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. 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 human 8,12,13 and the rat apelin receptors. 14 Apelin possesses various cardiovascular functions (for reviews, [15][16][17] ). Apelin and its receptor have been detected in the endothelial cells of large conduit arteries, coronary vessels, and the endocar-

Multifocal FMD was mostly found in women and unifocal FMD in young men with more severe stenosis and kidney ischemia. The documented prevalence of familial cases was 11% in this series, the true prevalence being probably higher because only a few siblings were examined by angiography. Familial cases all exhibited the multifocal type and were more commonly bilateral than were sporadic cases.

Autosomal dominant pseudohypoaldosteronism type 1 (adPHA1) is a rare condition that is characterized by renal resistance to aldosterone, with salt wasting, hyperkalemia, and metabolic acidosis. It is thought of as a mild disorder; affected children's symptoms respond promptly to salt therapy, and treatment is not required after childhood. Mutations in the mineralocorticoid receptor gene (MR) cause adPHA1, but the long-term consequences of MR deficiency in humans are not known. Herein are described six novel adPHA1-causing MR mutations (four de novo) and evidence that haploinsufficiency of MR is sufficient to cause adPHA1. Furthermore, genotype-phenotype correlation is reported in a large adPHA1 kindred. A number of cases of neonatal mortality in infants who were at risk for adPHA1 were identified; coupled with the frequent identification of de novo mutations in affected individuals, this suggests that the seemingly benign adPHA1 may have been a fatal neonatal disorder in previous eras, preventing propagation of disease alleles. In contrast, it is shown that adult patients with adPHA1 are clinically indistinguishable from their wild-type relatives except for presumably lifelong elevation of renin, angiotensin II, and aldosterone levels. These data highlight the critical role of MR in the maintenance of salt homeostasis early in life and illuminate the sodium dependence of pathologic effects of renin and angiotensin II. They furthermore argue that nongenomic effects of aldosterone play no significant role in the long-term development of cardiovascular disease.

Abstract-There is uncertainty about the contribution of angiotensin-converting enzyme (ACE) to angiotensin II formation, with recent studies suggesting that non-ACE enzymes may be the predominant pathway of angiotensin II formation in kidney, heart, and lung. To investigate the role of ACE in angiotensin II formation, we measured angiotensin I and II levels in blood, kidney, and heart of 2 mouse genetic models (ACE.1 and ACE.4) of reduced somatic ACE gene expression and in blood, kidney, heart, lung, adrenal, and brain of mice administered the ACE inhibitor lisinopril. We also measured the levels of bradykinin (1-9) and its ACE metabolite bradykinin (1-7). Reduced ACE gene expression and ACE inhibition had similar effects on angiotensin and bradykinin peptide levels. Angiotensin II levels were reduced by 70% to 97% in blood, 92% to 99% in kidney, 93% to 99% in heart, 97% in lung, and 85% in adrenal and brain. The marked reductions in angiotensin II/angiotensin I ratio indicated that ACE was responsible for at least 90% of angiotensin I conversion to angiotensin II in blood, kidney, heart, lung, and brain, and at least 77% in adrenal.Blood bradykinin (1-9) levels were increased 6.4-fold to 8.4-fold. Heart bradykinin (1-9) levels were increased in ACE.4 mice and the bradykinin (1-7)/bradykinin (1-9) ratio was reduced in kidney and heart of ACE.4 mice and heart of lisinopril-treated mice. These studies demonstrate that ACE is the predominant pathway of angiotensin II formation in blood and tissues of mice and plays a major role in bradykinin (1-9) metabolism in blood and, to a lesser extent, in kidney and heart. Key Words: mice Ⅲ angiotensin-converting enzyme Ⅲ angiotensin I Ⅲ angiotensin II Ⅲ bradykinin A ngiotensin-converting enzyme (ACE) inhibitors are of established benefit for the treatment of cardiovascular and renal disease. However, there is continuing uncertainty about the mechanism of their therapeutic benefit and the effect of ACE inhibition on angiotensin II levels. Many patients receiving ACE inhibitor therapy fail to show reduction in angiotensin II levels, leading to the proposal that alternate enzymes such as chymase may convert angiotensin I to angiotensin II. 1 In support of this proposal, Wei et al 2 reported that although plasma angiotensin II levels of ACE gene knockout (KO) mice were reduced to below the limit of detection, angiotensin II levels in kidney, heart, and lung of ACE KO mice were no different from the levels in wild-type (WT) mice. These authors also reported that chymase levels were increased 14-fold in kidney and 1.5-fold in heart of ACE KO mice, in comparison with WT mice, and they suggested that prolonged suppression of ACE activity may lead to the induction of alternate enzymatic pathways of angiotensin II formation in tissue. 2 We and others have shown that ACE inhibition produces marked reduction in angiotensin II levels in blood and tissues of rats and humans. [3][4][5][6] However, ACE inhibition is reported to have variable effects on angiotensin II levels in mice. 7 To fu...