News Physiol Sci 15: 61-67, 2000;
1548-9213/00 $5.00
News in Physiological Sciences, Vol. 15, No. 2, 61-67,
April 2000
© 2000 Int. Union Physiol. Sci./Am. Physiol. Soc.
Interface Properties of Circumventricular Organs in Salt and Fluid Balance
Eckhart Simon
E. Simon is Professor and Head of the Physiology Department at Max-Planck-Institute for Physiological and Clinical Research, William G. Kerckhoff-Institute, D-61231 Bad Nauheim, Germany.
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Abstract
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The "sensory" circumventricular organs, with their leaky blood-brain barriers, permit contact between brain neurons and blood-borne molecules. Body fluid balance and cardiovascular control involve established interface functions of subfornical organs. Their recently identified target functions for hormones released during digestion suggest that they may coordinate fluid and food intake.
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Introduction
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Circulating hormones are known to affect central nervous control of various autonomic and neuroendocrine activities. The question, how these rather large molecules get access to their target neurons in the brain, is not a trivial one because the brain capillaries generally constitute a blood-brain barrier (BBB) that is impenetrable to many organic compounds and ions. The BBB is established by a continuous endothelium with a dense arrangement of glial processes on the brain side of the capillary basilar membrane. It normally protects the brain from potentially harmful constituents circulating in the blood. Passage across the intact BBB is biochemically and locally selective. Lipophilic messenger molecules may diffuse through the lipid bilayers of the endothelial cell walls. Several more polar compounds are transported across the BBB endothelia by specific molecular carriers. Transfer of most large molecules is only possible in several small structures, where the BBB is "leaky" due to fenestrated endothelial cells. Among these structures the posterior pituitary, median eminence, and pineal gland release neurohormones from specialized nerve endings into the bloodstream. Others serve as targets on which circulating agents act to influence brain functions and have been termed "‘sensory’ circumventricular organs" (CVOs) by Johnson and Gross (1993; cited in Ref. 7). The term CVO was originally coined to account for the topography of a number of functionally heterogeneous structures bordering the inner walls of the brain ventricles. The "lamina terminalis," i.e., the median section of the rostral wall of the third cerebral ventricle, is the site of location of two sensory CVOs involved in the control of salt and fluid balance. Ventrally, the organum vasculosum laminae terminalis (OVLT) lines the recessus supraopticus and is a site of osmoreception. Important as a target for circulating angiotensin II (ANG II), the subfornical organ (SFO) is located dorsal and caudal to the anterior commissure. Circulating osmoregulatory hormones, in particular antidiuretic hormone (ADH), are monitored by the third sensory CVO, the area postrema (AP), which is located at the dorsal surface of the medulla oblongata and bordered ventrolaterally by the nuclei of the solitary tract (NTS). The tight ependymal layer separating the ventricular cavities from the sensory CVOs and the arrangement of capillaries and neuroglial elements suggest that their neurons are positioned as targets for molecules carried with the blood stream (Fig. 1A
). Since CVOs are brain structures, their neurons are, in principle, interneurons. They not only send axons into, but also receive inputs from, other brain areas. Thus a sensory CVO bears an analogy to an "intelligent interface": it receives primary inputs (from the blood) and modulatory feedback inputs (from the brain), carries out signal processing by local intercellular (synaptic and/or humoral) interactions, and eventually sends its integrated output into the brain.
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FIGURE 1. Schematic histology of a sensory circumventricular organ (CVO; A) and modified presentations of data related to role of angiotensin (ANG) II in control of water and salt intake. A: sizes of capillaries (c) and arteriole (art) are exaggerated to show details. Capillaries are leaky because endothelial layer (indicated by black patches surrounding c) is fenestrated. Glial elements and tight ependymal layer that separates ventricular cavity (ventr) from interstitium of CVO are shown in light gray. Neurons are shown in dark gray; they may interact synaptically, and axons may enter from (in) or project toward (out) brain neurons. B: water intake of dogs stimulated by intravenously infused ANG II or 5% NaCl. Compared with dogs with an intact subfornical organ (SFO-c; hatched bars) SFO-lesioned dogs (SFO-x; closed bars) drink only in response to NaCl and not to ANG II. C: discharge rate of a rat SFO neuron recorded extracellularly in a slice preparation. ANG II and ANG I equally activate neuron. Upper traces show spike configurations at points of time during recording that are indicated by circled numbers. D: sodium-deprived sheep ingest sodium as a bicarbonate solution on control days (c, hatched bars) before and after a test day (t1 and t2,, closed bars). On test day t1, endogenous ANG II synthesis was blocked with converting enzyme inhibitor captopril (capt), causing reduced sodium intake. On test day t2, sodium intake was restored when captopril was combined with ANG II supplied by intravenous infusion. From Thrasher et al. (1982; cited in Ref. 7; B), Rauch and Schmid (1999; cited in Ref. 10; C) and Weisinger et al. (1987; cited in Ref. 3; D).
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This review deals with sensory CVOs primarily as targets for circulating messengers modulating central control of salt and fluid balance. Because this system is linked to the control of cardiovascular performance and ingestive behavior, these topics will be dealt with, inasmuch as they have contributed to the elucidation of the principles underlying receptive CVO functions. Their interconnections with major integrative brain nuclei and with neuronal and neuroendocrine efferent systems have been reviewed in detail by Gross (1987; cited in Ref. 7). The role of the OVLT in the generation of fever (2) is, however, an example for target functions of sensory CVOs in the control of further, physiological and pathophysiological, autonomic adjustments.
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Historically, the SFO is the foremost sensory CVO discovered as a target for ANG II
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Renin, a kidney-derived enzyme, liberates from angiotensinogen, a circulating protein synthetized by the liver, the precursor decapeptide angiotensin I (ANG I), which is converted into the active octapeptide ANG II by the ubiquitous ANG I-converting enzyme (ACE). This cascade is termed the renin-angiotensin system (RAS). Production of renin in the macula densa of the nephron, and ultimately of ANG II, is increased when renal blood flow, nephron perfusion, or NaCl delivery to its distal segment is reduced and, further, by sympathetic/adrenergic stimulation, i.e., typically under conditions of reduced circulatory filling, whatever the reason may be. This state requires, as an immediate response, the maintenance of arterial pressure by arteriolar constriction and by an increase in heart rate, if necessary, to keep cardiac output sufficiently high, and subsequently requires the restitution of the extracellular fluid (ECF) volume by reducing the outputs of salt and water and by increasing salt and water ingestion. Acting on targets in the periphery, ANG II contributes to the immediate response by its vasoconstrictor action, and it supports ECF conservation by stimulating the adrenal cortex to secrete aldosterone, which increases sodium reabsorption in the nephron. The central ANG II action discovered first was stimulation of thirst as a response to expand ECF volume by water ingestion.
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The SFO mediates thirst stimulation by high levels of circulating ANG II
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How the SFO as a central ANG II target was discovered illustrates the progress of experimental strategies establishing, for the first time, the sensory function of a CVO: intravenous vs. intracarotid ANG II injections revealed a stronger dipsogenic efficiency of the latter route of application; SFO lesions most effectively impaired the dipsogenic action of circulating ANG II (Fig. 1B
); and intracranial ANG II microinjections were most dipsogenic if they involved the SFO (4). As supplementary histochemical evidence, the rat SFO was shown to exhibit enhanced expression of an immediate early gene product, the Fos protein, after intravenous infusion of ANG II (9). According to Sanvitto et al. (1997; cited in Ref. 1), severe dehydration upregulates ANG II receptor density and its mRNA, but even moderate dehydration was shown to increase the mRNA signal for the AT1A subtype of the ANG II receptor (1), which drives the inositol-trisphosphate/diacylglycerol/calcium (IP3/DAG/Ca2+) second messenger system (Gebke et al., 1998; cited in Ref. 1), as is typical for the mammalian brain. As the electrophysiological correlate, ANG II exerted an exclusively excitatory action on a majority (~75%) of the SFO neurons, and patch-clamp studies identified inactivation of potassium channels as the underlying mechanism, similar to neurons excited by ANG II in other brain regions (13).
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Circulating vs. intrinsic brain ANG II: a challenge for the SFO as a relevant ANG II target
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The existence of the intrinsic brain RAS (RASB) is well documented. According to Bunnemann et al. (1993; cited in Ref. 4), all steps, from precursor synthesis to ANG II formation, are accomplished by neuroglial elements, including the synaptic release of ANG II as a neuropeptide, and ANG II histochemistry and ANG II receptor autoradiography have shown that "angiotensinergic" neurons and their target cells constitute a network extending throughout the entire brain stem. In CVOs, RAS and RASB may interact, since brain enzymes analogous to ACE may locally generate ANG II from circulating ANG I. Indeed, ANG II and ANG I infused intravenously are similarly dipsogenic in the rat, and even in an in vitro slice preparation of the rat SFO, ANG II and ANG I are equally effective in exciting the same SFO neuron (Fig. 1C), both actions being equally inhibited by losartan, a specific blocker of the AT1 receptor (10).
According to microinjections of ANG II analogs and blockers on the brain side of the BBB, the RASB participates in the activation of thirst and salt appetite (4) and activates cardiovascular sympathetic innervation and ADH release [Fitzsimons (1980a); cited in Ref. 4], i.e., it mediates the full pattern of measures to counteract reduced ECF filling. The coincident actions of ANG II on either side of the BBB have raised questions as to whether or not each route of access to brain structures is physiologically relevant. Skeptics may consider thirst stimulation by circulating ANG II as a mere emergency reaction to excessive ANG II blood levels. Indeed, distinct drinking responses are elicited mostly (but not exclusively) by raising circulating ANG II to levels in the high physiological range or higher. Proponents of a physiological role of only brain-intrinsic ANG II are in the comfortable position of arguing that the similarly high or even higher ANG II concentrations necessary to elicit drinking or other responses by intracranial injections may be locally attained where ANG II is released as a central nervous intercellular messenger. Since angiotensinergic neurons innervate CVOs, it may even be argued that high systemic ANG II doses might just mimic what is induced physiologically by local synaptic ANG II release, an argument that cannot be rebutted a priori. Thus the pros and cons provided by convergent lines of evidence from different experimental approaches have to be balanced carefully before statements proclaiming or rejecting the physiological role of the SFO, and of the CVOs in general, as targets for circulating ANG II or for its precursor ANG I, which may be converted locally into ANG II.
Stimulation of salt appetite by circulating ANG II acting on CVOs, indeed, required an imaginative experiment to demonstrate it clearly (Fig. 1D). It proceeded from the state of chronic sodium deficiency in sheep which, as ruminants, produce large amounts of saliva, rich in sodium, that is normally swallowed with the food. The sheep were made sodium deficient by means of an outward parotid fistula that led to chronic saliva loss. In this condition, plasma ANG II was elevated and the sheep preferred to drink sodium bicarbonate solution instead of water to compensate for the sodium loss. Inhibition of endogenous ANG II formation by treating the animals with an ACE blocker reduced sodium bicarbonate ingestion. Although the ACE blocker may well have suppressed both systemic and brain-intrinsic ANG II formation, it was found that ANG II applied intravenously, but not when injected into the brain ventricles, reestablished sodium bicarbonate drinking. Consequently, an ANG II target on the blood but not the brain side of the BBB must have been involved.
Antidiuresis due to enhanced release of ADH is a consistent response to ANG II when microinjected into hypothalamic structures or forebrain ventricles. Stimulation of ADH release by circulating ANG II is more difficult to demonstrate, due to the direct vasoconstrictor action of ANG II and the resulting rise in arterial blood pressure (Part), which, according to Reid et al. (1982; cited in Ref. 4), activates the baroreceptor reflex and thereby inhibits ADH release. To meet this difficulty in experiments on conscious dogs, the rise in Part during intravenous infusion of ANG II was pharmacologically balanced by coinfusing a vasodilatatory agent. In this condition, ANG II infused intravenously greatly elevated plasma ADH, and the well-known inverse relationship between Part and ADH plasma concentration was shifted to much higher pressure levels as a consequence of the ANG II-induced facilitation of ADH release (Fig. 2A).
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FIGURE 2. Modified presentations of data demonstrating central actions of plasma ANG II and plasma hyperosmolality on antidiuretic hormone (ADH) and osmotic thirst. A: closed circles show plasma arginine vasopressin (AVP) concentration in conscious dogs as a function of arterial pressure (Part) elevated by an intravenous infusion of ANG II but subsequently reduced to normal by intravenous coinfusion of vasodilatator sodium nitroprusside (SNP). Closed triangles show lowering Part in control dogs to subnormal values by infusing SNP alone, which produces a much smaller increase in plasma AVP than in combination with ANG II. Open symbols represent corresponding pre-/postinfusion relationships. B, left: plasma AVP rises above control (contr) when hypertonic NaCl solution is infused intravenously in dogs with intact organum vasculosum laminae terminalis (OVLT-c, hatched bars). OVLT lesioning (OVLT-x, closed bars) abolishes response. At right (shaded background), OVLT-x similarly attenuates drinking response to hypertonic NaCl. From Szczypaczewska et al. (1993; cited in Ref. 7; A) and Thrasher et al. (1982; cited in Ref. 7; B).
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Salt gland secretion is a specific osmoregulatory response of marine or estuarine birds exposed to high salt intake and limited access to fresh water (5). The parasympathetically driven glands are located in the orbital cavities and secrete almost pure NaCl solution at a concentration that may exceed that of seawater. Besides naturally adapted birds, the domestic duck adapted to hypertonic saline as drinking fluid is a suitable animal model. Birds in this condition are at risk of water deprivation and temporarily experience hyperosmolality in combination with reduced ECF, by which large increases in ANG II plasma levels are stimulated. Butler et al. (1989; cited in Ref. 5), confirmed that rising plasma ANG II acted centrally as an inhibitor of salt gland secretion, probably as a means to maintain ECF volume even at the expense of a further rise in osmolality. In the salt-adapted duck, Gerstberger et al. (1987; cited in Ref. 5) identified upregulation of ANG II binding and Matsumura and Simon (1990; cited in Ref. 5) found increased neuronal ANG II sensitivity as evidence for the target function of SFO neurons. However, Gerstberger et al. (1984; cited in Ref. 5) had also shown that ANG II microinjections into the third cerebral ventricle of salt-adapted ducks inhibited salt gland secretion. Thus, in addition to circulating ANG II, the RASB is a further inhibitory component in central nervous salt gland control.
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The OVLT is involved in salt and fluid balance, but its specific functions are not well defined
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Osmoreception by the OVLT and the adjacent anteroventral third ventricular region follows from the observation that increases in water intake and ADH release, as typical responses to increased body fluid osmolality, are attenuated if these structures are lesioned (Fig. 2B). How signals are generated by the presumed osmosensors of the OVLT has remained enigmatic, mostly because its small neurons are difficult to analyze. Transduction by stretch-sensitive cation channels similar to those found in the magnocellular neurons producing ADH (3) is a possibility, but the functional properties of OVLT neurons seem to be generally peculiar. This is indicated by their presumed function as targets for circulating pyrogens (2) and, with respect to salt and fluid balance, by the properties of their receptors for ADH. When the responsiveness of rat OVLT neurons to the mammalian ADH, arginine vasopressin (AVP), was studied in primary cell cultures, each AVP-responsive neuron revealed V1 receptor properties when tested with a specific blocker (7). In addition, however, about one-third were influenced by the specific V2 agonist dD-AVP, suggesting a transduction mechanism involving adenylate cyclase, and Jurzak and Gerstberger (1995; cited in Ref. 7) showed that dD-AVP unexpectedly induced a rise in cytosolic calcium, as is typical for the V1 receptor-coupled IP3/DAG/Ca2+ second messenger system. The physiological significance of this rather unusual AVP responsiveness of OVLT neurons is presently obscure, but since the AVP threshold concentration is in the subnanomolar range, it might constitute a feedback of plasma AVP on central control activities.
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The AP mediates AVP-induced baroreflex resetting: a paradigmatic role for a sensory CVO
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Increases in ECF tonicity and major body fluid losses stimulate the secretion of ADH, which is produced by the magnocellular neurons of the supraoptic nuclei (SON) and paraventricular nuclei (PVN) in the anterior hypothalamus and transported axonally to the posterior pituitary, where it is released into the pericapillary space from modified nerve endings. ADH release is controlled by two major opposing afferent inputs. Stimulatory osmosensor signals originate in the magnocellular neurons themselves and are further provided by OVLT neurons and possibly by additional periventricular osmosensors [Korf et al. (1982) and Kanosue et al. (1990), cited in Ref. 5] and vagal osmosensory afferents. Inhibitory signals originate from vagal/glossopharyngeal afferents carrying the signals from the arterial (high pressure) baroreceptors and from the distension (low pressure) receptors in the walls of the intrathoracic veins and the atria that serve to monitor blood volume.
In the periphery, the main targets for ADH are the nephrons in the kidney. In mammals, AVP acts on the V2 receptor subtype to enhance the water permeability of the collecting ducts. The potent vasoconstrictor action of AVP in mammals is mediated by the V1 receptor subtype of the vascular smooth muscle cells but is not readily perceptible in the range of normal plasma levels.
Central actions of circulating AVP in mammals were first recognized indirectly. As summarized by Cowley and Liard (1987; cited in Ref. 7) arterial pressure rose more sensitively and steeply with increasing AVP doses when the high- and low-pressure receptor afferents were severed and even more so when access of AVP to the brain was totally prevented. The central action of circulating AVP was shown to consist of baroreflex potentiation, leading to enhanced bradycardia and inhibition of sympathetic cardiovascular innervation. Undesser et al. (1985; cited in Ref. 7) provided evidence in lesioning studies that the AP was, indeed, the site of AVP action involved. The presence of AVP receptors, mostly of the V1 subtype (7), in the AP corresponds to its function as an AVP target.
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Sensory CVOs are sites of convergence for different humoral messengers to the brain
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The OVLT is known to serve as a target for body fluid properties as different as osmotic pressure and circulating pyrogens, suggesting the general possibility of a wide scope of body-to-brain interface functions of sensory CVOs. Consequently, studies of CVOs might provide new insights into a multitude of coordinating interactions of endocrine and humoral factors with central nervous control activities. Recent studies of the SFO and AP illustrate the successes, but also the experimental difficulties, in substantiating these expectations.
In the SFO, the foremost sensor of hormonal thirst stimulation, the presence of molecular receptors other than for ANG II initiated the analysis of their functions. Receptors for natriuretic peptides seem to mediate their mostly antagonistic central interference with ANG II [Schütz et al. (1992b); cited in Ref. 5]. Expression of receptors for calcitonin gene-related peptide (CGRP) in the SFO would primarily suggest a local modulatory influence of this widespread neuropeptide. However, in the SFO, receptors related to but different from those for CGRP (12) specifically bind two circulating CGRP-related peptides, exciting fractions of SFO neurons comparable to those stimulated by ANG II and at similar concentrations: calcitonin (CT), which is secreted by thyroid parafollicular cells, supports calcium fixation; and amylin, which is cosecreted with insulin by the ß-cells of the pancreatic islets, antagonizes some of the peripheral insulin actions. Since the secretion of both hormones is enhanced after a meal and during digestion, it is suggestive of the idea that their action on the SFO might be responsible, at least in part, for the well-known link between food intake and what its termed "postprandial drinking." The assumption that CT (14) and amylin [Riediger et al. (1999); cited in Ref. 12] might stimulate water intake in a way analogous to ANG II was, indeed, confirmed in the rat. Figure 3A presents the dipsogenic CT action as an example and further shows that the drinking response to CT was not abolished by blocking the effective ANG II receptor, and, likewise, it shows that the dipsogenic action of amylin also remained unaffected. The similar dose-response relationships for ANG II and these peptides at the neuronal level are illustrated for CT in Fig. 3B. Apparently, CT and amylin act directly as dipsogens and not indirectly by influencing the peripheral RAS or the RASB. That several circulating hormones may act in concert to control fluid intake is a new insight relieving the doubts about the relevance of circulating hormones for thirst stimulation that are raised by the rather high threshold concentrations found when ANG I, ANG II, CT, amylin, and possibly other, still-unknown messengers are tested separately.
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FIGURE 3. Modified presentations of data indicating links established by CVOs between food and fluid intake. A: drinking is stimulated in rats by subcutaneous injection of calcitonin (CT) compared with controls (contr). AT1 receptor antagonist losartan (Los) does not change water intake per se and does not abolish drinking in response to CT (CT+Los). B: neuron of a rat SFO recorded extracellularly in a slice preparation is equally excited by ANG II and CT. Insets: dose-response relationships for ANG II and CT. C: same kind of recording from a rat area postrema (AP) neuron shows activation by amylin and, in inset, dose-response relationship. D, left: cumulative food intake of rats during 1 and 2 h of observation after intraperitoneal control injection of saline (open bars) or amylin (hatched bars) when AP is intact (AP-c). Right: when same experiment is carried out in AP-lesioned rats (AP-x), anorectic effect of amylin is abolished. A and B are from Ref. 14, C is from Ref. 11 and unpublished observations, and D is from Ref. 8.
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The water-conserving renal actions of ADH plausibly suggest that it might stimulate water intake as well, acting on a CVO. However, experimental evidence in mammals has remained equivocal (7). Assuming that the SFO might be involved as a target, its neuronal responsiveness was studied in vitro on rats. However, Anthes et al. (1997; cited in Ref. 7) showed that AVP, unlike ANG II and the other dipsogenic hormones, excited and inhibited minor and equal fractions of SFO neurons. On the other hand, a comparative study by Schmid et al. (1995; cited in Ref. 7) on the duck SFO showed that the avian ADH, arginine vasotocin (AVT), as well as AVP, uniformly excited a large fraction of neurons in vitro, and Schmid and Simon (1996; cited in Ref. 7) found that intravenous infusion of AVT in conscious, normally hydrated ducks indeed stimulated water intake. However, even for the duck, circulating ADH may be excluded as a physiological dipsogen because of the high AVT doses required to induce drinking. They might rather mimic local actions of ADH released synaptically from vasopressinergic/vasotocinergic nerve endings that were shown to enter the SFO from the brain in both mammals and birds. In the duck, the uniformly excitatory action of this input might provide a facilitatory drive for neurons receiving a hormonal, thirst-stimulating message, whereas in mammals, the same input seems to exert a more complex modulatory action.
The AP serves as a multifunctional chemoreceptor organ [Borison (1989); cited in Ref. 7] and is involved, at least as an integrative structure, in the control of sodium and fluid intake [Miselis et al. (1987); cited in Ref. 7]. It further seems to mediate attenuation by circulating ANG II of cardiovascular baroreflex control in mammals, opposite to the influence of AVP. This follows from arterial hypertension with little, if any, bradycardia, which is observed as a central effect of circulating ANG II. As summarized by Bishop and Hay (1993; cited in Ref. 7), the involvement of the AP was clearly shown for dogs, whereas studies on rats were less conclusive. In view of the consistently hypertensive action of ANG II observed in both mammals and birds, when it acts on the brain side of the BBB, and of evidence for the SFO and perhaps the OVLT as additional targets for centrally mediated hypertensive ANG II actions in mammals, the specific contribution of the AP is difficult to define. Most notable is the observation of Fink et al. (1987; cited in Ref. 7) that certain chronic effects of long-term intravenous infusion of ANG II, like progressive arterial hypertension in rats and enhanced sympathetic activity, after initial depression, in rabbits, were abolished by AP ablation. Electrophysiological analysis has, so far, helped little to elucidate the neuronal basis of the opposing ANG II and AVP actions, because each hormone excited as well as inhibited part of the AP neurons and the relationship between inhibition and excitation depended on the presence of synaptic interconnections. Hegarty et al. (1996; cited in Ref. 7), carried out an in vivo analysis of NTS neurons, on which primary and secondary baroreceptor inputs as well as inputs from AP neurons converge, and found parallel rather than opposite effects of intravenous infusions of ANG II and AVP, contrary to what would be expected. The authors concluded that the mixed influence of these peptides does not clearly correlate with the reported attenuation and enhancement of the baroreflex by circulating ANG II and AVP, respectively.
Encouraging in their consistency, though, are recent data in support of the AP as a target for a functionally quite different peptide, amylin. Recordings in vitro from rat AP neurons showed that they responded very sensitively with excitation to amylin in a dose-dependent manner (Fig. 3C). Most interesting was a high degree of congruence between amylin sensitivity and the excitatory action of glucose on the same AP neuron (11). Considering that amylin may stimulate water intake by acting on the SFO and inhibit food intake by acting on the AP (8), according to lesioning experiments (Fig. 3D), these new data seem to have revealed an additional level of autonomic coordination based on functional links, in this case between satiety and thirst, that are established by two distant and differently connected sensory CVOs as targets for the same messenger.
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Perspectives
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In this review, emphasis has been placed on exemplary roles of sensory CVOs in salt and fluid balance and related control systems. There is ample evidence that other homeostatic functions are also under the control of signals generated by CVOs. Moreover, the function of one CVO may be shared, perhaps with a different response profile, by another CVO. In effect, sensory CVOs are important as sites of convergence for a multitude of circulating messengers that inform the brain about what is going on humorally in the body. Information to the brain that is transduced by a sensory CVO is modulated in the CVO itself by local neuronal interactions and by neurons entering the CVO from the brain. Therefore, knowledge about CVO interconnections [Gross (1987); cited in Ref. 7] is essential. Promising in this respect are recently developed neurotropic toxin and viral tracing techniques (6).
Studies of CVOs as targets for a particular circulating messenger have to consider that the same messenger may be intrinsic to the brain. This applies to ANG II and is a possibility for ADH and for CGRP as a functional analog of CT and amylin. To deal with this problem, microinjection and lesioning techniques have to be adapted to the smallness of the CVOs. Combining these methods with electrophysiological and histochemical analyses may help in attaining a degree of (in)consistency of the data to permit supporting or rejecting the idea of a putative interface function of a particular CVO for a particular hormone.
The comparative analysis of CVOs as targets has shown that a particular function may be dominant in one species or class but weakly represented, or even virtually nonexistent, in other species or classes. This caveat has to be observed generally in the analysis of autonomic control, as exemplified by the role of the hypothalamus as a thermosensor (15). Thus conclusions based on even the most convincing set of data obtained in one species in vivo or in vitro, and even more so in primary cell cultures or cultured cell lines, should be extrapolated only with caution.
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Introduction
Historically, the SFO is...
