Neurosecretion and sodium excretion

Kidney International, Vol. 6 (1974), P. 323—330

Neurosecretion and sodium excretion JULIUS LEE and HUGH E. DEWARDENER Departments of Physiology and Medicine, Charing Cross Hospital Medical School, London, England

Over the last few years there has been an accumula-

presented by de Wardener et al in 1961 [2]. It consisted of a cross-circulation experiment between dogs. Both

tion of observations which indicate that there is a humoral substance other than aldosterone which influences renal sodium excretion. The findings by

dogs were given large amounts of aldosterone and vasopressin in order to eliminate variations of these hormones as influencing factors. The dog to which saline was administered had a substantially greater

numerous authors have demonstrated that this humoral factor increases the excretion of sodium in response to expansion of the extracellular fluid (ECF) volume. While experiments in this field have been mainly car-

natriuresis than the other, although the eventual dilutional changes in the blood of the two dogs and the changes in arterial pressure, para-aminohippurate (PAH) and inulin clearances were the same. Since

ried out using animals, this mechanism may also operate in man. This review first presents the evidence

for the hypothesis that there is such a hormone. We have then allowed ourselves the privilege of putting

the dog with the volume expansion had the greater rise

forward the evidence which suggests that this hormone

that part of the natriuresis was induced by a change in

may be a neurosecretion, while acknowledging the

concentration of some circulating substance other

fact that this evidence is indirect. We are aware of the possibility of being criticized for presenting what some might regard as a biased review, but we feel that this approach will stimulate further work in this field. The suggestion that the hypothalamus might secrete a substance which controls urinary sodium excretion directly was advanced in 1957 by Smith [1]. He con-

than aldosterone. The hypothesis that there was such a humoral substance did not initially receive widespread acceptance. Rather, there has been an emphasis on the subsequent

sidered that the known mechanisms controlling the

It had always been appreciated by those who advanced

renal excretion of sodium could not adequately explain

the humoral hypothesis that expansion of plasma volume of dogs with large amounts of i.v. admini-

in urinary sodium excretion, the authors suggested

discovery that physical factors such as peritubular capillary hydrostatic pressure and, possibly, plasma oncotic pressure could influence sodium excretion.

the changes in excretion of this ion which occurred under different physiological conditions. He proposed that the neurosecretory substance was antinatriuretic and he stated, "The precise control of sodium balance must be very old, probably dating back to the earliest

stered saline would induce large dilutional changes in

the composition of the blood, and that such gross physical changes would make it difficult to discern a humoral effect. In order to overcome this valid objection, many investigators designed experiments which avoided changes in physical factors. The main modification introduced was to expand the volume of the animal with blood which was in equilibrium with its

fresh water vertebrates. This circumstance leads to

the speculation that a primaeval antinatriuretic hormone X may have been secreted by some part of the neuraxis before the adenohypophysis and adrenal cortical tissue acquired their importance in sodium balance." [1]. The first basic experiment favoring the presence of a circulating substance, other than aldosterone, which influenced urinary sodium excretion was probably

own, essentially by circulating the animal's blood through a reservoir, initially containing 3% albumin

in Hartmann's solution. After circulation of the blood for one hour through the reservoir, equilibration had occurred. The blood volume of the animal could then be expanded with blood in equilibrium with

its own. The blood volume of the dog was thus en-

© 1974, by the International Society of Nephrology. 323

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hanced without adding any foreign substance and

responsible for part of the natriuresis caused by blood

without a change of plasma oncotic pressure or packed cell volume (Bahiman et al [3]). In some experiments

volume expansion. In an endeavor to determine

the kidneys were either denervated or isolated and perfused at constant pressure. Bahiman et a! [3]

whether this humoral messenger could influence ionic movements in renal tubular cells, in vitro experiments

kidney. Tobian, Coffee and McCrea [4] and Kaloyanides and Azer [5] used isolated kidneys from rats and

were carried out by Clarkson, Talner and de Wardener [10]. They used fragments of renal tubules (mainly proximal) incubated in plasma from dogs before and during volume expansion. Incubation in plasma from dogs with blood volume expansion re-

dogs, respectively, while Lichardus and Nizet [6] transplanted a dog kidney into the neck. Despite

sulted in higher intracellular sodium and lower potassium concentrations in these tubular fragments. This

maintained constant renal artery perfusion by placing

a snare around the aorta, and also denervated one

variations in technique with denervated kidneys per-

result was considered to be an indication that the

fused at constant pressure, all the various authors

plasma contained a substance which inhibited sodium transport. Other workers have claimed that urine or

reported an increase in sodium excretion on expansion of the blood volume. Thus, it appears that the kidneys, whether perfused

at the end of the artery'or via plastic tubes, are able to respond to an increase in blood volume by increasing sodium excretion. The only contact the denervated kidney has with the rest of the body is via the blood stream and, as the expansion of this volume is with

equilibrated blood, the factor influencing sodium excretion must be some change in concentration of a humoral agent. The humoral component of the natriuretic effect of

blood volume expansion has also been admirably confirmed in cross-circulation experiments [7, 8]. This phenomenon can be demonstrated only if the initial blood volume expansion of the donor rat is sustained by continuously reinfusing its urine back into its circulation [7]; otherwise, the blood volume falls and

the humoral component is at an insufficient level to induce natriuresis in the recipient.

dialysate samples of blood from volume-expanded animals inhibit sodium transport in vitro or increase urine sodium excretion when given to another animal [11—14].

It is appreciated that these in vitro experiments are always subject to criticism in that the results obtained are from preparations which are far removed from the normal physiological state. However, there remains the observations that animals with volumes expanded with equilibrated blood do have a natriuresis and that this appears to be mediated by humoral transmitter. It is relevant to consider comparative physiology in the elucidation of such a problem, and, therefore,

evidence supporting the view that sodium may be actively excreted from an organism will now be considered. This manner of approach is an example which Smith [1] himself always felt to be a reasonable one. There are invertebrate examples which provide evidence of enhanced sodium excretion either because

These experiments did not, however, provide defini-

of increased blood volume or of a change in the

tive information on how this humoral agent acts.

environment. In the former case there is the classical example of Rhodnius prolixus (sometimes referred to

Even though it was clear that the humoral component of blood volume expansion can be demonstrated at a time when the renal blood flow and glomerular filtra-

tion rate are falling (Kaloyanides and Azer [5]), it was not clear whether the hormone acted by altering intrarenal hemodynamics, or by directly inhibiting sodium transport in the proximal or distal tubules, or the collecting ducts. In favor of a direct action of the

hormone on sodium transport was the finding of Nutbourne et al [9]. In their experiments it was shown

that the blood from a dog undergoing natriuresis induced by expansion of volume with equilibrated blood induced a fall of short circuit current across the isolated perfused frog's skin. The fall of short circuit current is an index that active sodium transport had decreased. The authors concluded that there is a substance circulating in the blood of a volume-expanded dog which influences sodium transport, and that a change in the concentration of this substance may be

as the assassin bug) which is a vector of Trypanosoma cruzi. The urinary system consists of four blind-

ended malpighian tubules which float in the hemolymph of the abdominal cavity. The formation of urine is therefore entirely one of active secretion from

the hemolymph into the lumen of the malpighian tubules. The morphology of the tubular wall is similar

to that of the proximal tubule in man except that there are many mitochondria in the brush border. When this insect has a meal, it sucks up to ten times its own weight of blood. This is an acute volume expansion with a vengeance. The ingestion of blood distends the insect's abdominal cavity and stretches a set of lateral abdominal muscles. This in turn stimulates intramuscular nerve endings, thereby increasing the rate of afferent impulses which are transmitted to a fused ganglionic mass situated in the mesothorax. Within this portion of the central nervous system,

Neurosecretion and sodium excretion

there are neurosecretory cells. These contain a substance which is released into the hemolymph when the abdominal cavity is distended. This substance produces

a massive increase in urinary sodium by the active extrusion of this ion into the tubular system [15—17]. Another fascinating example is that of the prawn (the brine shrimp). If the concentration of sodium chloride in seawater is increased to the point at which sodium begins to precipitate out of the solution (for example, in the extraction process of salt from seawater), this invertebrate is able to survive in the resulting environ-

ment of high salt concentration which one might think would preclude the existence of any cellular

325

possess the ability to actively secrete sodium and this is achieved by the nasal glands [25]. It will be recalled that birds cannot excrete high salt concentrations in the urine and so sodium balance appears to be maintained by this unusual mechanism. While this does not directly support the possibility of sodium secretion by the mammalian kidney, it does provide evidence for the existence of such a sodium-excreting mechanism elsewhere.

Because neurohypophysial hormones have been reported to influence sodium excretion, these hormones have been considered to be possible candidates for the

function. It is able to live because it can actively pump

hormonal factor responsible for the natriuresis of volume expansion. The effect of neurohypophysial

sodium out of the gills against this gradient. If the gills are destroyed, this prawn is still able to live in seawater, but it is no longer able to survive in this

hormones on sodium excretion has been the subject of much controversy for many years, some authors claiming that these hormones increase sodium excre-

incredibly high concentration of sodium chloride [18]. Here we thus have two intriguing examples of invertebrate organisms maintaining homeostasis by the pro-

tion in the mammalian series (with particular reference to man) while others deny it. This aspect is therefore considered in some detail. Shannon [26] showed that infusions of neurohypo-

prolixus.

cess of pumping sodium into the exterior; this is certainly due to a neurosecretion in the Rhodnius When moving from the invertebrate to the verte-

physial extracts containing both vasopressin and oxytocin (less than 20 mU/hr of Pituitrin/100 g) to rats given water, 0.05% saline or Ringer's solution

brate class, it would be reasonable to seek in the latter

induced natriuresis. In man, it is generally accepted

an analogous organ to the neurohemal one. Indeed, such a gland does exist in the vertebrate series—the

that Pituitrin extracts produce no effect on renal

posterior pituitary gland, or in some fish the urophysis

[19]. In the teleosts, the urophysis (the structure of this tissue is essentially similar to that of the neurohypophysis) is ideally situated to control the kidneys,

since the venous drainage empties into the caudal vein and, thereby, into the renal portal system [20]. It has been shown that extracts of the urophysis not

sodium excretion, although in 1936 Smith and Mackay [27] found that natriuresis occurred during the first two days of treatment with 0.5 ml of "Pituitrin surgical" daily in normal men. Sawyer [28] found that doses above 10 mU/100 g of Pitressin (vasopressin extract of the neurohypophysis) administered subcutaneously to rats caused natriuresis, while Schroder et al [29] showed that doses

of 100 U were sufficient to produce this change in hydrated rats. Natriuresis was produced in dogs with doses of Pitressin, 8 mU/kg [30]; in hydrated dogs

only reduce sodium excretion by the kidney but may also stimulate sodium transport outwards across the gill [21]. While it is true that fish possess aldosterone, the quantity present is so small that it is very doubtful

Pitressin infusions of 15 to 20 mU/hr increased sodium

that it plays any part in the regulation of sodium balance

excretion [31]. In addition, Chan and Sawyer [32]

[22]. Bern [20], discussing this aspect, even excludes

found that injections of large doses of Pitressin to hydrated and dehydrated dogs resulted in natriuresis, and in 1962 they [33] confirmed that infusions of Pitressin to hydrated dogs could also cause natriuresis, albeit

the existence of aldosterone in this class. It would seem that here it is the urophysis which controls sodium excretion and one of its actions is the active extrusion of sodium from the cells to the exterior. If one now considers the amphibians and reptiles, where the urophysis is absent, it is necessary to consider the part played by the neurohypophysis. Here it is

generally accepted that vasotocin increases tubular reabsorption of sodium [23, 24]. These classes are examples in which a hormone increases tubular reab-

sorption, whereas in the higher vertebrates and in man, one is seeking for a hormone which either blocks

sodium reabsorption or promotes sodium secretion. Hence, it is interesting to record that marine birds

transient. In humans, considerable natriuresis was observed in two boys following a subcutaneous injection of Pitressin, by Manchester in 1932 [34]. In 1952, Sawyer [28] showed that subcutaneously

administered doses of more than 10 mU of Pitocin (oxytocin extracts of the neurohypophysis) to rats given 0.05% NaC1 resulted in increased excretion of sodium. Similarly, Brunner et al [35] found increased sodium excretion in rats treated with 31 and 125 mU of oxytocin (Orasthin, Hoeschst) administered subcutaneously.

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Highly purified arginine-vasopressin administered in supramaximal antidiuretic doses to dogs in water diuresis caused natriuresis, whereas in lightly hydrated dogs, no such effect was observed [36]. Highly purified

lysine vasopressin, on the other hand, has not been shown to have any effect on sodium excretion in dogs [37] or man [38]. Barnafi et al [39] showed that both synthetic arginine and lysine vasopressins injected subcutaneously increased renal excretion of sodium and potassium in rats loaded with a solution of NaCI and KCL. Chan

[40] found slight natriuresis when synthetic lysine vasopressin was administered to hydrated rats, while

Atherton, Hai and Thomas [41] showed that this effect was transient. Brooks and Pickford [36] found that highly purified oxytocin administered simultaneously with vasopressin to dogs either in water diuresis or antidiuresis resulted in an increased rate of excretion of sodium and potassium. Oxytocin alone administered i.v. during a water diuresis in dogs failed to increase sodium excretion.

theless, the natriuretic action of this hormone should not be ignored. It is possible that an octapeptide of similar structure, as yet unidentified, may exist whose natriuretic action could justify its classification as the "natriuretic hormone". Apart from the neurohypophysial hormones, what possible known chemical messenger could the un-

known hormone be? The search has exposed the natriuretic properties of several substances, including prostaglandins [48], calcitonin [49], alpha-melanocytestimulating hormone [50], kallikreins [51], prolactin [52] and insulin [53], and parathyroid hormone [54]. However, it is accepted that there are several objections to any of these circulating substances being the unknown hormone which increases sodium excretion in response to an expansion of body fluids. Some of the evidence that the unknown natriuretic hormone may arise from the brain is provided by the work of Cort et al [55]. They found that there was a

natriuretic substance in the jugular venous blood

Natriuresis was observed, however, when oxytocin

following carotid arterial occlusion which was chemically related to, but probably not, oxytocin and which

was injected i.v. in large or small doses into the carotid

originated from the posterior hypothalamic region.

artery of dogs with a low rate of urine flow. This finding indicated that there might be a hormonal action via the central nervous system to induce this enhanced excretion of salt by a mechanism other than by the known neurohypophysial hormones. Croxatto and Labarca [42] showed that administration of synthetic oxytocin increases renal excretion of sodium in rats. Doses of synthetic oxytocin, 2.5 and 5.0 mU, injected subcutaneously into rats loaded with NaCl and KCI solution increased renal excretion of sodium and potassium [40, 43, 44]. In hydrated and

dehydrated dogs, administration of large doses of Syntocinon produced natriuresis [32].. However, Schrier et a! [45] were unable to implicate oxytocin as the natriuretic hormone involved in the natriuresis of volume expansion in dogs. An earlier report by Thomson [46] showed that oxytocin was not a natriuretic factor in man and this has now been generally accepted. However, there is the report of Holecek and Horkey [47], even though it is highly conjectural, that when patients with premenstrual edema (which

Subsequently, in 1969, Sedláková, Lichardus and Cort

[56] suggested that oxytocin and certain analogues caused the release of another peptide of small mol wt from some intracranial structure. This substance acted on the kidney to increase sodium rejection. This finding would account for the earlier observation by Brooks and Pickford [36].

Another finding favoring the hypothesis that the natriuretic hormone comes from the brain has been described by Lockett [57]. A cat kidney was perfused at a constant pressure with a heart-lung preparation. The blood used in the perfusion circuit came from either a normal or a headless cat, that is, an animal in which the brachiocephalic and left subclavian arteries had been ligatured. Lockett found that the addition of 10 ml of saline to the 120 ml of blood perfusing the kidney caused an increase in sodium excretion only if the blood came from a normal animal, whereas if the blood perfusing the kidney was taken from a headless animal, the addition of 10 ml of saline did not cause a rise in sodium excretion. Lockett's conclusions about

was assumed to be due to excess vasopressin secretion inducing slight retention) were given oxytocin, natriuresis occurred. One cannot better the conclusions reached by Bentley in 1971 [23] that in mammals the neurohypophysial

these experiments are inescapable. "The responses given by the isolated cat kidney to dilution of the circulating blood with saline are not attributable to

hormones may, in an unpredictable way, increase

dilution of blood from headless donors with saline caused no change in the parameters measured." And "It is evident that the hormone responsible for the reduction in renal Na transport in response to salt

sodium excretion in the rat, dog, camel and sheep, but not man. Vasopressin is secreted in response to a fall

of fluid volume and is, therefore, unlikely to be involved in the natriuresis of volume expansion. Never-

changes in the concentration of plasma proteins or the haematocrit or to activation of plasma kinins because

loading is dependent on the presence of a hormone of

Neurosecretion and sodium excretion

327

intracranial origin, either for its release or for its

anatomical site of action of this hormone on the renal

effect."

tubular system is discussed. It will be for others to determine whether this is of vascular or enzymatic

In 1957 Smith [1] had already suggested that the hypothalamus in man might secrete a substance which controls sodium excretion. Indeed, we would suggest

that the original conception of Smith still applies

origin. Volume expansion causes the inhibition of proximal tubular sodium reabsorption, and the resulting increas-

today.

ed amount of sodium which is delivered out of the

There is some indirect evidence to support the

proximal tubule is more than sufficient to account for

suggestion that the hypothalamus may be the site of the natriuretic hormone. Electrolytic lesions of the posterior hypothalamus diminish the natriuretic response to volume expansion [58, 59]. In addition, it is

the accompanying natriuresis [66]. For this reason, the decrease in sodium reabsorption by the proximal

not unreasonable to assume that sodium balance

tubule was considered for some time to be the mechanism by which sodium excretion increased after infusion of saline. However, recent evidence has accumulated

should be controlled from a neural area closely related to that which regulates water balance, since both are

which indicates that the proximal tubule may not

mutually related in the regulation of body volumes.

excretion as was previously suggested [67—70].

Conroy and Mills [60] have shown that there is a diur-

controlled by the hypothalamus [61], we should like to advance the hypothesis that the diurnal variation of sodium excretion is also controlled by this part of the brain, and that it exerts this control not via the adrenals, but by a chemical messenger acting directly on the renal tubular cells. As this substance would be

By infusing hyperoncotic albumin solutions into dogs, which cause an increase in plasma volume but not of interstitial fluid volume, Howards et al [67] were able to demonstrate that the preferential expansion of plasma volume, although causing an inhibition of proximal sodium reabsorption (measured by micropuncture of superficial nephrons) comparable with that after extracellular volume expansion, produces very little increase in sodium excretion. A similar dissociation between proximal sodium reabsorption and urinary sodium excretion has been

released by nerve endings directly into the blood

shown by measuring sodium excretion following

system to act on a distant organ, it would be a neurosecretion. Furthermore, we would suggest that this substance may be the unidentified natriuretic hormone. It is worthy to note that the sodium-retaining agent vasotocin was originally regarded as an interesting analogue of one of the mammalian neurohypophysial hormones before it was appreciated that this hormone was a natural secretion of the lower vertebrates. Of interest is the fact that another analogue of the neurohypophysial hormones, namely 4-Leucine-arginine

volume expansion both in the presence and absence of decreased proximal reabsorption, in the same dogs

nal variation of urinary sodium excretion in man, although the mechanism whereby this is induced is unknown. However, since the diurnal variation of plasma adrenocorticotropic hormone (ACTH) is

vasopressin, is a potent natriuretic substance [62].

While the unidentified natriuretic hormone cannot be

oxytocin or vasopressin, it would be tempting to speculate that a similar substance is synthetized in the hypothalamic region. This speculation gains indirect support from the interesting claim that vasotocin may

be found in the pituitary glands of fetal sheep and seals [63]. More direct evidence is the recent finding that there is a natriuretic substance in the posterior

pituitary [64] and in the hypothalamic region [65] which is not vasopressin or oxytocin. The final section of this review will be devoted to the site of action in the tubular system of this unknown hormone and whether the hormone acts by decreasing sodium reabsorption or by increasing sodium secretion. It must be emphasized that, in this review, only the

have as important a role in the regulation of sodium

[69]. In these studies it was shown that volume expansion with Ringer's solution had the expected effect of inhibiting proximal sodium reabsorption and causing increased fractional sodium excretion. However, the subsequent infusion of hyperoncotic albumin solution

into the renal artery restored proximal sodium reabsorption to control values, but 70% of the natriuresis remained. These results indicate that increased delivery from the proximal tubule contributes only a minor fraction to the increased sodium excretion. Although these conclusions were based on results from micropuncture experiments of superficial nephrons, which are subject to criticism in that changes in superficial nephrons are not necessarily representative of changes in deep nephrons, Knox et al [69] attempted to counter such criticism by measuring phosphate excretion as an index of total proximal sodium reabsorption throughout the kidney. The use of phosphate

excretion is dependent on the assumption that the bulk of phosphate reabsorption occurs in the proximal

tubule [71, 72] and that phosphate reabsorption is closely related to proximal sodium reabsorption under a variety of conditions [73, 74]. Knox et al [69] found

that fractional phosphate excretion was increased

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Lee/de Wardener

during Ringer's solution loading, but fell close to control values after renal arterial albumin infusion, indicating that changes in superficial nephron reab-

nately, in these experiments volume expansion was with saline, so the possibility that the collecting duct changes were due to dilutional changes rather than

sorption were parallelled by changes in deep nehprons.

hormonal changes cannot be discounted. It is essential that all experiments used in investigating the properties of the natriuretic hormone (on the kidney) should

The natriuresis following volume expansion is, thus, largely due to changes in sodium transfer at a site distal to the proximal convoluted tubule. There is some evidence for believing that the collecting duct plays an important role. Sonnenberg [75] punctured superficial distal convoluted tubules of the kidneys of rats which had been chronically sodium- and DOCAloaded or had been chronically sodium-deprived. He

be performed on isolated denervated kidneys per-

then repunctured the same sites following either volume expansion with blood, or exchange of the blood of the recipient with that of an unexpanded donor animal. Although in both groups of animals

has a natriuresis induced by an, as yet, unknown

there was a large natriuresis in response to expansion, there was little inhibition of sodium reabsorption up to the end of the distal convoluted tubule. It was found that end-distal sodium delivery in some "exchange-

occurring substance. Although the evidence for this unknown substance being of neurohypophysial origin

transfusion" rats was comparable with the delivery

confirmed. Since some analogues of the neurohypophysial hormones have a natriuretic action, the tentative hypothesis advanced is that such a substance is synthetized in the hypothalamic region and that the

in some expanded animals (even though sodium excretion was much higher in the latter). In addition,

the sodium excretion in the expanded, chronically sodium-loaded rats was greater than the quantity of sodium delivered from the distal tubules, suggesting that the extra sodium was added to the collecting duct. An alternative explanation could be the presence of a

disproportionate end-distal sodium load from deep nephrons. However, as Sonnenberg pointed out, the ratio of superficial nephron filtration rate to total kidney glomerular filtration rate (GFR) in expanded chronically sodium-loaded rats was 0.91, whereas in expanded sodium deficient rats, it was 0.62; thus, such an explanation is not tenable for the sodium-

fused at constant pressure and that the animal perfusing the kidney should have its blood volume expanded with blood with which it is in equilibrium.

In conclusion, it would be fair to summarize the situation by stating that the volume-expanded animal mechanism; however, the present evidence would lend

support to the presence of a hormone; indeed, a hormone which is probably not a known naturally has been closely examined (and indeed, perhaps undue

emphasis placed on this possibility), it cannot be

unknown hormone is therefore a neurosecretion. Finally, although the evidence is far from complete, it now appears possible that this hormone may act on the renal distal nephron either to block reabsorption of sodium or possibly to promote the active extrusion of sodium. Reprint requests to Dr. H. E. de Wardener, Department of Medicine, Charing Cross Hospital Medical School, London W.6, England.

loaded rats. While agreeing that the major site control-

ling sodium excretion is the collecting duct, other investigators (for example, Stein et al [70]) have not been able to produce evidence of sodium addition to the tubular fluid, but suggest that the mechanism is

only an inhibition of sodium reabsorption in the collecting duct. Stein et al [70] produced extracellular volume expansion in one group of rats by administration of Ringer's solution, while into a second group hyperoncotic albumin solution was infused, in order to expand the intravascular volume only. Sodium excretion was greater in the Ringer-loaded animals, but the

amount of sodium present at the end of the distal tubule in both groups was similar, so that the difference in urinary sodium excretion between the two groups was due to diminished handling of sodium in the collecting ducts. As the amount of sodium excreted

in both groups was less than the amount delivered, there was no evidence of sodium secretion. Unfortu-

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