Reciprocal regulation of plasma apelin and vasopressin by osmotic stimuli.

Apelin is a neuropeptide that co-localizes with vasopressin (AVP) in magnocellular neurons and is involved in body fluid homeostasis. Osmotic stimuli have opposite effects on the regulation of apelin and AVP secretion in animal models, but whether this is true in humans is unknown. This study investigated the relationship among osmolality, apelin, and AVP in 10 healthy men after infusion of hypertonic saline or loading with water to increase and decrease plasma osmolality, respectively. Increasing plasma osmolality was accompanied by a parallel, linear increase in plasma AVP concentration and by a decrease in plasma apelin concentration. In contrast, decreasing plasma osmolality by water loading reduced plasma AVP concentration and rapidly increased plasma apelin concentration. These findings suggest that regulation of apelin secretion contributes to the maintenance of body fluid homeostasis. J Am Soc Nephrol 19: 1015–1024, 2008. doi: 10.1681/ASN.2007070816 The osmotic pressure of body fluids is maintained within a remarkably narrow range in healthy adults. Body fluid homeostasis depends on neuronal pathways bearing very sensitive osmoreceptors,1 located along the lamina terminalis, including the circumventricular organs, such as the subfornical organ and the organum vasculosum of the lamina terminalis as well as the median preoptic nucleus.2 The subfornical organ and organum vasculosum of the lamina terminalis are neuronally interconnected with each other as well as with the median preoptic nucleus and the hypothalamic paraventricular and supraoptic nuclei.3 These neuronal pathways convert small changes in osmolality into a neuronal signal to neurons that influence sensations of thirst and systemic arginine vasopressin (AVP) release,2 thereby adjusting the intake or output of water to counteract changes in solute concentration.4,5 A recently discovered peptide, apelin, may also play a major role in the maintenance of body fluid homeostasis. Apelin, initially isolated from bovine stomach extracts,6 is the endogenous ligand of the human orphan G protein– coupled receptor APJ (putative receptor protein related to the angiotensin receptor AT1).6,7 It is a 36 –amino acid peptide (apelin 36) derived from a single 77–amino acid precursor, proapelin.6,8,9 Proapelin has a fully conserved C-terminal 17–amino acid sequence, apelin 17 (K17F), including the pyroglutamyl form of apelin 13 (pE13F). K17F and pE13F both are present in rat brain and plasma,10 and apelin 36 is present in testis and uterus.11 All peptides exhibit a high affinity for the human8,12,13 and the rat apelin receptors.14 Apelin possesses various cardiovascular functions (for reviews,15–17). Apelin and its receptor have been detected in the endothelial cells of large conduit arteries, coronary vessels, and the endocarReceived July 25, 2007. Accepted November 13, 2007 Published online ahead of print. Publication date available at www.jasn.org. Correspondence: Dr. Catherine Llorens-Cortes, INSERM, Unit 691, Collège de France, Paris, F-75005 France. Phone: 33-1-4427-16-63; Fax: 33-1-44-27-16-67; E-mail: c.llorens-cortes@ college-de-france.fr Copyright 2008 by the American Society of Nephrology CLINICAL RESEARCH www.jasn.org J Am Soc Nephrol 19: 1015–1024, 2008 ISSN : 1046-6673/1905-1015 1015 dium of the right atrium.18 –20 Apelin injection decreases BP in animals,9,21–23 via nitric oxide production.21 Apelin has a positive inotropic effect both on isolated perfused rat hearts ex vivo24 and on normal and postmyocardial infarction rat hearts in vivo.25 Apelin administration in mice reduces left ventricular preload and afterload and increases contractile reserve and cardiac output.26 Finally, apelin-deficient mice develop heart failure with aging.27 Apelin and its receptor both are widely distributed in the brain9,14,28,29 but are particularly abundant in the supraoptic nucleus and paraventricular nucleus, where they co-localize with AVP in magnocellular neurons.10,29 –31 Intracerebroventricular injection of K17F inhibits the typical phasic firing pattern of AVP neurons in lactating rats, resulting in decreased systemic AVP release and increased aqueous diuresis.10 Moreover, water deprivation in rats while increasing systemic AVP release and causing depletion of hypothalamic AVP stores decreases plasma apelin concentrations and results in hypothalamic accumulation of the peptide. Thus, the two peptides are conversely regulated to optimize AVP release into the blood circulation and prevent additional water loss through the kidney.10 Whether such opposite regulation of apelin and AVP secretion in response to osmotic stimuli is found in humans remains unknown. The aim of this clinical investigation was to examine the relationship between plasma osmolality, plasma apelin, and plasma AVP in healthy adults in various states of hydration. Hydration was modified by administration of a hypertonic saline infusion and by water loading to increase and decrease plasma osmolality, respectively.