Proc. Natl. Acad. Sci. USA Vol. 93, pp. 7397-7404, July 1996 Physiology This contribution is part of the special series ofInaugural Articles by members of the National Academy of Sciences elected on April 25, 1995. Hypothalamic integration of body fluid regulation D. A. DENTON, M. J. MCKINLEY, AND R. S. WEISINGER Howard Florey Institute of Experimental Physiology and Medicine, University of Melbourne, Parkville, Victoria 3052, Australia Contributed by D. A. Denton, March 26, 1996 ABSTRACT The progression of animal life from the gressive invasion of diverse regions of the planet-jungles, the paleozoic ocean to rivers and diverse econiches on the planet's dry interior of continents, deserts, savannah, temperate for- surface, as well as the subsequent reinvasion of the ocean, ests, and the Alps. Also, there was reinvasion of the oceans, all involved many different stresses on ionic pattern, osmotic migrations entailing diverse environmental influences with pressure, and volume of the extracellular fluid bathing body potential to distort the stability of the fluid milieu of the tissues cells. The relatively constant ionic pattern of vertebrates of the organism. reflects a genetic "set" of many regulatory mechanisms- particularly renal regulation. Renal regulation of ionic pat- Constancy of the Milieu tern when loss of fluid from the body is disproportionate relative to the extracellular fluid composition (e.g., gastric The constancy of the milieu interieur, the condition of free life, juice with vomiting and pancreatic secretion with diarrhea) involves, inter alia, maintenance of a pattern of ionic compo- makes manifest that a mechanism to produce a biologically nents. John Fulton (3), in his book Selected Readings in the relatively inactive extracellular anion HCO3 exists, whereas History of Physiology, pointed out that MacCallum (4) gave no comparable mechanism to produce a biologically inactive historical and phylogenetic meaning to the constancy of the cation has evolved. Life in the ocean, which has three times the milieu interieur when he demonstrated the striking resem- sodium concentration of extracellular fluid, involves quite blance between the ionic components of the blood sera and different osmoregulatory stress to that in freshwater. Terres- that of seawater, and, in particular, the ionic ratios. He trial life involves risk of desiccation and, in large areas of the suggested that tissue cells could only live within a relatively planet, salt deficiency. Mechanisms integrated in the hypo- narrow range of physicochemical conditions that represented thalamus (the evolutionary ancient midbrain) control water that of the ancient ocean, in which the cells of ancestral retention and facilitate excretion of sodium, and also control organisms had originated. As Metazoan organisms evolved the secretion of renin by the kidney. Over and above the and developed a closed circulatory system, they evolved organs multifactorial processes of excretion, hypothalamic sensors that regulated and kept the ionic pattern constant regardless reacting to sodium concentration, as well as circumventricu- of changes the external milieu underwent with time. The lar organs sensors reacting to osmotic pressure and angio- comparative constancy of this pattern of the extracellular tensin II, subserve genesis of sodium hunger and thirst. These fluids from elasmobranchs to Australian marsupials and the behaviors spectacularly augment the adaptive capacities of mammals (5, 6) reflects a basic genetic characteristic of animal animals. Instinct (genotypic memory) and learning (pheno- life, reflecting the "set" of a number of regulatory systems- typic memory) are melded to give specific behavior apt to the particularly renal regulation. metabolic status of the animal. The sensations, compelling With addition stress, as a result of an excess of a substance emotions, and intentions generated by these vegetative sys- entering the milieu, the rise in plasma concentration or load to tems focus the issue of the phylogenetic emergence of con- the renal tubules results in regulatory excretion. sciousness and whether primal awareness initially came from A broad evolutionary implication of pattern constancy the interoreceptors and vegetative systems rather than the emerges clearly in the face of subtraction stress distorting the distance receptors. ionic pattern, as can occur in higher mammals as a result of disease or, for that matter, human medical problems. For In the higher mammals, the functions centered in the hypo- example, the stomach secretes fluid that has Cl- in large excess thalamus play a paramount role in integrating the many of Na (Cl/Na, -4-5), relative to the normal extracellular physiological systems controlling the milieu interieur. These proportions (Cl/Na, 0.7), HI being the electrically equivalent hypothalamic processes range from genetically determined cation. With large loss of acid gastric juice by vomiting, the patterns of ingestive behavior that correct body deficits and, in plasma level of Cl- falls and the level of HCOj3, an anion turn, involve associated cognitive and memory functions of the constantly produced in the body, may rise reciprocally 10-20 cortex, to the other extreme of the control of excretory meq/liter, the plasma pH being maintained near constant by processes, in a mode apt to the metabolic status of the animal. a compensatory rise in pCO2 as a result of regulatory depres- Some evolutionary aspects of body fluid control will be sion of respiration. The replacement of plasma Cl- by a described first as a general biological context of the mecha- relatively biologically inactive anion, HCO-, obviates the nisms in mammals. physiological need to excrete significant amounts of sodium in Mountain building, like the Grand Canyon uplift in the the urine to control the pattern. In striking contrast, with loss Cambrian and subsidence in the Ordivician periods, provided of alkaline pancreatic secretion as a result of diarrhea or conditions of rivers flowing into the ocean, and, probably intestinal fistulae or loss of parotid salivary secretion in during this time, protovertebrates with spindle body and segmentally arranged muscles adapted to rhythmic contrac- Abbreviations: ANG, angiotensin; CSF, cerebrospinal fluid; OVLT, tions evolved (reviewed in refs. 1 and 2). Later, irradiation of organum vasculosum of the lamina terminalis; AT1, ANG receptor vertebrates from estuaries, rivers, and swamps involved pro- subtype 1; ICV, intracerebroventricular. 7397 Downloaded by guest on September 28, 2021 7398 Physiology: Denton et al. Proc. Natl. Acad. Sci. USA 93 (1996) ruminants by drooling, there is a loss of Na+ in excess of C1- the nasal cavity. The salt glands excrete intermittently in relative to the extracellular proportions. Whereas in the case response to osmotic stress (9). Sensory elements in the cardiac of Cl- in excess of sodium subtraction, the necessity of area transmit via the vagus nerve. The secretion of salt glands electrical neutrality is achieved by capacity to produce a is mediated by acetylcholine, with possibly some influence of biologically relatively inactive anion, HCO3, in the case of the hormone prolactin during transition from freshwater to excess sodium subtraction, no analogous mechanism for the estuarine habitat, analogous to its role in osmoregulation of production of a biologically inactive cation has evolved. A rise migratory fish (11). of extracellular Cl/Na ratio begins and compensatory in- In contrast, the marine mammals like whales and seals creased pulmonary ventilation with reduction of pCO2 obvi- produce a urine much more concentrated than seawater and ates, to an extent, a fall in plasma pH. However, a crucial can make a net water gain from intake of seawater and feeding mechanism in these circumstances is that the kidney excretes on marine invertebrates and plankton. Cl- with electrically equivalent amount of NH' or K+, and this Comparative Anatomy of Hypothalamus. Given its major regulation occurs even though the plasma level of Cl- may be function in body fluid control in mammals to be elaborated below the so-called "renal threshold" initially thought to below, it is salient to note comparatively that the hypothalamus regulate excretion of ions and even though there is a reduction is a major anatomical component of the brain in fishes, of the load of Cl- to the renal tubules as a result of decline of amphibians, and reptiles. The pars magnocellularis of the circulation. Thus, ionic pattern and plasma pH are preserved, nucleus praeopticus is present in fishes and above, and in compatible with life, as a result of the renal mechanism reptiles it is clearly split into the paraventricular nucleus and operating on electrolyte relativity, rather than absolute supraoptic nucleus. There is progressive differentiation of the amounts or concentrations delivered to the tubules (7, 8). cytoarchitecture of the hypothalamus in the ascending series of Osmoregulation. Notwithstanding the demands of this par- lower vertebrates embodying cellular groups in the ventral ticular facet of regulation involving pattern, the maintenance region proximate to the infundibular stalk, and the mammil- of constancy of the volume of the tissue fluids and also the lary bodies have connections, such as the mammillothalamic concentration of the total solutes in the body are of prime tract, as in higher mammals. The hypothalamus is large in these importance. The problems that land-dwelling organisms en- primitive forms relative