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PubMed2002

Distribution of apelin-synthesizing neurons in the adult rat brain.

The peptide apelin originating from a larger precursor preproapelin molecule has been recently isolated and identified as the endogenous ligand of the human orphan G protein-coupled receptor, APJ (putative receptor protein related to the angiotensin receptor AT(1)). We have shown recently that apelin and apelin receptor mRNA are expressed in brain and that the centrally injected apelin fragment K17F (Lys(1)-Phe-Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe(17)) decreased vasopressin release and altered drinking behavior. Using a specific polyclonal antiserum against K17F for immunohistochemistry, the aim of the present study was to establish the precise topographical distribution of apelin immunoreactivity in colchicine-treated adult rat brain. Immunoreactivity was essentially detected in neuronal cell bodies and fibers throughout the entire neuroaxis in different densities. Cells bodies have been visualized in the preoptic region, the hypothalamic supraoptic and paraventricular nuclei and in the highest density, in the arcuate nucleus. Apelin immunoreactive cell bodies were also seen in the pons and the medulla oblongata. Apelin nerve fibers appear more widely distributed than neuronal apelin cell bodies. The hypothalamus represented, by far, the major site of apelin-positive nerve fibers which were found in the suprachiasmatic, periventricular, dorsomedial, ventromedial nuclei and in the retrochiasmatic area, with the highest density in the internal layer of the median eminence. Fibers were also found innervating other circumventricular organs such as the vascular organ of the lamina terminalis, the subfornical and the subcommissural organs and the area postrema. Apelin was also detected in the septum and the amygdala and in high density in the paraventricular thalamic nucleus, the periaqueductal central gray matter and dorsal raphe nucleus, the parabrachial and Barrington nuclei in the pons and in the nucleus of the solitary tract, lateral reticular, prepositus hypoglossal and spinal trigeminal nuclei. The topographical distribution of apelinergic neurons in the brain suggests multiple roles for apelin especially in the central control of ingestive behaviors, pituitary hormone release and circadian rhythms.

Animals↗

PubMedDate not supplied

[Apelin, a neuropeptide that counteracts vasopressin secretion].

Apelin is a peptide that was recently isolated as the endogenous ligand for the human orphan APJ receptor, a G protein-coupled receptor which shares 31 % amino-acid sequence identity with the angiotensin type 1 receptor. Apelin naturally occurs in the brain and plasma as 13 (pE13F) and 17 amino-acid (K17F) fragments of a single pro-peptide precursor. In transfected CHO cells, K17F and pE13F bind with high affinity to the rat APJ receptor, promote receptor internalization, and inhibit forskolin-induced cAMP formation. In the same cells, pE13F activates MAP kinase and PI3 kinase pathways. Apelin and APJ receptors are both widely distributed in the brain but are particularly highly expressed in the supraoptic (SON) and paraventricular (PVN) hypothalamic nuclei. Dual labeling studies demonstrate that within these two nuclei, apelin and its receptor are colocalized with vasopressin (AVP) in a subset of magnocellular neurons. In lactating rats, characterized by increases in both synthesis and release of AVP, central injection of apelin inhibits the phasic electrical activity of AVP neurons, reduces plasma AVP levels, and increases aqueous diuresis. Moreover, water deprivation, while increasing the activity of AVP neurons, reduces plasma apelin concentrations and induces an intra-neuronal pile up of the peptide, thereby decreasing the inhibitory effect of apelin on AVP release and preventing additional water loss at the kidney level. Taken together, these data demonstrate that apelin counteracts the effects of AVP in the maintenance of body fluid homeostasis. In addition, apelin and its receptor are present in the cardiovascular system, i.e. heart, kidney and vessels. Systemically administered apelin reduces arterial blood pressure, increases cardiac contractility and reduces cardiac loading. The development of non peptidic analogs of apelin may therefore offer new therapeutic avenues for the treatment of cardiovascular disorders.

Amino Acid Sequence↗

PubMed2006

TNFalpha up-regulates apelin expression in human and mouse adipose tissue.

We have recently identified apelin as a novel adipokine up-regulated by insulin and obesity. Since obesity and insulin resistance are associated with chronically elevated levels of both insulin and TNFalpha, the present study was performed to investigate a putative regulation of apelin expression in adipocytes by TNFalpha. Herein, we report a tight correlation between apelin and TNFalpha expression in adipose tissue of lean and obese humans. Apelin regulation by TNFalpha was further studied in cultured explants of human adipose tissue. The endogenous expression of TNFalpha in adipocytes isolated from the explants was accompanied by a 6-9 h subsequent increase of apelin expression in adipocytes. This increase was reversed by inhibiting TNFalpha expression with 100 microM isobutylmethylxanthine. In different mouse models of obesity, expression of both TNFalpha and apelin was also significantly increased in adipocytes of obese mice. Furthermore, short-term exposure to an i.p. injection of TNFalpha in C57Bl6/J mice induced an increase of apelin expression in adipose tissue as well as apelin plasma levels. Finally, a direct positive effect of TNFalpha has been shown in differentiated 3T3F442A adipocytes on apelin expression and secretion. The signaling pathways of TNFalpha for the induction of apelin were dependent of PI3-kinase, c-Jun NH2-terminal kinase (JNK), and MAPK but not PKC activation. All together, these findings suggest that apelin might be a candidate to better understand potential links between obesity and associated disorders such as inflammation and insulin resistance.

3T3 Cells↗

PubMed2006

Apelin and cardiac function in hemodialyzed patients: possible relations?

BACKGROUND: Apelin, a newly discovered adipocytokine, is produced by white adipose tissue and is also expressed in the kidney and heart. Increasing evidence suggests a role for apelin in the pathology of the cardiovascular system. Cardiovascular disease is a major contributor to the mortality and morbidity in patients with chronic renal failure. The aim of this study was to assess associations between apelin, coronary artery disease (CAD) and echocardiographic parameters in hemodialyzed patients. PATIENTS AND METHODS: We investigated plasma apelin levels (using commercially available kits) in 81 nondiabetic, clinically stable hemodialyzed patients (38 females, 43 males) with and without CAD. RESULTS: Patients with CAD were significantly older, with significantly increased left ventricular internal end-diastolic dimension (LVIDd), left ventricular internal end-systolic dimension (LVISd), right ventricle (RV), left atrium (LA), interventricular septum in diastole, left ventricle posterior wall in diastole (LVPW), aorta, pulmonary artery, significantly lower ejection fraction and apelin than patients without CAD. We observed statistically significant correlations between apelin and echocardiographic parameters: LVIDd, LVISd, RV, LA, right atrium, LVPW, aorta, and serum lipids: cholesterol, LDL, triglycerides. In multiple logistic regression analysis, the only associate of apelin was LVIDd. CONCLUSIONS: Apelin level was significantly lower in dialyzed patients with CAD and it was associated with cardiac function. Apelin might be involved in the pathophysiology of cardiovascular disease in chronic renal failure. Since apelin is an inotrope in normal and failing hearts, this finding may have clinical implications for future use of apelin as a novel inotropic agent also for patients with uremic cardiomyopathy.

Aged↗

PubMed2004

Immunocytochemical localization of the endogenous vasoactive peptide apelin to human vascular and endocardial endothelial cells.

Apelin, the proposed endogenous peptide ligand of the novel G-protein-coupled receptor APJ, has been shown to possess potent vasodilator and positive inotropic effects in rats and humans in vivo. However, in humans, no endogenous source of apelin has been reported. Therefore, based on the presence of APJ and mRNA encoding apelin in human tissues, we investigated the expression of apelin in fresh-frozen human tissue from right atrium, left ventricle, lung, kidney, adrenal and large conduit vessels using immunocytochemistry. Apelin-like immunoreactivity (apelin-LI) was detected in vascular endothelial cells lining blood vessels in the human heart, kidney, adrenal gland and lung and in endothelial cells of large conduit vessels. Apelin-LI was also present in endocardial endothelial cells lining recesses of the right atrium. Apelin-LI was not present or below the level of detection in cardiomyocytes, Purkinje's cells, pulmonary or renal epithelial cells, secretory cells of the adrenal gland, vascular smooth muscle cells, adipocytes, nerves and connective tissue. The restricted presence of apelin-LI in endothelial cells suggests that endothelial apelin may play a role as a locally secreted cardiovascular mediator acting on APJ receptors present on the vascular smooth muscle and on cardiac myocytes to regulate vascular tone and cardiac contractility.

Adrenal Glands↗

PubMed2005

Immunocytochemical localisation of the apelin receptor, APJ, to human cardiomyocytes, vascular smooth muscle and endothelial cells.

The novel G protein-coupled receptor APJ, recently paired with the proposed cognate peptide ligand apelin, mediates potent vasodilator and positive inotropic actions in rats. Radioligand binding showed apelin receptors in rat and human heart and human large conduit vessels. The specific cell types expressing the receptor, however, have not been determined. Apelin, the cognate receptor ligand, is present in endothelial cells. However, the exact pathway of endothelial apelin synthesis and secretion is not known. We therefore investigated the cellular distribution of APJ receptor-like immunoreactivity (APJ-LI) in a range of human tissues using immunocytochemistry and fluorescent double staining confocal microscopy. The same techniques were applied to determine the intracellular localisation of apelin-like immunoreactivity (apelin-LI) in cultured human umbilical vein endothelial cells (HUVECs). APJ-LI is present in endothelial cells, vascular smooth muscle cells and cardiomyocytes. Apelin-LI localises to secretory vesicles and the Golgi complex/endoplasmic reticulum of HUVECs. Apelin-LI does not co-localise with von Willebrand factor in Weibel-Palade bodies, suggesting synthesis of apelin via the constitutive pathway. The proximity of receptor and ligand in the human vasculature, together with evidence for local vascular apelin synthesis, suggests an important role for APJ/apelin as a paracrine cardiovascular regulator system.

Animals↗

PubMed2006

Apelin stimulates myosin light chain phosphorylation in vascular smooth muscle cells.

OBJECTIVE: Physiological roles of apelin and its specific receptor APJ signaling were investigated in vascular smooth muscle cells (VSMCs). The present study determined whether apelin activates myosin light chain (MLC), a major regulatory event in initiating smooth muscle contraction. METHODS AND RESULTS: To assess MLC activation, we performed Western blot and immunohistochemical studies using an antibody against the phospho-MLC. In VSMCs, apelin induces the phosphorylation of MLC in a concentration-dependent manner with a peak at 2 minutes. Pretreatment of VSMCs with pertussis toxin abolishes the apelin-induced phosphorylation of MLC. Inhibition of protein kinase C (PKC) with GF-109203X markedly attenuated the apelin-induced MLC phosphorylation. In addition, methylisobutyl amiloride, a specific inhibitor of the Na+/H+ exchanger (NHE), and KB-R7943, a potent inhibitor for the reverse mode of the Na+/Ca2+ exchanger (NCX), significantly suppressed the action of apelin. In wild-type mice, apelin phosphorylates MLC in vascular tissue, whereas it had no response in APJ-deficient mice by Western blot and immunohistochemistry. Apelin-induced phosphorylation of MLC was accompanied with myosin phosphatase target subunit phosphorylation. CONCLUSIONS: These results provide the first evidence to our knowledge for apelin-mediated MLC phosphorylation in vitro and in vivo, which is a potential mechanism of apelin-mediated vasoconstriction.

Adipokines↗

PubMed2005

The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo.

OBJECTIVE: The endogenous peptide apelin is differentially regulated in cardiovascular disease but the nature of its role in cardiac function remains unclear. METHODS: We investigated the functional relevance of this peptide using ECG and respiration gated magnetic resonance imaging, conductance catheter pressure-volume hemodynamic measurements, and echocardiography in vivo. In addition, we carried out histology and immunohistochemistry to assess cardiac hypertrophy and to localize apelin and APJ in the adult and embryonic mouse heart. RESULTS: Intraperitoneal injection of apelin (300 microg/kg) resulted in a decrease in left ventricular end diastolic area (pre: 0.122+/-0.007; post: 0.104+/-0.005 cm(2), p=0.006) and an increase in heart rate (pre: 537+/-20; post: 559+/-19 beats per minute, p=0.03). Hemodynamic measurements revealed a marked increase in ventricular elastance (pre: 3.7+/-0.9; post: 6.5+/-1.4 mm Hg/RVU, p=0.018) and preload recruitable stroke work (pre: 27.4+/-8.0; post: 51.8+/-3.1, p=0.059) with little change in diastolic parameters following acute infusion of apelin. Chronic infusion (2 mg/kg/day) resulted in significant increases in the velocity of circumferential shortening (baseline: 5.36+/-0.401; 14 days: 6.85+/-0.358 circ/s, p=0.049) and cardiac output (baseline: 0.142+/-0.019; 14 days: 0.25+/-0.019 l/min, p=0.001) as determined by 15 MHz echocardiography. Post-mortem corrected heart weights were not different between apelin and saline groups (p=0.5) and histology revealed no evidence of cellular hypertrophy in the apelin group (nuclei per unit area, p=0.9). Immunohistochemistry studies revealed APJ staining of myocardial cells in all regions of the adult mouse heart. Antibody staining, as well as quantitative real time polymerase chain reaction identified expression of both APJ and apelin in embryonic myocardium as early as embryonic day 13.5. CONCLUSIONS: Apelin reduces left ventricular preload and afterload and increases contractile reserve without evidence of hypertrophy. These results associate apelin with a positive hemodynamic profile and suggest it as an attractive target for pharmacotherapy in the setting of heart failure.

Animals↗

PubMed2006

Exercise training promotes expression of apelin and APJ of cardiovascular tissues in spontaneously hypertensive rats.

Because apelin may play an important regulatory role in human cardiac dysfunction, we investigated alterations in cardiovascular content of apelin and its receptor, APJ, during hypertension and the effect of exercise training on the cardiovascular apelin/APJ system in hypertensive animals. Spontaneously hypertensive rats (SHRs) underwent swimming training consisting of 54 swimming sessions of 60 min each (6 days/week for 9 weeks). Systolic blood pressure (SBP) was verified weekly by tail-cuff plethysmography. Apelin levels in plasma and cardiovascular tissues were determined by radioimmunoassay. The level of apelin/APJ mRNA was determined by RT-PCR. SHRs showed severe hypertension and pathological cardiomegaly. The level of apelin immunoreactivity (apelin-ir) in plasma and ventricular and aortic tissues was lower, by 40%, 40% and 42% (all P<0.01), respectively, in SHRs than in control Wistar-Kyoto rats, and the mRNA level of apelin and APJ in myocardium and aorta was markedly decreased. Compared with sedentary SHRs, swimming-trained SHRs showed decreased SBP and elevated mRNA expression of apelin and APJ in cardiovascular tissues and elevated apelin-ir level in plasma, myocardium and aorta (all P<0.01). SBP and level of apelin-ir in plasma and cardiovascular tissues were negatively correlated. Long-term swimming training relieved the pathogenesis of hypertension and reversed the downregulation of the cardiovascular apelin/APJ system induced by hypertension, which suggests that the improving effect of exercise training on hypertension could be mediated by upregulating the cardiovascular apelin/APJ system.

Animals↗

PubMed2001

The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism.

Apelin is an endogenous ligand of the human orphan receptor APJ. We detected apelin-like immunoreactivity in the adipocytes, gastric mucosa, and Kupffer cells in the liver. We also detected apelin-like immunoreactivity localized within the endothelia of small arteries in various organs. Further, it was found that mean arterial pressure after the administration of apelin-12, apelin-13, and apelin-36 at a dose of 10 nmol/kg in anaesthetized rats was reduced by 26+/-5, 11+/-4, and 5+/-4 mm Hg, respectively. In the presence of a nitric oxide (NO) synthase inhibitor, the effect of apelin-12 on blood pressure was abolished. Furthermore, the administration of apelin-12 (10 nmol/kg) in rats produced a transitory elevation of the plasma nitrite/nitrate concentration from a basal level of 21.4+/-1.6 to 27.0+/-1.5 microM. Thus, apelin may lower blood pressure via a nitric oxide-dependent mechanism.

Animals↗

PubMed1999

Apelin, the natural ligand of the orphan receptor APJ, is abundantly secreted in the colostrum.

By using a strategy that we have developed to search for the ligands of orphan seven-transmembrane-domain receptors [S. Hinuma et al., Nature 393 (1998) 272-276], we have recently identified a natural ligand, apelin, for the orphan 7TMR, APJ [K. Tatemoto et al., Biochem. Biophys. Res. Commun. 251 (1998) 471-476]. In this paper, we isolated rat and mouse apelin cDNAs, and analyzed the tissue distribution of apelin mRNA in rats. Although apelin mRNA was widely detected in a variety of tissues, the highest expression of apelin mRNA was detected in the mammary gland of pregnant rats. In the mammary gland, biologically active apelin and its mRNA considerably increased during pregnancy and lactation, and reached a maximal level around parturition. Moreover, a large amount of apelin (14-93 pmol/ml) was found to be secreted in the bovine colostrum, and it was still detectable even in commercial bovine milk. Since apelin partially suppressed cytokine production by mouse spleen cells in response to T cell receptor/CD3 cross-linking, the oral intake of apelin in the colostrum and milk might modulate immune responses in neonates.

Adipokines↗

PubMed2006

Plasma concentrations of the novel peptide apelin are decreased in patients with chronic heart failure.

BACKGROUND: Apelin, the novel endogenous ligand for the G-protein-coupled receptor APJ, has shown positive inotropic, vasodilatory and diuretic properties in animal studies. Differential expression and synthesis of apelin and APJ receptors have been observed in normal and failing human hearts, suggesting a possible role in cardiovascular homeostasis. Changes in plasma apelin concentrations in relation to heart failure have been described in small studies with conflicting results. Our aim was to evaluate plasma apelin concentrations in a large cohort of patients with chronic heart failure (CHF) across a broad spectrum of disease severity. METHOD AND RESULTS: Plasma apelin concentrations were measured in 202 patients with CHF secondary to left ventricular systolic dysfunction and 22 age-matched controls. Plasma apelin concentrations were significantly lower in patients with CHF, irrespective of NYHA class, ejection fraction or aetiology when compared to age-matched controls (0.85 [0.53-2.04] versus 3.76 [0.85-5.13] ng/ml, p<0.001). Apelin concentrations were correlated with peak VO(2) and right ventricular ejection fraction, but not with age, sex, body mass index, renal function or NT-proBNP concentrations. CONCLUSIONS: Plasma apelin concentrations are decreased in patients with CHF. The Apelin-APJ signaling pathway may be a potentially important mediator in the pathophysiological processes of heart failure and may therefore have potential therapeutic implications.

Adult↗

PubMed2006

Cardiac resynchronization therapy increases plasma levels of the endogenous inotrope apelin.

BACKGROUND: Cardiac resynchronization therapy (CRT) has been introduced to treat drug refractory chronic heart failure (CHF). Apelin, the endogenous ligand of the APJ receptor, is under evaluation for its potential role in human CHF pathophysiology. This study aims to assess whether biventricular pacing affects plasma apelin levels in patients with severe CHF. METHODS AND RESULTS: Fourteen patients (9 men, 5 women, mean age 68+/-13 years) undergoing biventricular pace-maker/ICD implantation were studied. Patients underwent baseline clinical and echocardiographic evaluation, and assessment of plasma apelin and NT-proBNP levels. The evaluation was repeated 48 h and 9+/-2 months after device implantation to assess the acute and chronic effects of CRT on apelin and NT-proBNP levels. Eight healthy age- and sex-matched subjects served as controls. In CHF patients, baseline apelin levels were reduced and NT-proBNP increased compared to control subjects (apelin: 0.47+/-0.2 vs. 0.97+/-0.3 ng/mL, p<0.001; NT-proBNP: 2007+/-114 vs. 229+/-72 pmol/L, p<0.001). Short-term evaluation did not reveal any effect of CRT on apelin or NT-proBNP levels. By contrast, at 9+/-2 months follow-up, CRT responders showed left ventricular reverse remodelling and an increase in ejection fraction, together with a significant increase in plasma apelin levels (0.99+/-0.1 vs. 0.47+/-0.2 ng/mL, p<0.001) and decrease in NT-proBNP (938+/-591 vs. 2007+/-114 pmol/L, p<0.05). CONCLUSIONS: Long-term CRT increases plasma levels of the endogenous inotrope apelin in patients with CHF.

Aged↗

PubMed2005

Apelin cells in the rat stomach.

Apelin is a recently discovered peptide that is the endogenous ligand for the APJ receptor. Apelin is produced in the central nervous system, heart, lung, mammary gland and gastrointestinal (GI) tract. The aim of this study was to identify by immunohistochemistry (IHC) cell types in the rat stomach that produce apelin peptide. IHC revealed abundant apelin-positive cells, primarily in the neck and upper base regions of the gastric glands in the mucosal epithelium. Apelin is not detected in the muscle layer. Apelin-positive cells were identified as mucous neck, parietal cells, and chief cells. Apelin is also identified in gastric epithelial cells that produce chromogranin A (CGA), a marker of enteroendocrine cells. The findings that apelin is expressed in gastric exocrine and endocrine cells agrees with and extends other data showing that apelin peptide is measurable in the gut lumen and in the systemic circulation by immunoassay.

Animals↗

PubMed2005

Regulation of apelin mRNA expression by insulin and glucocorticoids in mouse 3T3-L1 adipocytes.

The novel 36-amino acid peptide, apelin, is the endogenous ligand for the orphan receptor APJ. Apelin may play important roles in the regulation of the cardiovascular system and the hypothalamic-pituitary axis. It is a potent hypotensive agent and one of the most potent stimulators of cardiac contractility. In this study, we investigated the roles of apelin derived from adipocytes in the regulation of cardiovascular homeostasis. We found that both apelin and APJ mRNAs were expressed in isolated mouse adipocytes and that apelin mRNA levels increased during the differentiation of 3T3-L1 cells to adipocytes. We also found that the administration of insulin (1 nM-100 nM) increased, while that of dexamethasone (0.1 nM-100 nM) decreased the apelin mRNA levels in 3T3-L1 adipocytes in a dose-dependent manner, suggesting that insulin and glucocorticoids regulate apelin gene expression in adipocytes. We speculate that high glucocorticoid levels suppress apelin production and stimulate angiotensin II production in adipocyte, decreasing the counter-regulatory activity of apelin against the pressor action of angiotensin II, which might partly be involved in the mechanism underlying the development of obesity-related hypertension.

3T3-L1 Cells↗

PubMed2007

Utility of plasma apelin and other indices of cardiac dysfunction in the clinical assessment of patients with dilated cardiomyopathy.

Apelin is a recently discovered peptide ligand reported to be involved in the regulation of cardiovascular homeostasis. The exact role of apelin in the pathophysiology of congestive heart failure has remained obscure, and the reported circulating levels of apelin in patients with heart failure have been contradictory. To establish the role of apelin in the assessment of cardiac dysfunction we measured plasma apelin levels in 65 patients with congestive heart failure caused by idiopathic dilated cardiomyopathy (IDC) and 14 healthy volunteers by specific radioimmunoassay. IDC patients were carefully examined including echocardiography, both-sided cardiac catheterization and cardiopulmonary exercise test. In addition, plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), N-terminal pro-atrial natriuretic peptide (NT-proANP), interleukin (IL)-6, tumor necrosis factor alpha (TNF-alpha), epinephrine and norepinephrine were determined. Plasma apelin levels were similar in IDC patients (median 26.5 pg/ml, range<3.40-97.6 pg/ml) and in control subjects (median 24.1 pg/ml, range 19.0-28.7 pg/ml; p=NS). Unlike the levels of NT-proBNP, IL-6, TNF-alpha, and norepinephrine, plasma apelin levels did not reflect the severity of heart failure. Our study demonstrates that although disturbed apelin-APJ signalling in heart may play a role in the pathophysiology of heart failure, circulating apelin levels cannot be applied in the clinical assessment of patients with chronic left ventricular dysfunction.

Adult↗

PubMed2004

Dehydration-induced cross-regulation of apelin and vasopressin immunoreactivity levels in magnocellular hypothalamic neurons.

Apelin, a neuropeptide recently identified as the endogenous ligand for the G protein-coupled receptor APJ, is highly concentrated in brain structures involved in the control of body fluid homeostasis including the supraoptic (SON) and paraventricular (PVN) hypothalamic nuclei. To clarify the implication of apelin in the regulation of water balance, we sought to determine whether apelin colocalized with arginine vasopressin (AVP) in the rat SON and PVN. We also investigated the effects of water deprivation on the levels of apelin within these two nuclei by comparison with those of AVP. Using dual immunolabeling confocal microscopy, we found that a large proportion of apelin-immunoreactive neurons colocalized AVP within both the SON and PVN, but that the two peptides were segregated within distinct subcellular compartments inside these cells. Both the number and labeling intensity of magnocellular apelin-immunoreactive cells increased significantly after 24- or 48-h dehydration, whereas the number and labeling density of AVP-immunoreactive neurons significantly decreased. The dehydration-induced increase in apelin immunoreactivity was markedly diminished by central injection of a selective vasopressin-1 receptor antagonist. Conversely, the effect of dehydration was mimicked by a 16-min intracerebroventricular infusion of AVP, again in a vasopressin-1 receptor antagonist-reversible manner. These results provide additional evidence for the involvement of the neuropeptide apelin in the control of body fluid homeostasis. They further suggest that the dehydration-induced release of AVP from magnocellular hypothalamic neurons may be responsible for the observed increase in immunoreactive apelin levels within the same neurons and thus that the release of one peptide may block that of another peptide synthesized in the same cells.

Animals↗

PubMed2004

Behavioral, neuroendocrine and thermoregulatory actions of apelin-13.

As the distribution of apelinergic neurons in the brain suggests an important role of apelin-13 in the regulation of neuroendocrine processes, in the present experiments the effects of this recently identified neuropeptide on the open-field activity, the hypothalamo-pituitary-adrenal (HPA) system and the body temperature were investigated. I.c.v. administration of apelin-13 (1-10 microg) to rats caused significant increases in square crossing, rearing, plasma corticosterone release and core temperature, whereas it did not influence the spontaneous motor activity during telemetric observation. To determine the mediation of the actions of apelin, a corticotropin-releasing hormone (CRH) antagonist, the nonselective dopamine antagonist haloperidol, the selective dopamine D1 receptor antagonist SCH-23390 and the nitric oxide synthase inhibitor Nomega-nitro-L-arginine-methyl ester (L-NAME) were administered to the rats. The apelin-evoked HPA activation was diminished by preadministration of the CRH antagonist, while the dopamine antagonist and L-NAME attenuated only the square crossing and rearing induced by apelin-13. To characterize the transmission of the thermoregulatory action of apelin, animals were pretreated either with L-NAME, the CRH antagonist or with the cyclooxygenase inhibitor noraminophenazone. L-NAME and the CRH antagonist did not cause significant inhibition of the apelin-evoked increase in core temperature, while the cyclooxygenase inhibitor, applied 30 min before peptide treatment, did not prove effective in preventing the apelin-evoked thermoregulatory response, whereas when it was administered 2 h after the peptide treatment, it transiently and significantly reduced the hyperthermic response. The present data suggest that apelin-13 plays an important role in the regulation of behavioral, endocrine and homeostatic responses in the CNS, and dopamine, nitric oxide and prostaglandins seem to take part in the mediation of its effects. Since the corticosterone response could be blocked by the CRH antagonist, it is likely to be mediated through the activation of the CRH neurons.

Animals↗