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...

Our hypothesis is that oxytocin (OT) causes natriuresis by activation of renal NO synthase that releases NO followed by cGMP that mediates the natriuresis. To test this hypothesis, an inhibitor of NO synthase, L-nitroarginine methyl ester (NAME), was injected into male rats. Blockade of NO release by NAME had no effect on natriuresis induced by atrial natriuretic peptide (ANP). This natriuresis presumably is caused by cGMP because ANP also activates guanylyl cyclase, which synthesizes cGMP from GTP. The 18-fold increase in sodium (Na ؉ ) excretion induced by OT (1 g) was accompanied by an increase in urinary cGMP and preceded by 20 min a 20-fold increase in NO 3 ؊ excretion. NAME almost completely inhibited OT-induced natriuresis and increased NO 3 ؊ excretion; however, when the dose of OT was increased 10-fold, a dose that markedly increases plasma ANP concentrations, NAME only partly inhibited the natriuresis. We conclude that the natriuretic action of OT is caused by a dual action: generation of NO leading to increased cGMP and at higher doses release of ANP that also releases cGMP. OT-induced natriuresis is caused mainly by decreased tubular Na ؉ reabsorption mediated by cGMP. In contrast to ANP that releases cGMP in the renal vessels and the tubules, OT acts on its receptors on NOergic cells demonstrated in the macula densa and proximal tubules to release cGMP that closes Na ؉ channels. Both ANP-and OT-induced kaliuresis also appear to be mediated by cGMP. We conclude that cGMP mediates natriuresis and kaliuresis induced by both ANP and OT.Atrial natriuretic peptide (ANP) and oxytocin (OT) are natriuretic hormones that play a fundamental role in the regulation of extracellular fluid volume. The natriuretic action of ANP has been explained by its combination with ANP A receptors on kidney cells that convert GTP into cGMP by activating particulate guanylate cyclase (GC). This form of GC (GC A ) is the cell surface receptor for ANP (1). In contrast, OT is a potent natriuretic peptide and OT receptors occur in the kidney, but the mechanism of OT-induced natriuresis is not clearly understood (2-7).The release of ANP that follows blood volume expansion is partly mediated by renal and arterial baroreceptor input to the brain stem that stimulates OT release from the neurohypophysis. Circulating OT binds to its receptors in the right atrium and stimulates ANP release from atrial myocytes (8,9). Because the injection of OT evoked concomitant release of ANP and natriuresis (10), the natriuretic action of OT might be mediated by the release of ANP that activates renal GC A receptors localized in glomeruli, their afferent and efferent arterioles, and the tubules (11). ANP selectively dilates preglomerular vessels and constricts efferent arterioles, thereby increasing the filtration fraction (FF). If the glomerular filtration rate (GFR) and tubular reabsorption of sodium (Na ϩ ) remain constant, this increase in FF would provide an increased filtered load (FL) of Na ϩ , resulting in natriuresis (12).In addition t...

Results obtained in our laboratories have provided evidence for the participation of the hypothalamic atrial natriuretic peptide (ANP) neuronal system in the regulation of water and electrolyte homeostasis. The anterior ventral third ventricular (AV3V) region, a site of the perikarya of the ANP neurons, receives important afferent input from ascending serotoninergic axons. We hypothesized that the ascending serotoninergic tract might be involved in control of the liberation of ANP. Therefore, electrolytic lesions were produced in the mesencephalic dorsal raph6 nucleus (DRN), the site of perikarya of serotonin (5-HT) neurons whose axons project to the AV3V region. Rats with sham lesions constituted the control group. In a second group of animals, the serotoninergic system was depleted of 5-HT by lateral ventricular administration of p-chlorophenylalanine (PCPA), an amino acid that causes depletion of 5-HT from the serotoninergic neurons. Control animals were inJected with an equal amount of isotonic saline. The DRN lesions induced an increase of water intake and urine output beinning on the first day that lasted for 1 week after lesions were produced. There was a concomitant sodium retention that lasted for the same period of time.When water-loaded, DRN-lesioned and PCPA-injected animals showed diminished excretion of sodium, accompanied by a decrease in basal plasma ANP concentrations, and blockade of the increase in plasma ANP, which followed blood volume expansion by intraatrial injection of hypertonic saline. The results are interpreted to mean that ascending stimulatory serotoninergic input into the ANP neuronal system in the AV3V region produces a tonic stimulation of ANP release, which augments sodium excretion and inhibits water intake. Therefore, in the absence of this serotoninergic input following destruction of the serotoninergic neurons by DRN lesions or intraventricular injection of PCPA, an antinatriuretic effect is obtained that is associated with increased drinking, either because of sodium retention per se or removal of ANP-induced inhibition of release of the dipsogenic peptide, angiotensin II. The serotoninergic afferents also play an essential, stimulatory role in volume expansion-induced release of ANP and the ensuing natriuresis.Atrial natriuretic peptide (ANP), a hormone produced primarily by right atrial myocytes, plays an important role in hydromineral and cardiovascular homeostasis (1-3). In addition to the atrial myocytes, the peptide is produced in a brain ANP neuronal system. The cell bodies of the ANPergic neurons are located in the anterior, medial hypothalamus ranging dorsally from the paraventricular nuclei to the subfornical organ and to the anterior ventral third ventricular (AV3V) region ventrally. Axons from these neurons project to the median eminence and neural lobe of the pituitary gland (4-7). There the peptide is released into the hypophyseal portal vessels and gains access to the anterior pituitary sinusoids and thence to the systemic circulation. It is also rel...

Our previous studies have shown that stimulation of the anteroventral third ventricle (AV3V) region of the brain increases atrial natriuretic peptide (ANP) release, whereas lesions of the AV3V region or median eminence of the tuber cinereum block the release of ANP caused by blood volume expansion. These results suggest that participation of the central nervous system is critical to this response. The role of baroreceptors in the response was evaluated in the current research by studying the response of plasma ANP to blood volume expansion induced by intravenous injection of hypertonic saline solution (0.3 M NaCl, 2 ml/100 g of body weight, over 1 min) in conscious, freely moving male rats. Plasma samples were assayed for ANP by radioimmunoassay. In sham-operated rats, blood volume expansion induced a rapid increase in plasma ANP: the concentration peaked at 5min and remained elevated at 15 min after saline injection. One week after deafferentation of the carotid-aortic baroreceptors, basal plasma ANP concentrations were highly significantly decreased on comparison with values of sham-operated rats; plasma ANP levels S min after blood volume expansion in the deafferented rats were greatly reduced. Unilateral right vagotomy reduced resting levels of plasma ANP but not the response to blood volume expansion; resting concentrations of plasma ANP and responses to expansion were normal in bilaterally vagotomized rats. In rats that had undergone renal deafferentation, resting levels of ANP were normal but the response to blood volume expansion was significantly suppressed. The evidence indicates that afferent impulses via the right vagus nerve may be important under basal conditions, but they are not required for the ANP release induced by blood volume expansion. In contrast, baroreceptor impulses from the carotid-aortic sinus regions and the kidney are important pathways involved in the neuroendocrine control of ANP release. The evidence from these experiments and our previous stimulation and lesion studies indicates that the ANP release in response to volume expansion is mediated by afferent baroreceptor input to the AV3V region, which mediates the increased ANP release via activation of the hypothalamic ANP neuronal system. Atrial natriuretic peptide (ANP), which is primarily localized to the atrial myocytes, plays an important role in control of body fluid homeostasis by decreasing salt and water intake and increasing salt and water excretion (1-7). When the blood volume is expanded-for example, by intravenous injection of saline solution-ANP is released into the circulation and induces natriuresis, in part by direct action on the kidneys (8, 9). Natriuresis is also promoted by direct suppression of the release of aldosterone from the adrenal glomerulosa by ANP (1). ANP also inhibits the release of renin from the juxtaglomerular apparatus of the kidneys (10, 11), which decreases the release of angiotensin II, further decreasing the release of aldosterone. Since angiotensin II is an important mediator of sa...