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International audience; 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.

International audience; Circadian rhythms in mammals are synchronized to the light (L)/dark (D) cycle through messages relaying in the master clock, the suprachiasmatic nucleus of the hypothalamus (SCN). Here, we provide evidence that the SCN undergoes rhythmic ultrastructural rearrangements over the 24-h cycle characterized by day/night changes of the glial, axon terminal, and/or somato-dendritic coverage of neurons expressing arginine vasopressin (AVP) or vasoactive intestinal peptide (VIP), the two main sources of SCN efferents. At nighttime, we noted an increase in the glial coverage of the dendrites of the VIP neurons (+29%) that was concomitant with a decrease in the mean coverage of the somata (-36%) and dendrites (-43%) of these neurons by axon terminals. Conversely, glial coverage of the dendrites of AVP neurons decreased (-19%) with parallel increase in the extent of somatal (+96%) and dendritic (+52%) membrane appositions involving these neurons. These plastic events were concomitant with daily fluctuations in quantitative expression of glial fibrillary acidic protein (GFAP), which were then used as an index of structural plasticity. The GFAP rhythm appeared to be strictly dependent on light entrainment, indicating that structural reorganization of the SCN may subserve synchronization of the clock to the L/D cycle. Other results presented reinforced this view while showing that circulating glucocorticoid hormones, which are known to modulate photic entrainment, were required to maintain amplitude of the GFAP rhythm to normal values.

International audience; BACKGROUND:In contrast to other types of shock, anaphylactic shock decreases cerebral blood flow more than would be expected from severe arterial hypotension, thus potentially affecting survival through brain ischaemia/hypoxia. We hypothesised that epinephrine (EPI) used as a first-line treatment of anaphylactic shock and arginine vasopressin (AVP) proposed in case of EPI refractoriness may have different effects on brain oxygenation.OBJECTIVES:To compare the effect of EPI and AVP on brain oxygenation under similar macro-haemodynamic target values in an anaphylactic shock model.DESIGN:Prospective laboratory study.SETTING:University laboratory.ANIMALS:Male brown Norway rats (n = 27).INTERVENTIONS:Twenty-seven rats were sensitised with ovalbumin (OVA). Twenty rats had anaphylactic shock induced with OVA and were resuscitated with either 0.9% saline (OVA group), EPI (EPI group) or AVP (AVP group). Sensitised control rats received only 0.9% saline and no OVA (CON group).MAIN OUTCOME MEASURES:Mean arterial pressure (MAP), carotid artery blood flow (CaBF), cerebral cortical blood flow (CBF) and hippocampal oxygen partial pressure (PtiO2) were recorded.RESULTS:All rats in the OVA group died within 15 min. EPI and AVP restored comparable levels of MAP, carotid artery blood flow and CBF, and extended survival time. EPI was associated with biologically relevant and significantly (P < 0.05) higher PtiO2 values (nadir values at 20 min: 25.0 ± 2.2 mmHg) compared with the AVP group (14.9 ± 2.0 mmHg). The slopes of the correlations of MAP vs. PtiO2 and CBF were significantly steeper with AVP (more pressure dependence) compared with EPI. By the end of the experiment, hippocampal PtiO2 values between the EPI (24.1 ± 2.1 mmHg) and the AVP (20.8 ± 2.0 mmHg) groups were similar.CONCLUSION:At early, but not at late time points, resuscitation of anaphylactic shock with EPI or AVP to similar MAP and CBF endpoints resulted in hippocampal PtiO2 being significantly higher after EPI. In addition, the PtiO2 after EPI always remained above the threshold for brain hypoxia, whereas PtiO2 after AVP was below the hypoxic threshold most of the time. Because of this early brain hypoxia, AVP may not be the drug of first choice for resuscitation of anaphylactic shock.

International audience; How phospholipase D (PLD) is involved in myogenesis remains unclear. At the onset of myogenic differentiation of L6 cells induced by the PLD agonist vasopressin in the absence of serum, mTORC1 complex was rapidly activated, as reflected by phosphorylation of S6 kinase1 (S6K1). Both the long (p85) and short (p70) S6K1 isoforms were phosphorylated in a PLD1-dependent way. Short rapamycin treatment specifically inhibiting mTORC1 suppressed p70 but not p85 phosphorylation, suggesting that p85 might be directly activated by phosphatidic acid. Vasopressin stimulation also induced phosphorylation of Akt on Ser-473 through PLD1-dependent activation of mTORC2 complex. In this model of myogenesis, mTORC2 had a positive role mostly unrelated to Akt activation, whereas mTORC1 had a negative role, associated with S6K1-induced Rictor phosphorylation. The PLD requirement for differentiation can thus be attributed to its ability to trigger via mTORC2 activation the phosphorylation of an effector that could be PKCα. Moreover, PLD is involved in a counter-regulation loop expected to limit the response. This study thus brings new insights in the intricate way PLD and mTOR cooperate to control myogenesis.

International audience; How phospholipase D (PLD) is involved in myogenesis remains unclear. At the onset of myogenic differentiation of L6 cells induced by the PLD agonist vasopressin in the absence of serum, mTORC1 complex was rapidly activated, as reflected by phosphorylation of S6 kinase1 (S6K1). Both the long (p85) and short (p70) S6K1 isoforms were phosphorylated in a PLD1-dependent way. Short rapamycin treatment specifically inhibiting mTORC1 suppressed p70 but not p85 phosphorylation, suggesting that p85 might be directly activated by phosphatidic acid. Vasopressin stimulation also induced phosphorylation of Akt on Ser-473 through PLD1-dependent activation of mTORC2 complex. In this model of myogenesis, mTORC2 had a positive role mostly unrelated to Akt activation, whereas mTORC1 had a negative role, associated with S6K1-induced Rictor phosphorylation. The PLD requirement for differentiation can thus be attributed to its ability to trigger via mTORC2 activation the phosphorylation of an effector that could be PKCα. Moreover, PLD is involved in a counter-regulation loop expected to limit the response. This study thus brings new insights in the intricate way PLD and mTOR cooperate to control myogenesis.

International audience; Rhythmic biological functions in mammals are orchestrated by a circadian timekeeper in the suprachiasmatic nucleus of the hypothalamus (SCN) which precisely adjusts clock outputs to solar time through the process of photic synchronization. Entrainment to the 24-h light-dark cycle is known to act on the molecular loops which trigger circadian oscillations but is also thought to involve day-night adjustments in the intercellular phasing of the multiple component SCN oscillators. This view is supported by data showing that the SCN undergoes important rearrangements of its neuroglial architecture throughout the 24-h cycle. The present paper highlights our data showing in rat that the two main sources of SCN efferents, composed of neurons synthesizing either vasopressin (AVP) or vasoactive intestinal peptide (VIP), are differentially involved in day-night SCN neuroglial plasticity. We found that the synaptic inputs received by the VIP neurons, which are major integrators of photic signals in the retinorecipient SCN subregion, increased during the day while those received by the AVP neurons remained unchanged at day and night. Glutamatergic axons, known to convey photic information from the retina, together with nonglutamatergic axons, contribute to the synaptic remodellings on VIP neurons. Experimental data providing strong indication that these plastic events may subserve synchronization of the clock to the light-dark cycle and that the daily fluctuations of plasma glucocorticoid hormones may act as temporal endocrine signals that may modulate SCN neuroglial plasticity through the rhythmic release of serotonin are also reviewed.

International audience; BACKGROUND: Moderately cold head-out water immersion stimulates both baro- and cold-receptors, and triggers complex and contradictory effects on the cardiovascular system and its autonomic nervous control. OBJECTIVES: To assess the effects of water immersion and cold on cardiovascular status and related autonomic nervous activity. METHODS: Hemodynamic variables and indexes of autonomic nervous activity (analysis of heart rate and blood pressure variability) were evaluated in 12 healthy subjects during 3 exposures of 20 min each in the upright position, i.e., in air (AIR, 24-25 degrees C), and during head-out water immersion at 35-36 degrees C (WIn) and 26-27 degrees C (WIc). RESULTS: Plasma noradrenaline, systolic and diastolic blood pressure, and total peripheral resistances were reduced during WIn compared to AIR (263.9 +/- 39.4 vs. 492.5 +/- 35.7 pg x ml(-1), 116.5 +/- 3.7 and 65.4 +/- 1.7 mmHg vs. 140.8 +/- 4.7 and 89.8 +/- 2.8 mmHg, 14.1 +/- 1.0 vs. 16.3 +/- 0.9 mmHg x L(-1) x min, respectively) while they were increased during WIc (530.8 +/- 84.7 pg ml(-1), 148.0 +/- 7.0 mmHg, 80.8 +/- 3.0 mmHg, and 25.8 +/- 1.9 mmHg x L(-1) x min, respectively). The blood pressure variability was reduced to the same extent during WIc and Win compared to AIR. Heart rate decreased during WIn (67.8 +/- 2.7 vs. 81.2 +/- 2.7 bpm during AIR), in parallel with an increased cardiac parasympathetic activity. This pattern was strengthened during WIc (55.3 +/- 2.2 bpm). CONCLUSIONS: Thermoneutral WI lowered sympathetic activity and arterial tone, while moderate whole-body skin cooling triggered vascular sympathetic activation. Conversely, both WI and cold triggered cardiac parasympathetic activation, highlighting a complex autonomic control of the cardiovascular system.

International audience; The present study was aimed at investigating the autonomic nervous system influences on the fractal organization of human heart rate during sympathovagal interactions, with special emphasize on the short-term fractal organization in heart rate variability (HRV), as assessed by the scaling exponent (alpha(1)) of the detrended fluctuation analysis. Linear and non-linear HRV analyses were used to study the sympathetic and vagal modulation of heart rate in ten healthy men (mean +/- SEM; age 26 +/- 1 years) during conditions of 1) increased sympathetic activity and vagal withdrawal (head-up tilt), 2) decreased sympathetic activity and increased vagal outflow (thermoneutral upright head-out water immersion, WIn), and 3) simultaneous activation of the two arms of the autonomic nervous activity (upright head-out immersion in cold water, WIc). Hemodynamic and linear HRV results were consistent with previous reports during similar physiological conditions. alpha(1) increased significantly during head-up tilt (from 0.71 +/- 0.13 supine to 0.90 +/- 0.15 upright) and WIn (0.86 +/- 0.10) and was significantly decreased during WIc (0.61 +/- 0.15). Thus, alpha(1) increased when the cardiac autonomic interplay was altered in a reciprocal fashion, whatever the direction of the balance change. Conversely, alpha(1) decreased during the concomitant activation of both vagal and sympathetic activities. The results of linear analysis were necessary to precisely define the direction of change in autonomic control revealed by an increase in alpha(1), while the direction of change in alpha(1) indicated whether an increased vagal activity is coupled with a decreased or increased sympathetic activation. Using both linear and non-linear analysis of HRV may increase the understanding of changes in cardiac autonomic status.

International audience; The airways of mice deficient in the cAMP phosphodiesterase PDE4D gene are refractory to muscarinic cholinergic stimulation. This study was undertaken to determine whether altered smooth muscle contractility causes the PDE4D-/- phenotype. A major disruption in contractility was observed in isolated PDE4D-/- tracheas, with a 60% reduction in maximal tension and a fivefold decrease in sensitivity to muscarinic cholinergic agonists. Conversely, responses to KCl or arginine vasopressin were unaffected. PDE4D is the predominant PDE4 form in tracheal extracts and PDE4D mRNA is expressed in smooth muscle where muscarinic binding sites are most abundant. Cyclic AMP accumulation in response to acute G(s)alpha-coupled receptor stimulation was increased up to fourfold in the airway of PDE4D-/- mice when compared with wild-type. This increase in cAMP was associated with an increased sensitivity to PGE2-induced relaxation of the PDE4D-/-tracheas. Furthermore, a blockade of prostanoid accumulation in PDE4D-/- tracheas restored the response to muscarinic cholinergic stimulation in vitro and in vivo. These results demonstrate that PDE4D plays a key role in balancing relaxant and contracting cues in airway smooth muscle, suggesting that natural mutations in the PDE4D gene have profound effects on airway tone.

International audience; Renal sodium retention is responsible for ascites and edema in nephrotic syndrome. In puromycin aminonucleoside (PAN)-induced nephrosis, sodium retention originates in part from the collecting duct, and it is associated with increased Na,K-ATPase activity in the cortical collecting duct (CCD). The aims of this study were to evaluate whether the outer medullary collecting duct (OMCD) also participates to sodium retention and to determine the mechanisms responsible for stimulation of Na,K-ATPase in CCD. PAN nephrosis increased Na,K-ATPase activity in the CCD but not in OMCD. The two-fold increase of Na,K-ATPase activity in CCD was associated with two-fold increases in the number of alpha and beta Na,K-ATPase subunits mRNA determined by quantitative RT-PCR and of the total amount of Na,K-ATPase alpha subunits estimated by Western blotting. PAN nephrosis also increased two-fold the amount of Na,K-ATPase alpha subunit at the basolateral membrane of CCD principal cells, as determined by Western blotting after biotinylation and streptavidin precipitation and by immunofluorescence. The intracellular pool of latent Na,K-ATPase units also increased in size and was no longer recruitable by vasopressin and cAMP. This unresponsiveness of the intracellular pool of Na,K-ATPase to vasopressin was not the result of any alteration of the molecular and functional expression of the vasopressin V(2) receptor/adenylyl cyclase (AC) complex. It is concluded that PAN nephrosis (1) does not alter sodium reabsorption in OMCD, (2) is associated with increased synthesis and membrane expression of Na,K-ATPase in the CCD, and (3) alters the normal trafficking of intracellular Na,K-ATPase units to the basolateral membrane.

International audience; Because previous studies indicated that, in the rat collecting tubule, vasopressin (AVP)-sensitive adenylate cyclase (AC) is controlled by mineralocorticoids in the long term, the present study was designed to investigate whether such a control also exists in the short term. Therefore, we investigated the in vivo and in vitro effects of aldosterone on AC activity in cortical and outer medullary collecting tubules (CCD and OMCD, respectively) from adrenalectomized rats. Injection of aldosterone (10 micrograms/kg body wt) to adrenalectomized rats restored within 3 h AVP-sensitive AC activity in the CCD and OMCD up to the levels observed in the corresponding segments of adrenal intact rats. Similarly, incubating CCD or OMCD from adrenalectomized rats for 2.5 h in the presence of 10(-8) M aldosterone enhanced AVP-sensitive AC activity up to values similar to those found in normal rats. In vitro stimulation of AVP-sensitive AC activity was dose dependent with regard to aldosterone [apparent affinity constant (K0.5) approximately 10(-9) M], appeared after a 30-min lag period, and reached its maximum after 2-2.5 h. In addition, it was totally abolished by the antimineralocorticoid spironolactone, whereas the specific glucocorticoid antagonist RU 38486 had no effect. Finally, actinomycin D and cycloheximide totally abolished the in vitro action of aldosterone, demonstrating the involvement of protein synthesis in that process.