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 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.

The respiratory pattern generator modulates the sympathetic outflow, the strength of which is enhanced by challenges produced by hypoxia. This coupling is due to the respiratory-modulated presympathetic neurons in the rostral ventrolateral medulla (RVLM), but the underlining electrophysiological mechanisms remain unclear. For a better understanding of the neural substrates responsible for generation of this respiratory-sympathetic coupling, we combined immunofluorescence, single cell qRT-pCR, and electrophysiological recordings of the RVLM presympathetic neurons in in situ preparations from normal rats and rats submitted to a metabolic challenge produced by chronic intermittent hypoxia (CIH). Our results show that the spinally projected cathecholaminergic C1 and non-C1 respiratory-modulated RVLM presympathetic neurons constitute a heterogeneous neuronal population regarding the intrinsic electrophysiological properties, respiratory synaptic inputs, and expression of ionic currents, albeit all neurons presented persistent sodium current-dependent intrinsic pacemaker properties after synaptic blockade. A specific subpopulation of non-C1 respiratory-modulated RVLM presympathetic neurons presented enhanced excitatory synaptic inputs from the respiratory network after CIH. This phenomenon may contribute to the increased sympathetic activity observed in CIH rats. We conclude that the different respiratory-modulated RVLM presympathetic neurons contribute to the central generation of respiratory-sympathetic coupling as part of a complex neuronal network, which in response to the challenges produced by CIH contribute to respiratory-related increase in the sympathetic activity.

Our previous studies have shown that stimulation of the anterior ventral third ventricular region increases atrial natriuretic peptide (ANP) release, whereas lesions of this structure, the median eminence, or removal of the neural lobe of the pituitary block ANP release induced by blood volume expansion (BVE). These results indicate that participation of the central nervous system is crucial in these responses, possibly through mediation by neurohypophysial hormones. In the present research we investigated the possible role of oxytocin, one of the two principal neurohypophysial hormones, in the mediation of ANP release. Oxytocin (1-10 nmol) injected i.p. caused significant, dose-dependent increases in urinary osmolality, natriuresis, and kaliuresis. A delayed antidiuretic effect was also observed. Plasma ANP concentrations increased nearly 4-fold (P < 0.01) 20 min after i.p. oxytocin (10 nmol), but there was no change in plasma ANP values in control rats. When oxytocin (1 or 10 nmol) was injected i.v., it also induced a dose-related increase in plasma ANP at 5 min (P < 0.001). BVE by intra-atrial injection of isotonic saline induced a rapid (5 min postinjection) increase in plasma oxytocin and ANP concentrations and a concomitant decrease in plasma arginine vasopressin concentration. Results were similar with hypertonic volume expansion, except that this induced a transient (5 min) increase in plasma arginine vasopressin. The findings are consistent with the hypothesis that baroreceptor activation of the central nervous system by BVE stimulates the release of oxytocin from the neurohypophysis. This oxytocin then circulates to the right atrium to induce release ofANP, which circulates to the kidney and induces natriuresis and diuresis, which restore body fluid volume to normal levels.Our previous studies have shown that the central nervous system controls atrial natriuretic peptide (ANP) release; osmotic, cholinergic, and noradrenergic stimulation of the anterior ventral third ventricular (AV3V) region induces ANP release (1). Conversely, lesions of the AV3V region decreased resting plasma ANP concentrations and largely blocked ANP release in response to blood volume expansion (BVE) (2). Neurons containing ANP, termed ANPergic neurons, have their perikarya in the AV3V region and axons that project to the median eminence and neural lobe of the pituitary gland (3-5). These appear critical to the volume expansion-induced release of ANP since antisera directed against ANP injected into the third ventricular region of rats (6) or sheep (7) can inhibit volume expansion-induced ANP release.Lesions of the median eminence or neural lobe of the pituitary gland, which interrupt neuronal pathways projecting from the AV3V region to the neurohypophysis, blocked volume expansion-induced ANP release (2). Therefore, we hypothesized that release of one or more neuropeptides from the neurohypophysis caused the increase in ANP release after volume expansion. As indicated above, the axons of ANP neurons terminate in the neuro...

Long-term exposure to intermittent hypoxia may lead to important cardiovascular dysfunctions, such as hypertension. Rodent models of chronic intermittent hypoxia (CIH) have been used to study the mechanisms underlying the increase in mean arterial pressure (MAP) observed after exposure to CIH. Several studies suggest that the hypertension of rats submitted to CIH is associated with an increase in sympathetic activity. However, there are no studies documenting the direct measurement of sympathetic activity in conscious freely moving rats exposed to CIH. Therefore, the present study aimed to evaluate whether or not the increase of MAP in rats exposed to CIH is associated with an increase in sympathetic activity. To reach this goal, we analysed the effect of ganglionic blockade on baseline MAP as well as the plasma levels of catecholamines. Rats submitted to CIH (fractional inspired O 2 of 6%, for 40 s in every 9 min, 8 h day −1 ) for 35 days (n = 31) exhibited a significant increase in MAP compared with control rats (n = 28) maintained under normoxia (112 ± 2 versus 103 ± 1 mmHg, P = 0.0003). The injection of the ganglionic blocker hexamethonium resulted in a similar fall in MAP in CIH and control groups (−46 ± 2 versus −41 ± 3 mmHg). However, hexamethonium after previous antagonism of the angiotensin II type 1 (AT 1 ) receptors with losartan produced a larger decrease in MAP in the CIH than in the control group (−58 ± 2 versus −50 ± 2 mmHg, P = 0.0165). The injection of losartan itself produced no major changes in the baseline MAP in both groups. The measurement of plasma catecholamines showed an increase in plasma noradrenaline (10.12 ± 0.90 versus 4.74 ± 0.32 ng ml −1 , P = 0.0042) in rats exposed to CIH compared with control rats. These data provide strong evidence to support the concept that rats submitted to CIH exhibit an increase in sympathetic activity, which seems to be determinant in the maintenance of hypertension in this experimental model.

Studies of body volume expansion have indicated that lesions of the anteroventral third ventricle and median eminence block the release of atrial natriuretic peptide (ANP) into the circulation. Detailed analysis of the lesions showed that activation of oxytocin (OT)-ergic neurons is responsible for ANP release, and it has become clear that activation of neuronal circuitry elicits OT secretion into the circulation, activating atrial OT receptors and ANP release from the heart. Subsequently, we have uncovered the entire functional OT system in the rat and the human heart. An abundance of OT has been observed in the early development of the fetal heart, and the capacity of OT to generate cardiomyocytes (CMs) has been demonstrated in various types of stem cells. OT treatment of mesenchymal stem cells stimulates paracrine factors beneficial for cardioprotection. Cardiovascular actions of OT include: i) lowering blood pressure, ii) negative inotropic and chronotropic effects, iii) parasympathetic neuromodulation, iv) vasodilatation, v) anti-inflammatory activity, vi) antioxidant activity, and vii) metabolic effects. OT actions are mediated by nitric oxide and ANP. The beneficial actions of OT may include the increase in glucose uptake by CMs and stem cells, reduction in CM hypertrophy, oxidative stress, and mitochondrial protection of several cell types. In experimentally induced myocardial infarction in rats, continuous in vivo OT delivery improves cardiac healing and cardiac work, reduces inflammation, and stimulates angiogenesis. Because OT plays anti-inflammatory and cardioprotective roles and improves vascular and metabolic functions, it demonstrates potential for therapeutic use in various pathologic conditions.

-Salt loading (SL) and water deprivation (WD) are experimental challenges that are often used to study the osmotic circuitry of the brain. Central to this circuit is the supraoptic nucleus (SON) of the hypothalamus, which is responsible for the biosynthesis of the hormones, arginine vasopressin (AVP) and oxytocin (OXT), and their transport to terminals that reside in the posterior lobe of the pituitary. On osmotic challenge evoked by a change in blood volume or osmolality, the SON undergoes a functionrelated plasticity that creates an environment that allows for an appropriate hormone response. Here, we have described the impact of SL and WD compared with euhydrated (EU) controls in terms of drinking and eating behavior, body weight, and recorded physiological data including circulating hormone data and plasma and urine osmolality. We have also used microarrays to profile the transcriptome of the SON following SL and remined data from the SON that describes the transcriptome response to WD. From a list of 2,783 commonly regulated transcripts, we selected 20 genes for validation by qPCR. All of the 9 genes that have already been described as expressed or regulated in the SON by osmotic stimuli were confirmed in our models. Of the 11 novel genes, 5 were successfully validated while 6 were false discoveries. transcriptome; supraoptic nucleus; water restriction; salt load; neuroendocrine TERRESTRIAL LIFE requires that the osmolality of the extracellular fluid (ECF) is strictly controlled. Increased ECF osmolality results in water leaving the cell, reducing intracellular fluid (ICF) volume, while increasing ICF osmolality, which will compromise the metabolic processes necessary for life. Chronic increases in ECF osmolality can be brought about experimentally by a high intake of salt (salt loading, SL) or by water deprivation (WD) (5). In the absence of drinking fluid (WD), extracellular and intracellular fluid volumes decrease, as water and sodium are inevitably lost in sweat and urine leading to hypovolemia and, as a consequence of dehydration-induced natriuresis, sodium depletion (14,35). This depletion of sodium means that WD animals also display enhanced salt appetite (14). In contrast, SL increases body sodium content, causing an increase in ECF volume, but a decrease in the volume of the ICF (35).Angiotensin II (ANG II), atrial natriuretic peptide (ANP), arginine vasopressin (AVP), and oxytocin (OXT) are the main hormones involved in the control of hydromineral homeostasis in mammals (5). ANP is synthesized and secreted into the bloodstream in response to stretching of the right atrial muscle cells by increased blood volume. Once in the bloodstream, ANP has a potent natriuretic effect, acting on the distal convoluted tubule of the nephron to inhibit sodium reabsorption (13,44). ANP is an important indicator of blood volume. AVP and OXT release are stimulated by hypovolemia, hypertonicity, and hypernatremia, among other stimuli (36). Circulating levels of AVP correlate with plasma osmolality (4) and thirst perce...

These data indicate that central nitric oxide arising from the inducible nitric oxide synthase pathway plays an important inhibitory role in vasopressin release during experimental septic shock and may be responsible for the hypotension occurring in this vasodilatory shock.

Peptides isolated from atrial extracts possess potent natriuretic and diuretic activities. In general, these peptides, called atrial natriuretic factors (ANFs), oppose the actions of the water-conservatory peptides angiotensin II and vasopressin and are released from the heart in response to atrial stretch as a consequence of increased venous return. The recent description of ANF-like immunoreactivity in brain regions associated with the control of water intake suggested a role for these peptides in the neurogenic mechanisms of thirst. Intracerebroventricular (third ventricle) infusion of 1.0 or 2.0 nmol of ANF in conscious, overnight-dehydrated rats signiflcantly inhibited subsequent water intake over a 2-hr test period. Intravenous infusion of 2.0 nm01, but not 1.0 nmol, of ANF resulted in a similar inhibitory action, suggesting that ANF released from the heart might act centrally to inhibit water intake by an action at one or more of the circumventricular organs. Water intake induced by central infusion of angiotensin 1 (9.6 and 25 pmol) in normally hydrated rats was significantly inhibited by prior infusion of 2.0 nmol of ANF. Water intake induced by higher doses of angiotensin II was not altered significantly by prior infusion of ANF. These results indicate a possible physiologic role for ANF in the hypothalamic control of water intake and reveal that the cardiac peptides can act centrally, as well as peripherally, to assist in the normalization of extracellular fluid volume.Neurogenic mechanisms responsible for the induction of drinking behavior require an intact hypothalamus as well as blood-brain-barrier-free regions adjacent to the hypothalamus, through which changes in plasma osmolality and content of neuropeptides, such as angiotensin II, can be detected. The importance of these regions, collectively known as circumventricular organs, has been demonstrated experimentally by ablation studies which revealed that at least two circumventricular organs, the organum vasculosum lamina terminalis (OVLT) and the subfornical organ, are critical areas for the detection of stimuli that result in water intake (1, 2). Indeed, osmotically induced water intake is blocked in rats bearing lesions ofthe anterior, ventral portion ofthe third cerebral ventricle (3), a region containing the organum vasculosum lamina terminalis and the subfornical organ (4); and the dipsogenic resporse to infused angiotensin II is altered in rats bearing lesions in the subfornical organ and organum vasculosum lamina terminalis (2,3,5,6). Both neuropeptides such as angiotensin II and vasopressin and neurotransmitters such as acetylcholine have been identified as likely cellular messengers in the integrated, central control of water intake, and interactive effects of these agents must, at least in part, explain the mechanism of thirst. The overall result of these interactions is not only the initiation of drinking but also the reabsorption of water in the kidney secondary to vasopressin release, with the result that extracellular flui...