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Neuroendocrine Control of Body Fluid Metabolism

Physiol Rev 84: , 2004; /physrev Neuroendocrine Control of Body Fluid Metabolism JOSÉ ANTUNES-RODRIGUES, MARGARET DE CASTRO, LUCILA L. K. ELIAS, MARCELO M. VALENÇA, AND SAMUEL
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Physiol Rev 84: , 2004; /physrev Neuroendocrine Control of Body Fluid Metabolism JOSÉ ANTUNES-RODRIGUES, MARGARET DE CASTRO, LUCILA L. K. ELIAS, MARCELO M. VALENÇA, AND SAMUEL M. McCANN Departments of Physiology and Internal Medicine, School of Medicine of Ribeirao Preto, University of São Paulo, Ribeirao Preto, São Paulo, Brazil; and Pennington Biomedical Research Center, Department of Basic Sciences, Louisiana State University, Baton Rouge, Louisiana I. Introduction 170 II. Vasopressin and Oxytocin Effects on Water Metabolism 171 A. The hypothalamo-neurohypophysial system 171 B. Osmotic control of vasopressin release 172 C. Volume control of vasopressin release 174 D. Vasopressin and oxytocin receptors 175 E. Actions of vasopressin and oxytocin 176 III. The Renin-Angiotensin System in the Brain 177 A. General aspects of the brain angiotensin system 177 B. Functions of brain angiotensin in thirst 178 C. Functions of brain angiotensin in salt intake 179 D. Angiotensin receptors 180 E. Interactions with other hormones 180 IV. Autonomic Nervous System and Body Fluid Metabolism 181 A. Role of the sympathetic nervous system innervation of the kidney in sodium excretion 181 B. CNS regulation of the renal sympathetic nerve activity 182 C. Role of -adrenergic and cholinergic receptors in control of natriuresis 182 V. The Neuroendocrine Regulation of Atrial Natriuretic Peptide Secretion 183 A. Control of hydromineral balance by a brain neural circuit 183 B. CNS neurotransmitters/neuromodulators and modulation of hydromineral homeostasis 184 C. Natriuretic hormones and hydromineral balance 186 D. The brain ANPergic neurons in water and salt intake 187 E. The brain ANP system in the control of cardiovascular and renal functions 188 F. Afferent inputs to the brain ANPergic system 188 G. Role of the brain in ANP release in response to increased extracellular [Na ] and acute blood volume expansion 189 H. Efferent pathways of the CNS and the cardiac release of ANP 190 VI. Interaction Between Neurohypophysial Hormones and Atrial Natriuretic Peptide 190 A. Effects of oxytocin on the release of ANP from the heart 190 B. Effects of vasopressin on cardiac function 191 C. Actions of oxytocin and vasopressin in the kidney 192 VII. Conclusions and Perspectives 192 Antunes-Rodrigues, José, Margaret de Castro, Lucila L. K. Elias, Marcelo M. Valença, and Samuel M. McCann. Neuroendocrine Control of Body Fluid Metabolism. Physiol Rev 84: , 2004; / physrev Mammals control the volume and osmolality of their body fluids from stimuli that arise from both the intracellular and extracellular fluid compartments. These stimuli are sensed by two kinds of receptors: osmoreceptor-na receptors and volume or pressure receptors. This information is conveyed to specific areas of the central nervous system responsible for an integrated response, which depends on the integrity of the anteroventral region of the third ventricle, e.g., organum vasculosum of the lamina terminalis, median preoptic nucleus, and subfornical organ. The hypothalamo-neurohypophysial system plays a fundamental role in the maintenance of body fluid homeostasis by secreting vasopressin and oxytocin in response to osmotic and nonosmotic stimuli. Since the discovery of the atrial natriuretic peptide (ANP), a large number of publications have demonstrated that this peptide provides a potent defense mechanism against volume overload in mammals, including humans. ANP is mostly localized in the heart, but ANP and its receptor are also found in hypothalamic and brain stem areas involved in body /04 $15.00 Copyright 2004 the American Physiological Society 169 170 ANTUNES-RODRIGUES ET AL. fluid volume and blood pressure regulation. Blood volume expansion acts not only directly on the heart, by stretch of atrial myocytes to increase the release of ANP, but also on the brain ANPergic neurons through afferent inputs from baroreceptors. Angiotensin II also plays an important role in the regulation of body fluids, being a potent inducer of thirst and, in general, antagonizes the actions of ANP. This review emphasizes the role played by brain ANP and its interaction with neurohypophysial hormones in the control of body fluid homeostasis. I. INTRODUCTION The precise regulation of the volume and osmolality of body fluids is fundamental to survival. Sodium chloride (NaCl) represents an important constituent of the extracellular compartment and is the major determinant of the plasma osmolality as well as extracellular fluid volume. All vertebrates maintain plasma osmolality and extracellular volume primarily by regulating the ingestion and urinary excretion of water and electrolytes. For example, such animals develop a special behavioral sensation, thirst, that is defined as a need or desire to drink that leads the animal to increase water intake. An elevation in the plasma osmolality, and consequent cellular dehydration, is the most potent stimulus of thirst. In mammals, a minimal increase in the plasma osmolality of 1 2% induces thirst. A decrease in the extracellular fluid volume, although less effective, is also capable of generating thirst. A 10% reduction in blood volume or in arterial pressure both will induce an animal to drink water. Sodium intake occurs later, but initially the animal looks for water. Several other conditions can induce thirst, independent of changes in volume or plasma osmolality, e.g., dry mouth and breathing dry air. However, oral ingestion of water produces only a transient satiation of thirst. Because animals with esophageal or gastric fistulae are not satiated by peroral water ingestion but only by replacing the deficit through the fistula, it is apparent that absorption of water into the bloodstream also is required for satiation (for review, see Refs. 17, 18, 110, 111, 153, 254, 257, 335, 344, 371, 547, 549). The classic studies of Verney (537) introduced the concept of effective osmolality (i.e., increased extracellular osmolality induced by solutes that do not cross the cell membrane) and the presence of osmoreceptors involved in arginine vasopressin (AVP) release in response to increased osmolality. Andersson, McCann, and co-workers (9 13) postulated that an osmoreceptor was a sodium sensor located in brain regions within the blood-brain barrier, and it could be involved in the control of sodium appetite as well as in the control of sodium excretion in response to changes in brain extracellular fluid sodium concentration. It is accepted that in the genesis of thirst there is an important role for osmoreceptor-na receptor cells located in the circumventricular organs (CVO) of the anterior aspect of the third ventricle. These structures contain sensory cells that respond to variations in the plasma osmotic pressure or the sodium concentration of plasma and cerebral spinal fluid (CSF). It should be pointed out that equiosmolar NaCl hypertonic solution is a more effective stimulus than nonsaline hypertonic solutions (345). Lesions in the region of the anteroventral portion of the third ventricle (AV3V), involving the ventral part of the median preoptic nuclei (MnPO), induce permanent or temporary adipsia (13, 65, 305). Sodium receptors have been demonstrated also in afferent neural terminals adjacent to the hepatic, renal, and intestinal vessels. Liver receptors are activated by an increase in [Na ]inthe portal vein, augmenting hepatic afferent vagal inputs to the nucleus of the solitary tract (NTS) that generate efferent signals increasing renal sodium excretion, and concomitantly decreasing intestinal sodium absorption (230). In some species, such as the rat, increased production and release of angiotensin II (ANG II) into the systemic circulation mediates thirst in response to a reduction in the extracellular volume. Central nervous system (CNS)-generated ANG II is also an important thirst inducer, acting as a neurotransmitter on ANG II-sensitive neurons in brain structures such as the subfornical organ (SFO) or organum vasculosum of the lamina terminalis (OVLT), both of which are CVO of the lamina terminalis. ANG II may be the mediator of the thirst induced by hypertonic saline (2% NaCl) microinjected into the cerebral ventricle (in rat, mouse, sheep, and rabbit), since the dipsogenic effects can be decreased by the previous administration of losartan, an AT 1 ANG II receptor antagonist (337, ). In addition, Franci et al. (171) demonstrated that dehydration-induced drinking could be blocked by injection of ANG II antiserum in the third ventricle of male rats. It is known that when water is offered to a waterdeprived animal, it will begin drinking within 3 10 min and continue until the thirst is satiated. Interestingly, the process of thirst satiation commences even before plasma osmolality is normalized; thus, even while plasma osmolality has not been corrected, the volume of water drunk usually is the amount needed to return osmolality to normal. This may occur through stimuli originating in the mouth, pharynx, or stomach and conveyed by afferent impulses to CNS structures involved in the integrative response. During the last four decades a number of studies have attempted to identify brain areas specifically involved in satiety, regulation of plasma osmolality, water/ electrolyte ingestion, and excretion. The first studies to NEUROENDOCRINE CONTROL OF BODY FLUID METABOLISM 171 determine the synaptic transmitters in the CNS circuits that control body fluid homeostasis were published in the 1960s by Grossman (197, 198). He demonstrated that hypothalamic cholinergic or noradrenergic stimulation induced an increase in water or food intake. Cholinergic and angiotensinergic stimulation of the AV3V region caused a rapid increase in water intake in normal hydrated animals, as well as increased natriuresis (21, 152, 155, 197). Intracerebroventricular (icv) injection of carbachol (a cholinergic agonist) also evoked dramatic natriuretic, kaliuretic, and antidiuretic responses similar to the effects observed with central (icv) injection of hypertonic saline (121). Thus it became clear that both -adrenergic and cholinergic synapses are involved in the control of both natriuresis and kaliuresis. Microinjection of agonists and antagonists of these neurotransmitters into the septal area, AV3V, or the third ventricle altered the natriuretic, kaliuretic, and carbachol-induced antidiuretic responses (72, 73, 120, 170, 172, 351, 365, 431, 432, 443, 444). Phentolamine, an -adrenergic antagonist, abolished the natriuretic response to third ventricle injection of hypertonic saline, norepinephrine, or carbachol. Meanwhile, isoproterenol, a -adrenergic agonist, exhibited an antinatriuretic and antikaliuretic effect. In contrast, propranolol, a -receptor blocker, induced natriuresis and kaliuresis when injected alone and also potentiated the natriuretic response to carbachol. Cholinergic blockade with atropine decreased the response to norepinephrine and blocked the natriuretic response to hypertonic saline (365, 366, 399). The lamina terminalis is a forebrain structure that contains the SFO, the MnPO, and the OVLT. The AV3V includes the ventral part of the MnPO and the OVLT. The AV3V and SFO region contains neurons that are sensitive to changes in plasma or CSF osmolality (50, 207, 340, 384, 385, 386), and these cells have direct connections with the paraventricular nucleus (PVN) (204, 356, 480, 550). Also, a direct connection from the region of the lamina terminalis to the raphé nuclei and locus ceruleus (LC) has been described (483). These connections appear to be important to induce the hormonal, sympathetic nervous system, and behavioral changes that restore the body fluid balance as described below. Sly et al. (482) demonstrated a polysynaptic pathway connecting neurons in the brain areas controlling body fluid balance to the kidney, by injecting the Bartha strain of pseudorabies virus into the kidney of rats. The application of this neurotropic virus resulted in retrograde infections, which permitted the identification of higher order neurons (putative third and fourth order) in regions of the forebrain including the OVLT, MnPO, SFO, bed nucleus of the stria terminalis, anteroventral periventricular nucleus, medial and lateral preoptic area, supraoptic nucleus (SON), retrochiasmatic nucleus, primary motor cortex, and the visceral area of the insular cortex. Renal innervation (considered to be entirely sympathetic) participates in the control of three aspects of renal function: renal blood flow, tubular reabsorption of electrolytes, and renin secretion. Thus renal sympathetic nerves regulate the function of the vasculature, the tubules, and the juxtaglomerular granular cells that, following activation of -adrenergic receptors, cause an increase in renin secretion rate and renal blood flow and a reduction in urinary sodium excretion (115, 116). In summary, mammals control the volume and osmolality of their body fluids in response to stimuli that arise from both the intracellular and extracellular fluid compartments. These stimuli are sensed by two kinds of receptors: osmoreceptor-na receptors (plasma osmolality or sodium concentration) and volume or pressure receptors. This information is conveyed to specific areas of the CNS responsible for an integrated response, which is dependent on the integrity of the AV3V (OVLT and MnPO) and SFO. In addition, the PVN, SON, LC, dorsal raphé nuclei (DRN), and the lateral parabrachial nuclei, among others, also represent important structures involved in hydromineral balance. Such structures, once stimulated, can determine responses that involve 1) the induction of thirst, salt appetite, or both; 2) changes in sympathetic activity; 3) activation of the renin-angiotensin-aldosterone system; or 4) secretion of AVP and oxytocin (OT) from the neurohypophysis and natriuretic peptides from the heart. II. VASOPRESSIN AND OXYTOCIN EFFECTS ON WATER METABOLISM A. The Hypothalamo-Neurohypophysial System The hypothalamo-neurohypophysial system is located in the medial part of the anterior hypothalamus and comprises the paired PVN on each side of the dorsolateral wall of the third ventricle and the paired SON. The perikarya of the magnocellular neurons responsible for the synthesis and release of OT and AVP are located in both the PVN and SON (292). The PVN contains a preponderance of OT neurons and the SON a preponderance of AVP neurons. The axons of these neurons form the hypothalamo-hypophysial tract, which terminates in the neurohypophysis. Some of these axons terminate in the median eminence in juxtaposition to the capillaries of the hypophysial portal veins, whereas most terminate in the neural lobe (32, 66, 214, 424). The AVP and OT released in the median eminence are transported by the hypophysial portal vessels to the anterior lobe of the pituitary gland where they act to stimulate the release of ACTH and prolactin, respectively (333, 334, 336). The AVP and OT released from the neural lobe are in part transported by the short portal vessels to the anterior lobe, and the blood from both lobes empties into the hypophysial veins to return to the heart (409). 172 ANTUNES-RODRIGUES ET AL. OT and AVP are synthesized and released by magnocellular neurosecretory neurons classified into AVP- and OT-producing subtypes. Recent evidence from qualitative RT-PCR experiments on single cells confirms the fact that the majority of magnocellular neurons coexpress both peptide mrnas. Furthermore, there is some OT and AVP mrna coexpression in virtually all of the magnocellular neurons in the SON of the hypothalamus (559). However, because PCR grossly magnifies the mrna content, it is clear that most of these neurons express only one of these peptides at a functionally significant level. Changes in the firing pattern and frequency of magnocellular neurons in response to relevant physiological stimuli regulate the circulating levels of their secreted hormones (196, 424). The electrophysiological profiles of OT and AVP neurons can be distinguished from each other, and from that of neurons in the immediately adjacent perinuclear zone (33). Oxytocinergic neurons possess properties that favor the production of short spike trains, which are enhanced during lactation (289, 492). In contrast, vasopressinergic magnocellular neurons in the hypothalamus exhibit phasic electrical activity that depends on intrinsic membrane properties and is influenced by extrinsic factors such as plasma osmolality, blood volume, and pressure (for review, see Ref. 32). OT and AVP, released from the soma and dendrites of neurons, bind to specific autoreceptors and induce an increase in intracellular [Ca 2 ]. In OT cells, the increase in [Ca 2 ] results from a mobilization of Ca 2 from intracellular stores, whereas in AVP cells, it results mainly from an influx of Ca 2 through voltage-dependent channels (99, 191). A selective afferent neural input to the vasopressinergic neurons provides a mechanism for the release of AVP independently of OT in response to appropriate physiological stimuli. Two alternative models of the neural pathways and transmitters involved in the activation of the supraoptic hypophysial tract have been suggested. Some authors have suggested the existence of an excitatory relay through a cholinoceptive area on the ventral surface of the brain stem that has been termed the nicotine-sensitive area because topical application of nicotine to this area in the cat causes the release of AVP without OT (51). Afferent input from a noradrenergic projection from the NTS to the SON has also been demonstrated (102, 553). With the use of combined retrograde tracerimmunofluorescence methods, OT and AVP neurons in the SON and PVN were shown to receive noradrenergic innervation that arises mainly from A1 neurons in the ventrolateral medulla (457). Furthermore, an inhibitory relay was demonstrated through the A1 group of noradrenergic neurons on the ventral surface, which selectively innervate the AVP-secreting neurons in the SON. This model implies an inhibitory role for norepinephrine acting on - or 2 -receptors and explains the antinatriuretic effect of -adrenergic receptor activation (72, 73, 365, 443). However, most investigations suggest an excitatory, rather than inhibitory, function of the A1 noradrenergic neurons involving 1 -receptors, consistent with the previously described stimulatory role of 1 -receptors in natriuresis (72, 73, 365, 443). The posterior magnocellular division of the PVN and SON is mainly innervated by the A1 noradrenergic cell group (93), and noradrenergic afferents have been shown to have a facilitatory role in the regulation of the activity of neurohypophysial AVP neurons (101, 102). The PVN receives a dense noradrenergic innervation from the A1 cell bodies of the caudal ventrolateral medulla, A2 cell bodies of the NTS, and A6 cell bodies of the LC. Noradrenergic neurons in the LC participate in the baroreflex activation of the diagonal band of Broca (195), which has been shown to be an integral component of the pathway regulating the baroreceptorinduced inhibition of AVP release and, possibly, the stimulation of OT release (94, 251). In addition, an inhibitory GABAergic pathway from the diagonal band of Broca preferentially innervates AVP-secreting SON neurons, supporting the view that the baroreflex-induced depression of SON firing may be mediated by GABA (252). B. Osmotic Control of Vasopressin Release The hypothalamo-neurohypophysial system plays a fundamental role in the maintenance of body fluid homeostasis by secreting AVP and OT in response to osmotic and nonosmotic stimuli (461). Microinjections of hypertonic saline into the AV3V area, the major central site for the regulation of body fluid composition, cardiovascular, and renal function, were first shown to induce an increase in water intake in goats by Andersson, Mc- Cann, and co-workers (9 13). These results
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