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The Neuroendocrine Control of Atrial Natriuretic Peptide Release J Antunes-Rodrigues1, ALV Favaretto1, J Gutkowska2 and SM Mccann3

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The Neuroendocrine Control of Atrial Natriuretic Peptide Release J Antunes-Rodrigues1, ALV Favaretto1, J Gutkowska2 and SM Mccann3 Molecular Psychiatry (1997) 2, 359–367 1997 Stockton Press All rights reserved 1359–4184/97 $12.00 REVIEW ARTICLE: A TRIBUTE TO SM McCANN The neuroendocrine control of atrial natriuretic peptide release J Antunes-Rodrigues1, ALV Favaretto1, J Gutkowska2 and SM McCann3 1Department of Physiology, School of Medicine, University of Sao Paulo, 14049 Ribeirao Preto, SP, Brazil; 2Laboratory of Biochemistry of Hypertension, Clinical Research Institute, University of Montreal, Montreal, Quebec, H2W 1R7 Canada; 3Pennington Biomedical Research Center (LSU), 6400 Perkins Road, Baton Rouge, LA 70808–4124, USA In the initial experiments reviewed here, we show that atrial natriuretic peptide (ANP) plays an important inhibitory role in the control of sodium chloride and water intake since injections of ANP into the third ventricle (3V) caused a reduction in dehydration-induced drinking and also the drinking of salt in salt-depleted rats. Attention was then turned to the possible role of the brain ANP neurons in producing natriuresis which had earlier been shown to be caused by stimulations within the anterior ventral third ventricular region (AV3V). Stimulation in this region by carbachol produced natriuresis accompanied by a dramatic increase in plasma ANP concentrations and increased content of the peptide in medial basal hypothalamus (MBH), neurohypophysis (NH) and anterior pituitary gland (AP), without alterations in the content of ANP in lungs or atria. This suggested that the natriuresis resulting from the stimulation is brought about, at least in part, by the release of ANP from the brain. Conversely, there was a dramatic decline in plasma ANP at both 24 and 128 h after AV3V lesions had been placed. In view of the much larger quantities of the peptide stored in the atria, it is probable that the changes in the atrial release of the peptide were the main factors altering plasma ANP, but that there was concomitant alteration in the release of brain ANP as well. Blood volume expan- sion (BVE) by intraatrial injection of isotonic saline in the rat is a profound stimulus for ANP release. Lesions in the AV3V region, median eminence, or neurohypophysectomy blocked BVE-induced release of ANP indicating the crucial participation of the CNS in the response of ANP and natriuresis. Baroreceptor impulses from the carotid-aortic sinus regions and the kidney are important in the neuroendocrine control of ANP release since deafferentation of these regions lowered basal plasma ANP concentrations and prevented the increase after BVE. The evidence indicates that the ANP release, in response to BVE, is mediated by afferent baroreceptor impulses to the AV3V, which mediates the increased ANP release via activation of the hypothalamic ANP neuronal system. Our recent data support the hypothesis that BVE causes the release of ANP from ANPergic neurons in the hypothalamus that in turn stimulates release of oxytocin from the neurohypophysis. This oxytocin acts to release ANP from the right atrium that has negative chrono- and inotropic effects in the right atrium to reduce car- diac output, thereby reducing effective circulating blood volume. Then, the released ANP cir- culates to the kidneys and evokes natriuresis to return circulating blood volume to normal. This is further accomplished by reduction in intake of water and salt mediated also by brain ANP. Keywords: antero-ventral third ventricle (AV3V) region; blood volume expansion; ANP; neurons; oxytocin; vasopressin; plasma ANP; thirst; salt intake; natriuresis; kaliuresis Introduction 1964) to do my postdoctoral studies under Professor McCann’s supervision. I am honored to participate in this satellite symposium I became interested in the central control of water of the Endocrine Society Meeting in honor of Professor and salt metabolisn in 1955 (in my second year as a SM McCann. I consider myself a very lucky person. In medical student) under the supervision of Professor all my life, I have received God’s blessing. First, my Covian, who had already shown that the hemidecorti- parents gave me important guidance; second, at the cate rat presented several endocrine changes. One of University in Medical School, I decided to work in the most evident effects was on the adrenal weight. At science because of my former Professor M Rolando that time, it was clear from the work of Fisher, Ingram Covian. And finally, I was really lucky choosing (in and Ranson,1 Andersson and McCann,2 Montemurro and Sevenson,3 and Smith and McCann,4 that the Correspondence: SM McCann, Pennington Biomedical Research hypothalamus was very important in the control of Center (LSU), 6400 Perkins Road, Baton Rouge, LA 70808-4124, water and electrolyte metabolism. Andersson and USA McCann2 were among the first to provide evidence that the central nervous system (CNS) controls salt balance. CNS control of ANP J Antunes-Rodrigues et al 360 With Dr Covian, we started to investigate the role saline.8 Our group in Brazil, and McCann with Orias played by the CNS in the control of salt intake.5 In our and Mariana Morris in the USA, carried out inde- laboratories, systematic studies were undertaken to pendent studies to investigate the effects of chol- determine the effects of bilateral localized lesions of inergic, adrenergic and hypertonic saline injections the rat hypothalamus on the free choice ingestion of into the 3V of conscious male rats made diuretic by tap water and 2% NaCl solution. After several experi- intragastic water load. Both natriuretic and kaliuretic ments were performed, it was possible to demonstrate responses and an increase in the Na+/K+ ratio were the existence of a neural circuit that controls the induced by intraventricular injection of noradrenalin sodium intake and/or excretion. This circuit seems to and carbachol, whereas dopamine had no effect. The involve the septal area and particularly the AV3V, beta receptor stimulator, isoproterenol, induced an amygdaloid complex and hypothalamus. The role antinatriuretic and antikaliuretic effect. To determine played by the circuit in sodium intake was demon- the nature of the receptors involved, we injected adre- strated by electrolytic lesions and by electrical and nergic blockers and found that the alpha adrenergic chemical stimulation. Lesions of the anterior medial blocker, phentolamine, abolished the natriuretic hypothalamus caused a decrease in the intake of saline response to intraventricular injection of either hyper- solution, while lesions in the anterior lateral hypo- tonic saline, noradrenaline or carbachol. In contrast, thalamus caused an increase in saline intake. Lesions the beta adrenergic blocker, propranolol, induced a of the septal area also increased salt intake. Lesions of natriuresis and kaliuresis when injected alone. Pro- the corticomedial region of the amygdala increased Na+ pranolol also potentiated the natriuretic response to intake and lesions of the basolateral region decreased carbachol. Cholinergic blockade with atropine dimin- it. When the same sites of the septum and amygdala ished the response to norepinephrine and blocked the that had altered Na+ intake were stimulated electri- natriuretic response to hypertonic saline.9 At that time cally, stimulation of the septal area was specific for with McCann, we suggested that sodium receptors in intake of this ion. Interaction studies provided evi- the ventricular wall modify renal sodium excretion by dence that the hypothalamus is the principal structure a stimulatory pathway involving cholinergic and alpha in the circuit regulating saline ingestion/excretion and adrenergic receptors and that it can inhibit sodium that the septum and amygdala have modulating influ- excretion by a tonically active beta receptor pathway. ences on its activity in this regard.6 Much later, these receptors were described by Petrovic To study the synaptic transmitters involved in these et al.10 effects, carbachol, noradrenaline and hypertonic saline Our group in Ribeirao Preto (Brazil) mapped the vari- solution (NaCl 2%) were microinjected into the septal ous pathways within the CNS controlling salt intake area or AV3V regions. They did not increase salt and excretion. Cholinergic and adrenergic stimulation intake, as occurs with the application of ANG-II; how- of the medial septal area, medial preoptic area, anterior ever, cholinergic and alpha-adrenergic pathways lateral hypothalamus, subfornical organ as well as the appear to be involved in the natriuretic and kaliuretic AV3V region induced a dose-related natriuresis effects obtained by microinjection of these neuro- accompanied by a lesser kaliuresis. Thus, considerable transmitters into the septal, AV3V or 3rd ventricle evidence indicates that the medial preoptic area, areas. Therefore, it was clear to us at that time that anterior, lateral hypothalamus, subfornical organ, structures controlling the intake of sodium were also AV3V, habenula, stria medullaris, supraoptic nucleus, implicated in the control of its urinary output. medial septal area and paraventricular nucleus are On the basis of McCann’s work on neural control of organized in a neural circuit involved in the regulation body fluids, I joined him in Philadelphia in 1964. We of water and sodium intake.11 evaluated the effect of various transmitters on water, The role played by the CNS in the control of renal sodium chloride and food intake and reported that the sodium excretion has also been demonstrated by sev- intraventricular (ICV) injection of carbachol induced a eral other laboratories.12–21 dramatic,
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