Body sodium and volume homeostasis.

MAINTENANCE OF A “MILIEU INTERIEUR,” which allows our cells to function away from the ancient sea, is one of the most important functions of the body. Maintenance of constant extracellular osmolarity and sodium concentration depends on a precise balance between intake and excretion of sodium and water. Intakes of water and sodium are governed by an urge driven by the lack of these substances, by habit, or by more or less wellfounded recommendations (43). Regulated excretion of the substances takes place mainly in the kidney. The aim of this “In Focus” article is to give a short overview of the regulation of body sodium and volume homeostasis, with an emphasis on recent developments, and focus on papers published in the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. Regulation of water and sodium intake. Variations in the composition of blood plasma are picked up in the brain by the small areas that lack a blood-brain barrier. These areas, the circumventricular organs, surround the ventricular system. Three of these are involved in body fluid homeostasis: the subfornical organ (SFO) and organum vasculosum laminae terminalis (OVLT), which are located in the anteroventral third ventricle, and the area postrema (AP), which is located at the transition of the fourth ventricle and the central canal of the spinal cord (12). Thirst. Hyperosmolarity is a strong stimulus for water intake. When exposed to hyperosmolality, osmoreceptor cells in the SFO and OVLT activate neurons projecting to the paraventricular nucleus (PVN) and supraoptic nucleus (SON) in the hypothalamus to stimulate thirst. The protooncogene c-Fos is an immediateearly response gene, which has become an excellent mapping tool to identify active cells in the nervous system. It is activated in response to a wide range of stimuli and its expression is barely detectable under basal conditions (18). Consistent with this, dehydration increased the expression of c-Fos in the OVLT, SFO, and SON in rats (11). Thirst is also induced by profound volume contraction, which is probably detected by stretch receptors in the heart (39). A fall in arterial blood pressure increases thirst in response to intracerebroventricular ANG II (41). Conversely, thirst is inhibited by increased arterial blood pressure, which is detected by arterial baroreceptors (36) and inhibits thirst induced by ANG II infusion, hypovolemia, or hyperosmolarity (35). ANG II is a strong dipsogenic agent. Circulating ANG II stimulates AT1 receptors in the SFO of rats (39), and intracerebroventricular injection of ANG II stimulates c-Fos expression in median preoptic nucleus (MnPO), SFO, PVN, and SON (21). On repetitive stimulation, there is desensitization to this response, which is associated with an increase in AT1 receptor protein expression (21). Thirst induced by intracerebroventricular hypertonic saline in sheep is inhibited by administration of intracerebroventricular losartan, which is an AT1 receptor antagonist (44). Upregulation of AT1 receptors in most regions inside the blood-brain barrier is one of the characteristics of the TGR(ASrAOGEN)680 transgenic rat and, in keeping with this, the drinking response to intracerebroventricular injection of ANG II is enhanced compared with controls (22). Lactating rats have increased dipsogenic responsivity to intracerebroventricular ANG II. An AT1 antagonist reduced drinking in lactating rats, but not in control rats, again pointing to a central role for ANG II in the control of thirst (33). In mice lacking the AT1a receptor, dehydration caused a smaller increase in plasma vasopressin concentration than in control mice. At the same time there was an enhanced response in the expression of c-Fos and vasopressin mRNA in the PVN (23), suggesting that the role of AT1 receptor activation is not a simple one. In the baboon, intracerebroventricular infusions of ANG III were as potent as ANG II in stimulating thirst and intake of NaCl solution, suggesting that ANG III could be a major effector peptide in the regulation of ingestive behavior (6). As shown before in rats, it has now been demonstrated in primates (baboons) that subcutaneously injected aldosterone acts synergistically with intracerebroventricular ANG II to induce thirst (31). Central thromboxane A2/prostaglandin H2 (TP) receptors may contribute to the dipsogenic response to ANG II, inasmuch as intracerebroventricular treatment with an antagonist of TP receptors decreased the dipsogenic response to ANG II and because a TP agonist enhanced the response to ANG II (17). In addition, thirst is stimulated by gastric sodium loading, which is detected by sodium receptors in the abdominal viscera, such as hepatic portal osmoreceptors, before any increase in systemic plasma osmolality (37). The response is enhanced by simultaneous stimulation of the central osmoreceptors by dehydration and salt loading (37). Lesions in the SFO disrupt drinking after intragastric sodium loading, and the same