at least one year post transplantation with cyclosporine A or azathioprine as immunosuppressive agent. Fourteen healthy subjects were used as a control group. The urinary PGE2 excretion was significantly decreased in the renal transplant recipients on azathioprine therapy while it was unchanged in the patients treated with cyclosporine A. At the same time, a significant decrease in urinary excretion of sodium and potassium was found. On the other hand, a high elevation of blood PGE2 concentration was observed while no significant changes were seen in sodium and potassium in the blood of these renal transplant recipients. It is suggested that an association exists between urinary PGE2 reduction and immunosuppressive treatments in renal transplant recipients and that PGE2 may regulate intrarenal haemodynamics and influence renal tubular electrolyte excretion. Finally, urinary PGE2 can be used as an indicator of successful renal transplantation.     

Effect of sodium nitrate loading on electrolyte transport by the renal tubule.

Effects of sodium nitrate were compared with sodium chloride loading on transport of electrolytes by the nephron. Maximal levels of free water clearance/clomerular filtration rate (CH2O/GFR) averaged 8.4% with nitrate loading and 14.4% with saline loading. Since ethacrynic acid and chlorothiazide exert their major natriuretic effect in the distal nephron, the increment in Na ad Cl reabsorbed beyond the proximal tubule. The administration of these agents resulted in an increase in fractional sodium excretion (CNa/GFR) of 21.1%, urinary sodium excretion (UNaV) of 1,126 mueq/min, and urinary chloride excretion (UClV) of 848 mueq/min during nitrate loading compared with an increase in CNa/GFR of 37.6%, UNaV of 2,362 mueq/min, and UClV of 2,397 mueq/min during saline loading. The smaller diuretic-induced increment in Na and Cl excretion in the nitrate studies suggests, as do the hydrated studies, that less Cl and Na are reabsorbed in the distal nephron during nitrate than saline loading. At every level of UNaV, fractional bicarbonate reabsorption was higher, urine pH was lower, and urinary potassium excretion (UKV) was higher in the nitrate studies. Thus, compared with saline loading, sodium nitrate decreases chloride and sodium reabsorption in the distal nephron. The higher hydrogen and potassium secretion in the nitrate studies may be consequent to the decreased ability of the distal nephron to reabsorb chloride.     

Effect of substance P on CCK- or VIP-induced choleresis in anesthetized dogs.

10 anesthetized dogs were provided with acute common bile duct fistulas and the gallbladder was excluded. Hepatic bile output and biliary content of sodium, potassium and amylase were studied. 6 caval infusions were administered of CCK, 0.3 Ivy U.kg-1.min-1, with a superimposed infusion of SP, 20 ng.kg-1.min-1. 7 caval infusions were given of VIP, 50 ng.kg-1.min-1, with a superimposed infusion of SP, 20 ng. kg-1.min-1. CCK increased bile output and biliary content of sodium, potassium and amylase by 78-110%. The corresponding increase induced by VIP was 55-85%. Biliary pH was not influenced. SP abolished the effects of both CCK and VIP. It is suggested that all peptides studied influenced canalicular bile secretion by changing the electrolyte excretion.