We compared the effects of high and low dosages of antithyroid drugs in 113 patients with Graves' hyperthyroidism. The patients were randomly divided into 2 groups. In group A, 65 patients received either methimazole (MMI): 60 +/- 14.5 mg/day (mean +/- SD); range 40-100 mg/day, or propylthiouracil (PTU): 693 +/- 173 mg/day; range 500-1200 mg/day. These high doses were maintained throughout treatment with later addition of 50-75 micrograms T3 daily. Forty eight patients (group B) were treated with lower doses of MMI or PTU without thyroid hormone addition. The maintenance dose of MMI was 13.6 +/- 7 mg/day (range 5-25 mg/day) and that of PTU was 180 +/- 58 mg/day (range 100-300 mg/day). The treatment period was 15.1 +/- 4.2 (range 10-30) months for group A and 13.5 +/- 2.2 (range 12-20) months for group B. Remission occurred in 75.4% patients from group A and in 41.6% patients from group B (P less than 0.001). The mean follow-up was 42 +/- 14 months (17-81 months). The free T4 index (FT4I) in group A remained below the normal range during treatment. The mean FT4I, obtained during the course of treatment, of patients who went into remission from group A was significantly (P less than 0.001) lower than in relapsed patients (4.8 vs. 6.5). Moreover, there was an inverse correlation between mean FT4I and maintenance daily dose of either MMI (r = -0.567; P less than 0.001), or PTU (r = -0.379; P less than 0.01). A fall in microsomal antibody (MCHA) titer occurred mainly in remission patients, and was more significant (P less than 0.05) in group A patients. In contrast, 11 (7 from group B) of the 16 patients with an increase of microsomal antibody levels relapsed. The frequency of negative tests of thyroid-stimulating antibody was higher in group A patients (71%) than in group B (29%) at the end of therapy (P less than 0.01). No correlation was found between thyroid T3 suppressibility and either mean FT4I or thyroid-stimulatory antibody activity during treatment. Our findings show that patients treated with high doses of PTU or MMI throughout treatment have a higher remission rate when compared to those treated with a more conventional regimen. These results support the hypothesis that large antithyroid drug doses may have greater immunosuppressive effects than low dosage regimens. Furthermore, a high dosage regimen could permit the restoration of the immune surveillance mechanisms and, thus, lasting remission of Graves' disease.

Ension of the blood volume causes a release of atrial natriuretic peptde (ANP) that is believed to be important in induction of the subsequent natriuresis and diuresis which, in turn, acts to reduce the increase in blood volume. Since stimulation of the anteroventral portion of the third cerebral ventricle (AV3V) induced a rapid elevation of plasna ANP, whereas lesions of the AV3V were followed by a marked decline in plasmaconcentration ofthe peptide, we hypothesized that release ofANP fm the brain ANP Ceuronal system might be important to the control of plasma ANP. The perikarya of the ANP-containing neuron are densely distributed in the AV3V and their axons project to the median emience and neural lobe. To test the hypothesis that these neurons are involved in v n -induced ANP release, by using electrolysis we destroyed the AV3V, the site of the perikarya, in male rats. Other lesions were made in the median eminence and posterior pituitary, sites of termination of the axons of these neurons, and also hypophysectomy was performed in other animals. In conscious freely moving animals, volume expanson and stimulatin of plated ium receptors in the hypothalamus were induced by iijection of hypertonic NaCI solution [0.5 or 0.3 M NaCl; 2 mi/100 g (body weight)]. Volum ex n alone was induced with the same volume of an isotonic solution (NaCl or glucose). In the sham-operated rats, volume expansion with hypertonic or istonic solutions caused equivalent rapid increases in plasma ANP that peaked at 5 min and returned nearly to control values by 15 min. Lesions caused a decrease in the initial levels of plasna ANP on comparison with values from the sham-operated rats, and each type of lesion induced a highly s cant suppres sion of the response to volume expansion on sting 1-5 days after lesions were made. Because a common denominator of the lesions was emition of the brain ANP neuronal system, these results suggest that the brain ANP plays an important role in the mediation ofthe release ofANP that occurs after volume expnsio. Since the content of ANP in this system is much less than that in the atria, there must be a remarkable incase in synthesis and release of brain ANP assocated with this stimulus. It is also possible that blockade of volume-expansion-induced release of other neurohypophyseal hormones, such asendothelin, may block release ofANP from atrial myocytes. It is probable that volume ex io detete by stretch ofatrial and carotid-aortic baroreceptors causes afferent input to the brain ANP system, thereby causing increased release of the peptide from the median eminence and mural lobe. Our results A the importance of brain ANP to the control of ANP release to the blood.Atrial natriuretic peptide (ANP) plays an important role in control of body fluid homeostasis by promoting decreased salt and water intake and increased salt and water excretion (1-3). This peptide is released into the circulation after expansion of blood volume and induces the ensuing natriuresis in part by a direct action on the kidneys (...

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...

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The present article reviews the role of the serotoninergic system in the regulation of the sodium appetite. Data from the peripheral and icv administration of serotoninergic (5-HTergic) agents showed the participation of 5-HT2/3 receptors in the modulation of sodium appetite. These observations were extended with the studies carried out after brain serotonin depletion, lesions of DRN and during blockade of 5-HT2A/2C receptors in lateral parabrachial nucleus (LPBN). Brain serotonin depletion and lesions of DRN increased the sodium appetite response, in basal conditions, after sodium depletion and hypovolemia or after beta-adrenergic stimulation as well. These observations raised the hypothesis that the suppression of ascending pathways from the DRN, possibly, 5-HTergic fi bers, modifi es the angiotensinergic or sodium sensing mechanisms of the subfornical organ involved in the control of the sodium appetite. 5-HTergic blockade in LPBN induced to similar results, particularly those regarded to the natriorexigenic response evoked by volume depletion or increase of the hypertonic saline ingestion induced by brain angiotensinergic stimulation. In conclusion, many evidences lead to acceptation of an integrated participation resulting of an interaction, between DRN and LPBN, for the sodium appetite control.

The present work was carried out to investigate the role of angiotensin II type 1 (AT 1 ) receptors in nocturnal thirst and sodium appetite induced by classical models of osmotic and sodium depletion challenges in ovariectomized rats chronically treated with oil or oestradiol benzoate (EB, 20 μg per animal, S.C. daily). In both conditions, the animals were given saline or losartan (108 nmol per animal, I.C.V.), a selective AT 1 receptor blocker. Oestrogen therapy significantly reduced the water intake induced by water deprivation, sodium depletion produced by frusemide injected 24 h before, and S.C. acute frusemide plus captopril injection (FUROCAP protocol), with no alteration following S.C. hypertonic saline injection. In contrast, EB therapy decreased the salt intake induced by sodium depletion and FUROCAP protocols, with no alteration following water deprivation and S.C. hypertonic saline injection. Central AT 1 blockade inhibited the dipsogenic response induced by water deprivation, osmotic stimulation, chronic sodium depletion and FUROCAP protocols and inhibited the natriorexigenic response induced by sodium depletion in ovariectomized rats. Oestrogen therapy significantly attenuated the losartan-induced antidipsogenic and antinatriorexigenic actions following sodium depletion and FUROCAP protocols. These results indicate that ovariectomized rats express increased AT 1 receptor signalling related to thirst and sodium appetite responses. Oestrogen therapy and brain AT 1 receptor blockade weakened or markedly decreased the behavioural responses during the nocturnal period, a time at which brain angiotensinergic activity is expected to be more prominent. Finally, we demonstrated through different experimental protocols a clear-cut influence of oestrogenic status on the behavioural AT 1 -induced signalling response.

The present study aimed to investigate the role of angiotensin II (Ang II) on sodium appetite in rats subjected to a normal or a low-sodium diet (1% or > 0.1% NaCl) for 4 days. During sodium restriction, a reduction in water intake, urinary volume and sodium excretion was observed. After a low-sodium diet, we observed decreased plasma protein concentrations and haematocrit associated with a slight reduction in arterial pressure, without any significant changes in heart rate, natraemia, corticotrophin-releasing hormone mRNA expression in the paraventricular nucleus and corticosterone levels. After providing hypertonic saline, there was an increase in saline intake followed by a small increase in water intake, resulting in an enhanced saline intake ratio and the recovery of arterial pressure. Sodium deprivation increased plasma but not brain Ang I and II concentrations. A low-sodium diet increased kidney renin and liver angiotensinogen mRNA levels but not lung angiotensin-converting enzyme mRNA expression. Moreover, Ang II type 1a receptor mRNA expression was increased in the subfornical organ and the dorsal raphe nucleus and decreased in the medial preoptic nuclei, without changes in the paraventricular nucleus and the nucleus of solitary tract after a low-sodium diet. Blockade of AT(1) receptors or brain Ang II synthesis led to a reduction in sodium intake after a low-sodium diet. Intracerebroventricular injection of Ang II led to a similar increase in sodium and water intake in the control and low-sodium diet groups. In conclusion, the results of the present study suggest that Ang II is involved in the increased sodium appetite after a low-sodium diet.