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Thirst and sodium appetite
Thirst and sodium appet JamesT. Fitzsimons The survival of animals depends on the maintenance of a sufficient volume of extracellular fluid with an adequate sodium content. To meet this requirement the body has mechanismsthat regulate both thirst and sodium appetite, and in these the octapeptide hormone angiotensin II may play an important role.
In 1878, the year of his death, Claude Bernard (1813-1878) gave the most comprehensive description of his celebratedconcept that a necessarycondition for a free and independent physiological existence is that the composition of the blood and tissue fluid-i.e. the internal environment or extracellular fluid in which the cells are situated--should be constant [I]. Bernard went further than this by emphasizingthat the constancy is not passive but that it is actively maintained in respect of each of the components and physical characteristics of the internal environment. He believed that the central nervous system was responsible for achieving this constancy and that the sensationof thirst played a major part. It is the nervous system, aswe have said, which forms the link betweenacquisitions and losses.The sensationof thirst, which is dependentupon this system,makesitself evident every time the proportion of liquid in the body diminishes following some condition such as haemorrhageor abundant sweating; the animal therefore finds itself obliged to drink in order to repair the losses that it has incurred. But even this ingestion is regulated, in the sensethat it doesnot augmentthe amount of water present in the blood beyond a certain level: urinary and other excretions eliminate the surplus, like an overflow. The mechanisms which cause the quantity of water to vary and which re-establish it are therefore numerous; they set in motion a host of mechanisms of secretion, exhalation, ingestion and circulation which transport the ingested and absorbed liquid. These mechanisms are varied, but they lead to the sameresult: the presenceof water in the milieu intbieur in a sensibly determined proportion, a prerequisite of a free existence. (Translated from Bernard, 1878,p. 115) His clear statement on the importance of thirst in the regulation of the body fluids is especially worth remembering because many authors dealing with this aspect of homeostasis,to use Walter Bradford Cannon’s (187 l-1945) term, concentrate exclusively on renal mechanisms. The sensationof thirst has interestedphysiologists since at least the 18th century. Albrecht von Haller (1708-1777) attributed thirst to a dry mouth, oneof the classicaltheories that was vigorously defendedby Cannon in the Croonian lecture of 1918. A second classical theory, that thirst is a general sensation arising from a general need for water, stemmed from the work of the French school, especially from the observations of Guillaume Dupuytren (1771-1835), Francois Magendie (1783-1855), Claude Bernard, and the Genevan, Moritz Schiff (1823-1896). JarnesT.
Fitzsimons,
M.D.,Sc.D.
Is a graduate of the University of Cambridge. After serving for two years in the Royal Air Force at the Institute of Aviation Medicine, Farnborough. he returned to Cambridge, where he is now Reader in Physiology. His main professional interest is in the physiology of thirst and sodium appetite, and he is Chairman of the International Union of Physiological Sciences’ Commission on the Physiology of Food and Fluid Intake. Endeavour, (0 Pergamon
New Series Volume 4, No. 3,19&J Press, Printedin Great Britain)
Dupuytren found that dehydrated dogs no longer showed an interest in water when fluid was injected directly into the veins. Bernard showed that if water were drunk in the normal way but escapedto the exterior through an opening in the oesophagus or stomach, thirst was not relieved. Theseobservations demonstratedthat the passageof water through the mouth and throat was neither necessary nor sufficient to relievethirst. A third classical theory, not incompatible with the other two, was that of a local&d thirst centre in the central nervous system. This was first postulated by Carl Wilhelm Hermann Nothnagel (1841-1905) on the basis of his observations on a caseof suddenseverethirst in a man who on falling and being kicked by a horse had struck the back of his head although he had not lost consciousness.Support for the idea of a thirst centre camewith the work of Percival Bailey (1892-1973) and Frederic Bremer (1892- ) on experimental diabetesinsipidus in the dog, since they were able to produce primary neurogenic hyperdipsia by making lesions in the pituitary and adjacent hypothalamus. The importance of the hypothalamus was placed on a firm experimental footing by Bengt Andersson in Stockholm who caused copious drinking in goats by electrical stimulation of circumscribed regions of the hypothalamus through electrodes that had been implanted there previously. The most recent work on the physiology of thirst has of course been concerned with the development of these classical theories, but it is now recognisedthat they are not mutually exclusive, and that there are a variety of circumstances in which animals drink water and many different mechanisms involved [21. Apart from the realisation that thirst is multifactorial, one of the most important advances in the physiology of drinking behaviour has been the clear understanding that drinking under the control of the sensationof thirst is an emergency, life-preserving responseto fluid deficits and that in normal circumstances water intake is not under the control of thirst. As far as thirst itself is concerned, perhaps the most interesting recent development is the recognition that the hormone angiotensin II may play an important role in thirst and also in sodium appetite. Comparativeaspects
of drinking
Most truly terrestrial vertebrates-i.e. mammals, birds, and reptiles (figure l)-have well defined drinking habits, and give every appearance of experiencing thirst in the samesort of circumstancesin which man would be thirsty. Amphibia do not apparently drink but some,at least, show water-seeking behaviour when dehydrated. The sensation they experiencecould well be similar to thirst in the higher vertebrates.Even somefish drink; bony fish and thejawless hagfish and lampreys drink continuously when in sea water; freshwater specimensdo not. Migratory fish such as the eelare especially interesting becausethey drink when in seawater, presumably owing to the dehydrating action of the hypertonic environment, but they stop drinking when 97
they enter fresh water. However, the eel in fresh water can be madeto drink by subjecting it to injections of hypertonic NaCl or by bleedingit, procedurescommonly usedto make mammals drink [31. Unlike in the mammal, drinking in the eel appears to be entirely reflex since it continues after removal ofthe forebrain and midbrain. Sincethe fish lives in water, the neural mechanisms needed to ensure that enough is drunk are simpler than in a terrestrial mammal where the much more complicatedbehaviour of first finding and then drinking the water is required. Presumably this complexity of behaviour accounts for the encephalisation of drinking behaviour that is characteristic of terrestrial vertebrates, with the hypothalamus and associatedlimbic structures in the forebrain becoming the critical centresfor nervouscontrol.
Figure 1 Iguanas drinking in response to cellular (From Kaufman and Fitzsimons, see [I?]).
dehydration
The development of a specific appetite for sodium must also have been a significant factor in the evolutionary adaption to a terrestrial existence[41. Sodium is important becauseit is the principal extracellular cation and therefore blood volume dependson there being enough of it. Many animals can be assuredof enough sodium in the diet for the kidney to work upon in order to regulate body sodium. However, herbivorous animals, particularly those that live far from the sea, need extra salt and they look for it and consume it readily, Even carnivores may becomesodiumdeficient and in these circumstances they show a wellmarked and specific appetite for sodium. Although man may have difficulty in recognising the sensationassociated with sodium depletion, there are many accounts of what appears to be a specific sodium appetite. Furthermore, it seemsunlikely that it was an accident that salt occupies such a central position in human affairs. Causes
of drinking
and sodium
appetite
There are numerous causes of drinking. It is usual to distinguish betweenprimary or need-induceddrinking, and secondary drinking 121. In primary drinking there is a 98
relative or an absolute lack of water in one or other of the fluid spacesof the body so that drinking can reasonablybe attributed to this deficit, whereas in secondary drinking there does not appear to be any.immediate needfor water. Secondary drinking is not under the control of thirst but is determined by habit and diet. It has the characteristics of a circadian rhythm, drinking occurring mainly in association with feeding,and it continues even if the needsof the body for water are met in the unusual way of infusing water directly into the stomach or veins, bypassing the mouth altogether. Secondary drinking is the normal way in which the body’s water supplies are ensured,but little is known of its mechanisms. In order to survive, all animals need supplies of water, and although secondary drinking normally ensuresthat a
produced
by injection
of hypertonic
NaCl
surplus is available, there are circumstances in which a deficit of fluid builds up, requiring much more urgent restorative action. It is here that primary drinking under the control of thirst comesinto its own. The greater the deficit the more urgent the sensation,and the figurative useof the word thirst bears abundant witness of how imperious the sensationmay become. Sodium appetite is lessurgent and much slower in onset than thirst [2,4l. Nevertheless,a severelysodium-depleted animal shows a marked and specific appetite for sodium that appears to be the result of activation of an innate mechanism, and not the result of learning, although the responseis enhancedby experience. The main causesof primary drinking under the control of thirst are cellular dehydration and hypovolaemia (reduction in blood volume). Both signals may add their effects on thirst and there may be other signals as well. When the body is deprived of water, the extracellular fluid suffers the initial loss so that the extracellular osmolality tends to rise. Even as this is taking place the increased osmolality causes water to leave the cells, thereby equalising the increase in osmotic pressurethroughout the
body fluids. This results in the water loss being shared between the two major subdivision of the body fluids. Participating in the general cellular dehydration are osmoreceptors in the hypothalamus and basal forebrain region, the function of which is to arouse thirst and initiate drinking. These cells can also be stimulated by microinjections of hypertonic solutions of osmotically effective (i.e. dehydrating) substances in their immediate
Figure 2 Saggital section of a dog skull showing the arrangement for making intracranial injections into a conscious animal. The guide cannulae are positioned in the brain and attached to the skull by means of methyl methacrylate polymer and stainless-steel screws at a preliminary operation. A week or so later, when the dog has fully recovered from surgery, an injector attached to a micro-syringe by a length of polyethylene tubing is placed in the guide cannula and advanced until its tip is in the desired area of the brain. The injection in a volume of 1-2 ~1 isthen made and the injector removed,
vicinity. They therefore respond to their own dehydration, inducing behaviour that is generally appropriate for the whole body. Recently it has been suggested that the receptors which respond to cellular dehydration are sensitiveto changesin sodium concentration rather than to changesin the overall effectiveosmotic concentration of the extracellular fluid [51. Since increases in osmolality producing cellular dehydration almost always mean a rise in extracellular sodium-sodium with accompanying anion accounting for more than 90 per cent of extracellular osmolality-the distinction between an osmoreceptorand a sodium-sensitivereceptor is unimportant from a practical point of view. The precise signal to which the receptor for cellular dehydration respondsis therefore undecided. Hypovolaemia is not generally a marked featurein water deprivation sincethe circulation is protected at the expense of both the tissue (or interstitial) fluid and the cellular fluid. When there is severesodium loss, however, as may occur during prolonged heavy sweating, or in Addison’s disease (adrenal insufficiency) where excesssodium is lost in the urine, then hypovolaemia may become a significant cause not only of thirst but also of increasedsodium appetite. Some, at least, of the receptors for hypovolaemic thirst lie in the distensible walls of the vesselsof the low pressure side of the circulation in which most of the blood is situated (61.Thesereceptors are stretch receptors and they respond to overfilling of the circulation by an increased discharge along the sensory fibres of the vagi nerves which inhibits thirst and probably sodium appetite as well [2l. When the
Figure3
A dog drinking
in response
to intracranial
angiotensin.
blood volume falls, reduced afferent discharge in the vagi results in increasedthirst and sodium appetite and also in increased sympathetic discharge to the heart and circulation. Theseare appropriate physiological responses. POA 13 SF0 400
100
0
t
I
4
//
3/
l,’ :3/ I
10-12
I
lo-“ Dose of All
I
lo-'0
I
10-g
(mole)
Figure 4 The mean amounts of water drunk in response to intracranial injections of angiotensin II into the preoptic area (POA), subfornical organ (SFO), and lateral ventricle (LV). The number of observations are given next to each point. (From Fitzsimons, Kucharczyk, Et Richards, see j2.j).
99
minute (figure 3) and, after the larger doses,the amounts of water drunk within 10-20 minutes of injection approach what the animal would normally drink in 24 hours (figure 4). A secondbehaviour produced by injection of angiotensin II into the brain is increasedintake of solutions of sodium at concentrations that only sodium-depleted animals will normally drink 17, 81 (figure 5). This increased sodium appetite is slower in onset than thirst and lasts for many
Increased sympathetic activity stimulates cardiac output, increasesarteriolar tone, empties the blood reservoirs, and causestissue fluid to move into the capillaries. Therefore it enablesthe best use to be made of the existing supply of blood and tissue fluid so that the vital circulatory functions are preserved. It also activates the renin-angiotensin system,which, as we shall seenext, may contribute to thirst and sodium appetite,essentialresponsesfor the restoration of the body fluids to normal. 140 -
130 120-
110 -
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DAYS
Figure 5 Mean daily water (0) and 2.7% NaC (0) intakes (It S.E. of mean, number of rats in parentheses) of rats with access to both solutions in response to infusion of angiotensin II at the rates indicated into the 3rd cerebral ventricle over a period of 7 days. ‘PCO.05, **P<0.01,*‘*P<0.001 comparedwith the3 preinfusion base line days (From [8]).
The ranin-angiotensin appetite
system
in thirst
and sodium
Angiotensin II, an octapeptidehormone formed as a result of increased secretion of renin by the kidney, is a potent stimulus to thirst and sodium appetite when it is injected directly into the brain of a large number’ of different vertebrate species 12, 71 (figure 2). It causes normal drinking behaviour after a latency of usually less than a 100
hours after a single injection of angiotensin. The pattern of intakes produced by intracranial injection of angiotensin II is so similar to the pattern of early thirst and delayed sodium appetite which occurs in hypovolaemia, that it is tempting to conclude that the reninangiotensin system has a significant role to play in these behaviours in hypovolaemia. Renin is a proteolytic enzyme secretedinto the bloodstream by the juxtaglomerular cells
in the afferent arterioles of the kidneys in response to dehydration, sodium-depletion, and blood loss [91. It acts on renin substrate, an a2 globulin produced by the liver, breaking off a relatively inactive decapeptide,angiotensin I. As the blood passesthrough the lungs, two amino acids are cleaved from the C-terminal end of the angiotensin I moleculeto give the active octapeptide angiotensin II. This is a potent but short-lived substance that has numerous actions most of which, including thirst and sodium appetite, can be regarded as contributing to the maintenance of the circulation. The evidencefor involvement of renal renin in thirst is as follows 121.(1) Many of the proceduresthat stimulate renin secretion also cause thirst. These include, dehydration, blood loss, and sodium depletion. (2) Drinking in response to someof theseproceduresis attenuated or even abolished by removal of the endogenous source of renal renin by nephrectomy. (3) Drinking to theseproceduresmay also be attenuated by specific peptide antagonists of the reninangiotensin system [IO,1 11,What has not beenestablished, however, is the extent to which renal renin participates in so-called natural thirst, i.e. the thirst of water deprivation. The failure to demonstrate a role for angiotensin has often beenbecausecomplex thirst stimuli, in which angiotensinis only one of several factors involved, have been studied. When several factors operate, elimination of one may be compensatedfor by increased activation of the others. The variable effectsfollowing removal of renin by nephrectomy or administration of renin-angiotensin antagonists, and the sometimespoor correlation between drinking and plasma renin levels are therefore not unexpected.They indicate the variable contributions of renin and non-endocrine mechanisms to drinking induced by different thirstinducing procedures. The presenceof other isorenin-angiotensin systemsin the body, notably in the brain [121, has complicated the interpretation of the significance of angiotensin-induced thirst still further. It is unknown whether angiotensinsensitive tissue in the brain is normally acted upon by circulating angiotensin generated by renal renin, by angiotensin locally generated in the brain by cerebral isorenin, or by angiotensin from both sources.All that can be said at present is that blood-borne angiotensin can certainly causedrinking behaviour in the absenceof other thirst stimuli, and secondly, that angiotensin augments drinking responses to other stimuli which implies that it could have a physiological role in thirst in some circumstances. The role of angiotensin in sodium appetite is even more elusive. Blood-borne angiotensin seemsto have little effect on sodium intake, although intracranial administration of angiotensin is highly effective in eliciting sodium appetite. The mechanism and significance of this intracranial action
are unknown but it is conceivable that this is a manifestation of one of the functions of cerebralisorenin. Conclusions
Of all evolutionary adaptations to a terrestrial environment, possessionof an efficient thirst mechanism is one of the most important for survival. However, when environmental conditions are constant, water intake is not under the control of thirst. We appear to be able to predict future requirements of fluid from oropharyngeal cues and to drink the appropriate amount of water at mealtimes.Such drinking is called secondary drinking and it is not induced by an existing needfor water. When water is lacking it is essentialthat stepsbe taken to restore the body water as a matter of urgency. Loss of either cellular fluid or of extracellular fluid causesthirst and primary or need-induced drinking. Cellular deficits are detected by hypothalamic osmoreceptors which share in the general cellular dehydration. Extracellular deficits cause underfilling of the circulation and reduced sensory discharge from stretch receptors in the walls of the low pressure blood vessels. Inhibitory signals to thirst and sodium appetite are therefore reduced. In addition, increasedformation of angiotensin reinforces the effectsof these non-endocrine mechanisms on thirst and sodium appetite, although the extent and significance of this reinforcement are uncertain.
References 111Bernard, Claude. Leqons sur les ph&omPnes de ‘la vie communs aux animauxetauxkg&aux. Ball&e, Paris. 1878. [21 Fitzsimons, J. T. The Physiology of Thirst and Sodium Appetite. Monographs of the Physiological Society No. 35. Cambridge University Press, 1979. Hirano,T. J. Exp. Biol.,61,737, 1974. Denton, D. A. ‘Central nervous control of Na+ balance -relations to the renin-angiotensin system,’ (Ed. Kaufmann, W. & Krause, D. K.) pp. 103-l 11.Georg Thieme, Stuttgart. 1976. [51 Andersson, B. Physiol. Rev., 58,582,1978. [61 Gauer, 0. H. and Henry, J. P. ‘International Review of Physiology. Cardiovascular Physiology II,’ (Ed. Guyton, A. C. and Cowley, A. W.) Vol. 9, pp. 145-190. University Park Press, Baltimore. 1976. I71 Epstein, A. N. ‘Frontiers in Neuroendocrinology,’ (Ed. Ganong, W. F. and Martini, L.) Vol. 5, _ pp. . 101-134. Raven Press.New York. 1978. [81 Avrith, D. and Fitzsimons, J. T. J. Physiol. Lond., 30 1,349, 1980. no. 179-l 96. [91 Peart, W. S. ‘Peptide hormones.’ (Ed. Parsons.J. A.),.& Macmillan, London. 1976. [lOI Malvin, R. L., Mouw, D., and Vander, A. J. Science, New York, 197,171,1977. I111 Fitzsimons, J. T. and Moore-Gillon, M. J. (1979). J. Physiol. Lond., 295,76, 1979. (121 Phillips, M. I., Weyhenmeyer, J., Felix, D., Ganten, D., and Hoffman, W. E. (1979). Federation Proceedings, 38, 2260, 1979.
001%7162/60/0097-0101/$02.00/0
101
In 1878, the year of his death, Claude Bernard (1813-1878) gave the most comprehensive description of his celebratedconcept that a necessarycondition for a free and independent physiological existence is that the composition of the blood and tissue fluid-i.e. the internal environment or extracellular fluid in which the cells are situated--should be constant [I]. Bernard went further than this by emphasizingthat the constancy is not passive but that it is actively maintained in respect of each of the components and physical characteristics of the internal environment. He believed that the central nervous system was responsible for achieving this constancy and that the sensationof thirst played a major part. It is the nervous system, aswe have said, which forms the link betweenacquisitions and losses.The sensationof thirst, which is dependentupon this system,makesitself evident every time the proportion of liquid in the body diminishes following some condition such as haemorrhageor abundant sweating; the animal therefore finds itself obliged to drink in order to repair the losses that it has incurred. But even this ingestion is regulated, in the sensethat it doesnot augmentthe amount of water present in the blood beyond a certain level: urinary and other excretions eliminate the surplus, like an overflow. The mechanisms which cause the quantity of water to vary and which re-establish it are therefore numerous; they set in motion a host of mechanisms of secretion, exhalation, ingestion and circulation which transport the ingested and absorbed liquid. These mechanisms are varied, but they lead to the sameresult: the presenceof water in the milieu intbieur in a sensibly determined proportion, a prerequisite of a free existence. (Translated from Bernard, 1878,p. 115) His clear statement on the importance of thirst in the regulation of the body fluids is especially worth remembering because many authors dealing with this aspect of homeostasis,to use Walter Bradford Cannon’s (187 l-1945) term, concentrate exclusively on renal mechanisms. The sensationof thirst has interestedphysiologists since at least the 18th century. Albrecht von Haller (1708-1777) attributed thirst to a dry mouth, oneof the classicaltheories that was vigorously defendedby Cannon in the Croonian lecture of 1918. A second classical theory, that thirst is a general sensation arising from a general need for water, stemmed from the work of the French school, especially from the observations of Guillaume Dupuytren (1771-1835), Francois Magendie (1783-1855), Claude Bernard, and the Genevan, Moritz Schiff (1823-1896). JarnesT.
Fitzsimons,
M.D.,Sc.D.
Is a graduate of the University of Cambridge. After serving for two years in the Royal Air Force at the Institute of Aviation Medicine, Farnborough. he returned to Cambridge, where he is now Reader in Physiology. His main professional interest is in the physiology of thirst and sodium appetite, and he is Chairman of the International Union of Physiological Sciences’ Commission on the Physiology of Food and Fluid Intake. Endeavour, (0 Pergamon
New Series Volume 4, No. 3,19&J Press, Printedin Great Britain)
Dupuytren found that dehydrated dogs no longer showed an interest in water when fluid was injected directly into the veins. Bernard showed that if water were drunk in the normal way but escapedto the exterior through an opening in the oesophagus or stomach, thirst was not relieved. Theseobservations demonstratedthat the passageof water through the mouth and throat was neither necessary nor sufficient to relievethirst. A third classical theory, not incompatible with the other two, was that of a local&d thirst centre in the central nervous system. This was first postulated by Carl Wilhelm Hermann Nothnagel (1841-1905) on the basis of his observations on a caseof suddenseverethirst in a man who on falling and being kicked by a horse had struck the back of his head although he had not lost consciousness.Support for the idea of a thirst centre camewith the work of Percival Bailey (1892-1973) and Frederic Bremer (1892- ) on experimental diabetesinsipidus in the dog, since they were able to produce primary neurogenic hyperdipsia by making lesions in the pituitary and adjacent hypothalamus. The importance of the hypothalamus was placed on a firm experimental footing by Bengt Andersson in Stockholm who caused copious drinking in goats by electrical stimulation of circumscribed regions of the hypothalamus through electrodes that had been implanted there previously. The most recent work on the physiology of thirst has of course been concerned with the development of these classical theories, but it is now recognisedthat they are not mutually exclusive, and that there are a variety of circumstances in which animals drink water and many different mechanisms involved [21. Apart from the realisation that thirst is multifactorial, one of the most important advances in the physiology of drinking behaviour has been the clear understanding that drinking under the control of the sensationof thirst is an emergency, life-preserving responseto fluid deficits and that in normal circumstances water intake is not under the control of thirst. As far as thirst itself is concerned, perhaps the most interesting recent development is the recognition that the hormone angiotensin II may play an important role in thirst and also in sodium appetite. Comparativeaspects
of drinking
Most truly terrestrial vertebrates-i.e. mammals, birds, and reptiles (figure l)-have well defined drinking habits, and give every appearance of experiencing thirst in the samesort of circumstancesin which man would be thirsty. Amphibia do not apparently drink but some,at least, show water-seeking behaviour when dehydrated. The sensation they experiencecould well be similar to thirst in the higher vertebrates.Even somefish drink; bony fish and thejawless hagfish and lampreys drink continuously when in sea water; freshwater specimensdo not. Migratory fish such as the eelare especially interesting becausethey drink when in seawater, presumably owing to the dehydrating action of the hypertonic environment, but they stop drinking when 97
they enter fresh water. However, the eel in fresh water can be madeto drink by subjecting it to injections of hypertonic NaCl or by bleedingit, procedurescommonly usedto make mammals drink [31. Unlike in the mammal, drinking in the eel appears to be entirely reflex since it continues after removal ofthe forebrain and midbrain. Sincethe fish lives in water, the neural mechanisms needed to ensure that enough is drunk are simpler than in a terrestrial mammal where the much more complicatedbehaviour of first finding and then drinking the water is required. Presumably this complexity of behaviour accounts for the encephalisation of drinking behaviour that is characteristic of terrestrial vertebrates, with the hypothalamus and associatedlimbic structures in the forebrain becoming the critical centresfor nervouscontrol.
Figure 1 Iguanas drinking in response to cellular (From Kaufman and Fitzsimons, see [I?]).
dehydration
The development of a specific appetite for sodium must also have been a significant factor in the evolutionary adaption to a terrestrial existence[41. Sodium is important becauseit is the principal extracellular cation and therefore blood volume dependson there being enough of it. Many animals can be assuredof enough sodium in the diet for the kidney to work upon in order to regulate body sodium. However, herbivorous animals, particularly those that live far from the sea, need extra salt and they look for it and consume it readily, Even carnivores may becomesodiumdeficient and in these circumstances they show a wellmarked and specific appetite for sodium. Although man may have difficulty in recognising the sensationassociated with sodium depletion, there are many accounts of what appears to be a specific sodium appetite. Furthermore, it seemsunlikely that it was an accident that salt occupies such a central position in human affairs. Causes
of drinking
and sodium
appetite
There are numerous causes of drinking. It is usual to distinguish betweenprimary or need-induceddrinking, and secondary drinking 121. In primary drinking there is a 98
relative or an absolute lack of water in one or other of the fluid spacesof the body so that drinking can reasonablybe attributed to this deficit, whereas in secondary drinking there does not appear to be any.immediate needfor water. Secondary drinking is not under the control of thirst but is determined by habit and diet. It has the characteristics of a circadian rhythm, drinking occurring mainly in association with feeding,and it continues even if the needsof the body for water are met in the unusual way of infusing water directly into the stomach or veins, bypassing the mouth altogether. Secondary drinking is the normal way in which the body’s water supplies are ensured,but little is known of its mechanisms. In order to survive, all animals need supplies of water, and although secondary drinking normally ensuresthat a
produced
by injection
of hypertonic
NaCl
surplus is available, there are circumstances in which a deficit of fluid builds up, requiring much more urgent restorative action. It is here that primary drinking under the control of thirst comesinto its own. The greater the deficit the more urgent the sensation,and the figurative useof the word thirst bears abundant witness of how imperious the sensationmay become. Sodium appetite is lessurgent and much slower in onset than thirst [2,4l. Nevertheless,a severelysodium-depleted animal shows a marked and specific appetite for sodium that appears to be the result of activation of an innate mechanism, and not the result of learning, although the responseis enhancedby experience. The main causesof primary drinking under the control of thirst are cellular dehydration and hypovolaemia (reduction in blood volume). Both signals may add their effects on thirst and there may be other signals as well. When the body is deprived of water, the extracellular fluid suffers the initial loss so that the extracellular osmolality tends to rise. Even as this is taking place the increased osmolality causes water to leave the cells, thereby equalising the increase in osmotic pressurethroughout the
body fluids. This results in the water loss being shared between the two major subdivision of the body fluids. Participating in the general cellular dehydration are osmoreceptors in the hypothalamus and basal forebrain region, the function of which is to arouse thirst and initiate drinking. These cells can also be stimulated by microinjections of hypertonic solutions of osmotically effective (i.e. dehydrating) substances in their immediate
Figure 2 Saggital section of a dog skull showing the arrangement for making intracranial injections into a conscious animal. The guide cannulae are positioned in the brain and attached to the skull by means of methyl methacrylate polymer and stainless-steel screws at a preliminary operation. A week or so later, when the dog has fully recovered from surgery, an injector attached to a micro-syringe by a length of polyethylene tubing is placed in the guide cannula and advanced until its tip is in the desired area of the brain. The injection in a volume of 1-2 ~1 isthen made and the injector removed,
vicinity. They therefore respond to their own dehydration, inducing behaviour that is generally appropriate for the whole body. Recently it has been suggested that the receptors which respond to cellular dehydration are sensitiveto changesin sodium concentration rather than to changesin the overall effectiveosmotic concentration of the extracellular fluid [51. Since increases in osmolality producing cellular dehydration almost always mean a rise in extracellular sodium-sodium with accompanying anion accounting for more than 90 per cent of extracellular osmolality-the distinction between an osmoreceptorand a sodium-sensitivereceptor is unimportant from a practical point of view. The precise signal to which the receptor for cellular dehydration respondsis therefore undecided. Hypovolaemia is not generally a marked featurein water deprivation sincethe circulation is protected at the expense of both the tissue (or interstitial) fluid and the cellular fluid. When there is severesodium loss, however, as may occur during prolonged heavy sweating, or in Addison’s disease (adrenal insufficiency) where excesssodium is lost in the urine, then hypovolaemia may become a significant cause not only of thirst but also of increasedsodium appetite. Some, at least, of the receptors for hypovolaemic thirst lie in the distensible walls of the vesselsof the low pressure side of the circulation in which most of the blood is situated (61.Thesereceptors are stretch receptors and they respond to overfilling of the circulation by an increased discharge along the sensory fibres of the vagi nerves which inhibits thirst and probably sodium appetite as well [2l. When the
Figure3
A dog drinking
in response
to intracranial
angiotensin.
blood volume falls, reduced afferent discharge in the vagi results in increasedthirst and sodium appetite and also in increased sympathetic discharge to the heart and circulation. Theseare appropriate physiological responses. POA 13 SF0 400
100
0
t
I
4
//
3/
l,’ :3/ I
10-12
I
lo-“ Dose of All
I
lo-'0
I
10-g
(mole)
Figure 4 The mean amounts of water drunk in response to intracranial injections of angiotensin II into the preoptic area (POA), subfornical organ (SFO), and lateral ventricle (LV). The number of observations are given next to each point. (From Fitzsimons, Kucharczyk, Et Richards, see j2.j).
99
minute (figure 3) and, after the larger doses,the amounts of water drunk within 10-20 minutes of injection approach what the animal would normally drink in 24 hours (figure 4). A secondbehaviour produced by injection of angiotensin II into the brain is increasedintake of solutions of sodium at concentrations that only sodium-depleted animals will normally drink 17, 81 (figure 5). This increased sodium appetite is slower in onset than thirst and lasts for many
Increased sympathetic activity stimulates cardiac output, increasesarteriolar tone, empties the blood reservoirs, and causestissue fluid to move into the capillaries. Therefore it enablesthe best use to be made of the existing supply of blood and tissue fluid so that the vital circulatory functions are preserved. It also activates the renin-angiotensin system,which, as we shall seenext, may contribute to thirst and sodium appetite,essentialresponsesfor the restoration of the body fluids to normal. 140 -
130 120-
110 -
loo-
422
90-
I 6
so-
hi vi
70-
II E -
an-
1~10“~
l
s
mot
hr-’
3rd
V.%ltrlCle
50
.:
;)!):)
1 I
1
(10)
DAYS
Figure 5 Mean daily water (0) and 2.7% NaC (0) intakes (It S.E. of mean, number of rats in parentheses) of rats with access to both solutions in response to infusion of angiotensin II at the rates indicated into the 3rd cerebral ventricle over a period of 7 days. ‘PCO.05, **P<0.01,*‘*P<0.001 comparedwith the3 preinfusion base line days (From [8]).
The ranin-angiotensin appetite
system
in thirst
and sodium
Angiotensin II, an octapeptidehormone formed as a result of increased secretion of renin by the kidney, is a potent stimulus to thirst and sodium appetite when it is injected directly into the brain of a large number’ of different vertebrate species 12, 71 (figure 2). It causes normal drinking behaviour after a latency of usually less than a 100
hours after a single injection of angiotensin. The pattern of intakes produced by intracranial injection of angiotensin II is so similar to the pattern of early thirst and delayed sodium appetite which occurs in hypovolaemia, that it is tempting to conclude that the reninangiotensin system has a significant role to play in these behaviours in hypovolaemia. Renin is a proteolytic enzyme secretedinto the bloodstream by the juxtaglomerular cells
in the afferent arterioles of the kidneys in response to dehydration, sodium-depletion, and blood loss [91. It acts on renin substrate, an a2 globulin produced by the liver, breaking off a relatively inactive decapeptide,angiotensin I. As the blood passesthrough the lungs, two amino acids are cleaved from the C-terminal end of the angiotensin I moleculeto give the active octapeptide angiotensin II. This is a potent but short-lived substance that has numerous actions most of which, including thirst and sodium appetite, can be regarded as contributing to the maintenance of the circulation. The evidencefor involvement of renal renin in thirst is as follows 121.(1) Many of the proceduresthat stimulate renin secretion also cause thirst. These include, dehydration, blood loss, and sodium depletion. (2) Drinking in response to someof theseproceduresis attenuated or even abolished by removal of the endogenous source of renal renin by nephrectomy. (3) Drinking to theseproceduresmay also be attenuated by specific peptide antagonists of the reninangiotensin system [IO,1 11,What has not beenestablished, however, is the extent to which renal renin participates in so-called natural thirst, i.e. the thirst of water deprivation. The failure to demonstrate a role for angiotensin has often beenbecausecomplex thirst stimuli, in which angiotensinis only one of several factors involved, have been studied. When several factors operate, elimination of one may be compensatedfor by increased activation of the others. The variable effectsfollowing removal of renin by nephrectomy or administration of renin-angiotensin antagonists, and the sometimespoor correlation between drinking and plasma renin levels are therefore not unexpected.They indicate the variable contributions of renin and non-endocrine mechanisms to drinking induced by different thirstinducing procedures. The presenceof other isorenin-angiotensin systemsin the body, notably in the brain [121, has complicated the interpretation of the significance of angiotensin-induced thirst still further. It is unknown whether angiotensinsensitive tissue in the brain is normally acted upon by circulating angiotensin generated by renal renin, by angiotensin locally generated in the brain by cerebral isorenin, or by angiotensin from both sources.All that can be said at present is that blood-borne angiotensin can certainly causedrinking behaviour in the absenceof other thirst stimuli, and secondly, that angiotensin augments drinking responses to other stimuli which implies that it could have a physiological role in thirst in some circumstances. The role of angiotensin in sodium appetite is even more elusive. Blood-borne angiotensin seemsto have little effect on sodium intake, although intracranial administration of angiotensin is highly effective in eliciting sodium appetite. The mechanism and significance of this intracranial action
are unknown but it is conceivable that this is a manifestation of one of the functions of cerebralisorenin. Conclusions
Of all evolutionary adaptations to a terrestrial environment, possessionof an efficient thirst mechanism is one of the most important for survival. However, when environmental conditions are constant, water intake is not under the control of thirst. We appear to be able to predict future requirements of fluid from oropharyngeal cues and to drink the appropriate amount of water at mealtimes.Such drinking is called secondary drinking and it is not induced by an existing needfor water. When water is lacking it is essentialthat stepsbe taken to restore the body water as a matter of urgency. Loss of either cellular fluid or of extracellular fluid causesthirst and primary or need-induced drinking. Cellular deficits are detected by hypothalamic osmoreceptors which share in the general cellular dehydration. Extracellular deficits cause underfilling of the circulation and reduced sensory discharge from stretch receptors in the walls of the low pressure blood vessels. Inhibitory signals to thirst and sodium appetite are therefore reduced. In addition, increasedformation of angiotensin reinforces the effectsof these non-endocrine mechanisms on thirst and sodium appetite, although the extent and significance of this reinforcement are uncertain.
References 111Bernard, Claude. Leqons sur les ph&omPnes de ‘la vie communs aux animauxetauxkg&aux. Ball&e, Paris. 1878. [21 Fitzsimons, J. T. The Physiology of Thirst and Sodium Appetite. Monographs of the Physiological Society No. 35. Cambridge University Press, 1979. Hirano,T. J. Exp. Biol.,61,737, 1974. Denton, D. A. ‘Central nervous control of Na+ balance -relations to the renin-angiotensin system,’ (Ed. Kaufmann, W. & Krause, D. K.) pp. 103-l 11.Georg Thieme, Stuttgart. 1976. [51 Andersson, B. Physiol. Rev., 58,582,1978. [61 Gauer, 0. H. and Henry, J. P. ‘International Review of Physiology. Cardiovascular Physiology II,’ (Ed. Guyton, A. C. and Cowley, A. W.) Vol. 9, pp. 145-190. University Park Press, Baltimore. 1976. I71 Epstein, A. N. ‘Frontiers in Neuroendocrinology,’ (Ed. Ganong, W. F. and Martini, L.) Vol. 5, _ pp. . 101-134. Raven Press.New York. 1978. [81 Avrith, D. and Fitzsimons, J. T. J. Physiol. Lond., 30 1,349, 1980. no. 179-l 96. [91 Peart, W. S. ‘Peptide hormones.’ (Ed. Parsons.J. A.),.& Macmillan, London. 1976. [lOI Malvin, R. L., Mouw, D., and Vander, A. J. Science, New York, 197,171,1977. I111 Fitzsimons, J. T. and Moore-Gillon, M. J. (1979). J. Physiol. Lond., 295,76, 1979. (121 Phillips, M. I., Weyhenmeyer, J., Felix, D., Ganten, D., and Hoffman, W. E. (1979). Federation Proceedings, 38, 2260, 1979.
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