New benzylureas as a novel series of potent, nonpeptidic vasopressin V2 receptor agonists.

PubMed

Yea, Christopher M; Allan, Christine E; Ashworth, Doreen M; Barnett, James; Baxter, Andy J; Broadbridge, Janice D; Franklin, Richard J; Hampton, Sally L; Hudson, Peter; Horton, John A; Jenkins, Paul D; Penson, Andy M; Pitt, Gary R W; Rivière, Pierre; Robson, Peter A; Rooker, David P; Semple, Graeme; Sheppard, Andy; Haigh, Robert M; Roe, Michael B

2008-12-25

Vasopressin (AVP) is a hormone that stimulates an increase in water permeability through activation of V2 receptors in the kidney. The analogue of AVP, desmopressin, has proven an effective drug for diseases where a reduction of urine output is desired. However, its peptidic nature limits its bioavailability. We report herein the discovery of potent, nonpeptidic, benzylurea derived agonists of the vasopressin V2 receptor. We describe substitutions on the benzyl group to give improvements in potency and subsequent modifications to the urea end group to provide improvements in solubility and increased oral efficacy in a rat model of diuresis. The lead compound 20e (VA106483) is reported for the first time and has been selected for clinical development.

Vasopressin up-regulates the expression of growth-related immediate-early genes via two distinct EGF receptor transactivation pathways

PubMed Central

Fuentes, Lida Q.; Reyes, Carlos E.; Sarmiento, José M.; Villanueva, Carolina I.; Figueroa, Carlos D.; Navarro, Javier; González, Carlos B.

2008-01-01

Activation of V1a receptor triggers the expression of growth-related immediate-early genes (IEGs), including c-Fos and Egr-1. Here we found that pre-treatment of rat vascular smooth muscle A-10 cell line with the EGF receptor inhibitor AG1478 or the over-expression of an EGFR dominant negative mutant (HEBCD533) blocked the vasopressin-induced expression of IEGs, suggesting that activation of these early genes mediated by V1a receptor is via transactivation of the EGF receptor. Importantly, the inhibition of the metalloproteinases, which catalyzed the shedding of the EGF receptor agonist HB-EGF, selectively blocked the vasopressin-induced expression c-Fos. On the other hand, the inhibition of c-Src selectively blocked the vasopressin-induced expression of Egr-1. Interestingly, in contrast to the expression of c-Fos, the expression of Egr-1 was mediated via the Ras/MEK/MAPK-dependent signalling pathway. Vasopressin-triggered expression of both genes required the release of intracellular calcium, activation of PKC and β-arrestin 2. These findings demonstrated that vasopressin up-regulated the expression of c-Fos and Erg-1 via transactivation of two distinct EGF receptor-dependent signalling pathways. PMID:18571897

Novel down-regulatory mechanism of the surface expression of the vasopressin V2 receptor by an alternative splice receptor variant.

PubMed

Sarmiento, José M; Añazco, Carolina C; Campos, Danae M; Prado, Gregory N; Navarro, Javier; González, Carlos B

2004-11-05

In rat kidney, two alternatively spliced transcripts are generated from the V2 vasopressin receptor gene. The large transcript (1.2 kb) encodes the canonical V2 receptor, whereas the small transcript encodes a splice variant displaying a distinct sequence corresponding to the putative seventh transmembrane domain and the intracellular C terminus of the V2 receptor. This work showed that the small spliced transcript is translated in the rat kidney collecting tubules. However, the protein encoded by the small transcript (here called the V2b splice variant) is retained inside the cell, in contrast to the preferential surface distribution of the V2 receptor (here called the V2a receptor). Cells expressing the V2b splice variant do not exhibit binding to 3H-labeled vasopressin. Interestingly, we found that expression of the splice variant V2b down-regulates the surface expression of the V2a receptor, most likely via the formation of V2a.V2b heterodimers as demonstrated by co-immunoprecipitation and fluorescence resonance energy transfer experiments between the V2a receptor and the V2b splice variant. The V2b splice variant would then be acting as a dominant negative. The effect of the V2b splice variant is specific, as it does not affect the surface expression of the G protein-coupled interleukin-8 receptor (CXCR1). Furthermore, the sequence encompassing residues 242-339, corresponding to the C-terminal domain of the V2b splice variant, also down-regulates the surface expression of the V2a receptor. We suggest that some forms of nephrogenic diabetes insipidus are due to overexpression of the splice variant V2b, which could retain the wild-type V2a receptor inside the cell via the formation of V2a.V2b heterodimers.

Noncanonical control of vasopressin receptor type 2 signaling by retromer and arrestin.

PubMed

Feinstein, Timothy N; Yui, Naofumi; Webber, Matthew J; Wehbi, Vanessa L; Stevenson, Hilary P; King, J Darwin; Hallows, Kenneth R; Brown, Dennis; Bouley, Richard; Vilardaga, Jean-Pierre

2013-09-27

The vasopressin type 2 receptor (V2R) is a critical G protein-coupled receptor (GPCR) for vertebrate physiology, including the balance of water and sodium ions. It is unclear how its two native hormones, vasopressin (VP) and oxytocin (OT), both stimulate the same cAMP/PKA pathway yet produce divergent antinatriuretic and antidiuretic effects that are either strong (VP) or weak (OT). Here, we present a new mechanism that differentiates the action of VP and OT on V2R signaling. We found that vasopressin, as opposed to OT, continued to generate cAMP and promote PKA activation for prolonged periods after ligand washout and receptor internalization in endosomes. Contrary to the classical model of arrestin-mediated GPCR desensitization, arrestins bind the VP-V2R complex yet extend rather than shorten the generation of cAMP. Signaling is instead turned off by the endosomal retromer complex. We propose that this mechanism explains how VP sustains water and Na(+) transport in renal collecting duct cells. Together with recent work on the parathyroid hormone receptor, these data support the existence of a novel "noncanonical" regulatory pathway for GPCR activation and response termination, via the sequential action of β-arrestin and the retromer complex.

Water Sparing in Chronic Ethanol Exposure is Associated With Elevated Renal Estrogen Receptor Beta and Vasopressin V2 Receptor mRNA in the Female Rate

DTIC Science & Technology

2007-12-01

blockade of vasopressin V2 receptors reveals significant V2-mediated water reabsorption in Brattleboro rats with diabetes insipidus . Nephrol Dial...that from 1980 to 2005 the number of persons diagnosed with diabetes rose from 5.6 million to 15.8 million (12). Additionally, the prevalence of alcohol...Pressure Facts and Statistics. 12. CDC (2007) Diabetes Data & Trends. Centers for Disease Control and Prevention 13. Keyes, K. M., Grant, B. F., and

OPC-21268, an orally effective, nonpeptide vasopressin V1 receptor antagonist.

PubMed

Yamamura, Y; Ogawa, H; Chihara, T; Kondo, K; Onogawa, T; Nakamura, S; Mori, T; Tominaga, M; Yabuuchi, Y

1991-04-26

An orally effective, nonpeptide, vasopressin V1 receptor antagonist, OPC-21268, has been identified. This compound selectively antagonized binding to the V1 subtype of the vasopressin receptor in a competitive manner. In vivo, the compound acted as a specific antagonist of arginine vasopressin (AVP)-induced vasoconstriction. After oral administration in conscious rats, the compound also antagonized pressor responses to AVP. OPC-21268 can be used to study the physiological role of AVP and may be therapeutically useful in the treatment of hypertension and congestive heart failure.

Vasopressin facilitates excitatory transmission in slices of the rat dorso-lateral septum.

PubMed

Van den Hooff, P; Urban, I J

1990-01-01

The effect of vasopressin on neurons of the rat dorso-lateral septum (DLS) was studied in brain slices with intracellular microelectrodes. Two out of 13 neurons showed a small depolarization, spontaneous activity, and increased input resistances following a 15 min exposure to 10(-6) to 10(-8) M vasopressin (VP). These membrane effects disappeared completely within 3-5 min after the application. The remaining DLS neurons treated with these vasopressin concentrations showed an increase in glutamate-mediated excitatory postsynaptic potentials (EPSPs), evoked by stimulation of the fimbria fibers. As little as 10(-12) MVP increased these EPSPs markedly in nearly 80% of the cells studied. This increase in most of the cells disappeared within 15 min after the application period, whereas the increase in EPSPs induced by 10(-10) M VP outlasted the peptide application period for more than 30 min. Neither the blockade of GABA-ergic synaptic inhibition nor the pre-treatment of the neurons with d(CH2)5-Tyr(Me)-arginine vasopressin or 2-amino-5-phosphonovaleric acid (2-APV), antagonists for the V1 type of vasopressin receptor and NMDA receptors, respectively, interfered with the EPSPs potentiating effect of the peptide. It is concluded that a type of vasopressin receptor other then the V1 type is involved in the long-lasting potentiation of the primarily non-NMDA receptor mediated transmission in DLS neurons.

Nonpeptide vasopressin antagonists: a new group of hormone blockers entering the scene.

PubMed

Mayinger, B; Hensen, J

1999-01-01

After the story of success of hormone blockers for catecholamines, aldosterone and angiotensin II and their successful implementation into clinical practice another endocrine cardiovascular system has come into focus. It has long been known, that the hormone vasopressin plays an important role in peripheral vasoconstriction, hypertension and in several disease conditions with dilutional hyponatremia in edematous disorders, like congestive heart failure, liver cirrhosis, SIADH and nephrotic syndrome. A series of orally active nonpeptide antagonists against the vasopressin receptor subtypes has recently been synthesized and is now under intensive examination. Nonpeptide V1a-receptor specific antagonists, OPC 21268 and SR 49059, nonpeptide V2-receptor specific antagonists, SR 121463 A and VPA 985, and combined V1a-/V2-receptor antagonists, OPC 31260 and YM 087, have become available for clinical research. AVP-V2-receptor antagonists lead to a dose-dependent diabetes insipidus in animals and man. The term aquaretic drugs (aquaretics) has been coined for these drugs to highlight their different mechanism compared to the saluretic diuretic furosemide. V1a-receptor antagonists might offer new therapeutic advantages in the treatment of vasoconstriction and hypertension. Combined V1a-/V2-receptor antagonists might be beneficial in the treatment of congestive heart failure. Early results are promising and now need to be confirmed in large clinical studies.

Blockade of central vasopressin receptors reduces the cardiovascular response to acute stress in freely moving rats.

PubMed

Stojicić, S; Milutinović-Smiljanić, S; Sarenac, O; Milosavljević, S; Paton, J F R; Murphy, D; Japundzić-Zigon, N

2008-04-01

To investigate the contribution of central vasopressin receptors to blood pressure (BP) and heart rate (HR) response to stress we injected non-peptide selective V(1a) (SR49059), V(1b) (SSR149415), V(2) (SR121463) receptor antagonists, diazepam or vehicle in the lateral cerebral ventricle of conscious freely moving rats stressed by blowing air on their heads for 2 min. Cardiovascular effects of stress were evaluated by analyzing maximum increase of BP and HR (MAX), latency of maximum response (LAT), integral under BP and HR curve (integral), duration of their recovery and spectral parameters of BP and HR indicative of increased sympathetic outflow (LF(BP) and LF/HF(HR)). Moreover, the increase of serum corticosterone was measured. Exposure to air-jet stress induced simultaneous increase in BP and HR followed by gradual decline during recovery while LF(BP) oscillation remained increased as well as serum corticosterone level. Rats pre-treated with vasopressin receptor antagonists were not sedated while diazepam induced sedation that persisted during exposure to stress. V(1a), V(1b) and V(2) receptor antagonists applied separately did not modify basal values of cardiovascular parameters but prevented the increase in integral(BP). In addition, V(1b) and V(2) receptor antagonists reduced BP(MAX) whereas V(1a), V(1b) antagonist and diazepam reduced HR(MAX) induced by exposure to air-jet stress. All drugs shortened the recovery period, prevented the increase of LF(BP) without affecting the increase in serum corticosterone levels. Results indicate that vasopressin receptors located within the central nervous system mediate, in part, the cardiovascular response to air-jet stress without affecting either the neuroendocrine component or inducing sedation. They support the view that the V(1b) receptor antagonist may be of potential therapeutic value in reducing arterial pressure induced by stress-related disorders.

Functional rescue of the constitutively internalized V2 vasopressin receptor mutant R137H by the pharmacological chaperone action of SR49059.

PubMed

Bernier, Virginie; Lagacé, Monique; Lonergan, Michèle; Arthus, Marie-Françoise; Bichet, Daniel G; Bouvier, Michel

2004-08-01

In most cases, nephrogenic diabetes insipidus results from mutations in the V2 vasopressin receptor (V2R) gene that cause intracellular retention of improperly folded receptors. We previously reported that cell permeable V2R antagonists act as pharmacological chaperones that rescue folding, trafficking, and function of several V2R mutants. More recently, the vasopressin antagonist, SR49059, was found to be therapeutically active in nephrogenic diabetes insipidus patients. Three of the patients with positive responses harbored the mutation R137H, previously reported to lead to constitutive endocytosis. This raises the possibility that, instead of acting as a pharmacological chaperone by favoring proper maturation of the receptors, SR49059 could mediate its action on R137H V2R by preventing its endocytosis. Here we report that the beta-arrestin-mediated constitutive endocytosis of R137H V2R is not affected by SR49059, indicating that the functional rescue observed does not result from a stabilization of the receptor at the cell surface. Moreover, metabolic labeling revealed that R137H V2R is also poorly processed to the mature form. SR49059 treatment significantly improved its maturation and cell surface targeting, indicating that the functional rescue of R137H V2Rs results from the pharmacological chaperone action of the antagonist.

Noncanonical Control of Vasopressin Receptor Type 2 Signaling by Retromer and Arrestin*

PubMed Central

Feinstein, Timothy N.; Yui, Naofumi; Webber, Matthew J.; Wehbi, Vanessa L.; Stevenson, Hilary P.; King, J. Darwin; Hallows, Kenneth R.; Brown, Dennis; Bouley, Richard; Vilardaga, Jean-Pierre

2013-01-01

The vasopressin type 2 receptor (V2R) is a critical G protein-coupled receptor (GPCR) for vertebrate physiology, including the balance of water and sodium ions. It is unclear how its two native hormones, vasopressin (VP) and oxytocin (OT), both stimulate the same cAMP/PKA pathway yet produce divergent antinatriuretic and antidiuretic effects that are either strong (VP) or weak (OT). Here, we present a new mechanism that differentiates the action of VP and OT on V2R signaling. We found that vasopressin, as opposed to OT, continued to generate cAMP and promote PKA activation for prolonged periods after ligand washout and receptor internalization in endosomes. Contrary to the classical model of arrestin-mediated GPCR desensitization, arrestins bind the VP-V2R complex yet extend rather than shorten the generation of cAMP. Signaling is instead turned off by the endosomal retromer complex. We propose that this mechanism explains how VP sustains water and Na+ transport in renal collecting duct cells. Together with recent work on the parathyroid hormone receptor, these data support the existence of a novel “noncanonical” regulatory pathway for GPCR activation and response termination, via the sequential action of β-arrestin and the retromer complex. PMID:23935101

Functional Characterization of Vasopressin Type 2 Receptor Substitutions (R137H/C/L) Leading to Nephrogenic Diabetes Insipidus and Nephrogenic Syndrome of Inappropriate Antidiuresis: Implications for TreatmentsS⃞

PubMed Central

Rochdi, Moulay D.; Vargas, Gabriel A.; Carpentier, Eric; Oligny-Longpré, Geneviève; Chen, Stanford; Kovoor, Abraham; Gitelman, Stephen E.; Rosenthal, Stephen M.; von Zastrow, Mark

2010-01-01

Substitution of arginine-137 of the vasopressin type 2 receptor (V2R) for histidine (R137H-V2R) leads to nephrogenic diabetes insipidus (NDI), whereas substitution of the same residue to cysteine or leucine (R137C/L-V2R) causes the nephrogenic syndrome of inappropriate antidiuresis (NSIAD). These two diseases have opposite clinical outcomes. Still, the three mutant receptors were shown to share constitutive β-arrestin recruitment and endocytosis, resistance to vasopressin-stimulated cAMP production and mitogen-activated protein kinase activation, and compromised cell surface targeting, raising questions about the contribution of these phenomenons to the diseases and their potential treatments. Blocking endocytosis exacerbated the elevated basal cAMP levels promoted by R137C/L-V2R but not the cAMP production elicited by R137H-V2R, demonstrating that substitution of Arg137 to Cys/Leu, but not His, leads to constitutive V2R-stimulated cAMP accumulation that most likely underlies NSIAD. The constitutively elevated endocytosis of R137C/L-V2R attenuates the signaling and most likely reduces the severity of NSIAD, whereas the elevated endocytosis of R137H-V2R probably contributes to NDI. The constitutive signaling of R137C/L-V2R was not inhibited by treatment with the V2R inverse agonist satavaptan (SR121463). In contrast, owing to its pharmacological chaperone property, SR121463 increased the R137C/L-V2R maturation and cell surface targeting, leading to a further increase in basal cAMP production, thus disqualifying it as a potential treatment for patients with R137C/L-V2R-induced NSIAD. However, vasopressin was found to promote β-arrestin/AP-2-dependent internalization of R137H/C/L-V2R beyond their already elevated endocytosis levels, raising the possibility that vasopressin could have a therapeutic value for patients with R137C/L-V2R-induced NSIAD by reducing steady-state surface receptor levels, thus lowering basal cAMP production. PMID:20159941

Functional characterization of vasopressin type 2 receptor substitutions (R137H/C/L) leading to nephrogenic diabetes insipidus and nephrogenic syndrome of inappropriate antidiuresis: implications for treatments.

PubMed

Rochdi, Moulay D; Vargas, Gabriel A; Carpentier, Eric; Oligny-Longpré, Geneviève; Chen, Stanford; Kovoor, Abraham; Gitelman, Stephen E; Rosenthal, Stephen M; von Zastrow, Mark; Bouvier, Michel

2010-05-01

Substitution of arginine-137 of the vasopressin type 2 receptor (V2R) for histidine (R137H-V2R) leads to nephrogenic diabetes insipidus (NDI), whereas substitution of the same residue to cysteine or leucine (R137C/L-V2R) causes the nephrogenic syndrome of inappropriate antidiuresis (NSIAD). These two diseases have opposite clinical outcomes. Still, the three mutant receptors were shown to share constitutive beta-arrestin recruitment and endocytosis, resistance to vasopressin-stimulated cAMP production and mitogen-activated protein kinase activation, and compromised cell surface targeting, raising questions about the contribution of these phenomenons to the diseases and their potential treatments. Blocking endocytosis exacerbated the elevated basal cAMP levels promoted by R137C/L-V2R but not the cAMP production elicited by R137H-V2R, demonstrating that substitution of Arg137 to Cys/Leu, but not His, leads to constitutive V2R-stimulated cAMP accumulation that most likely underlies NSIAD. The constitutively elevated endocytosis of R137C/L-V2R attenuates the signaling and most likely reduces the severity of NSIAD, whereas the elevated endocytosis of R137H-V2R probably contributes to NDI. The constitutive signaling of R137C/L-V2R was not inhibited by treatment with the V2R inverse agonist satavaptan (SR121463). In contrast, owing to its pharmacological chaperone property, SR121463 increased the R137C/L-V2R maturation and cell surface targeting, leading to a further increase in basal cAMP production, thus disqualifying it as a potential treatment for patients with R137C/L-V2R-induced NSIAD. However, vasopressin was found to promote beta-arrestin/AP-2-dependent internalization of R137H/C/L-V2R beyond their already elevated endocytosis levels, raising the possibility that vasopressin could have a therapeutic value for patients with R137C/L-V2R-induced NSIAD by reducing steady-state surface receptor levels, thus lowering basal cAMP production.

Inhibitory effect of vasopressin receptor antagonist OPC-31260 on experimental brain oedema induced by global cerebral ischaemia.

PubMed

Molnár, A H; Varga, C; Berkó, A; Rojik, I; Párducz, A; László, F; László, F A

2008-03-01

The effects of the non-peptide vasopressin V(2) receptor antagonist 5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride (OPC-31260) on the cerebral oedema induced by general cerebral hypoxia were studied in rats. The general cerebral hypoxia was produced by bilateral common carotid ligation in Sprague-Dawley rats of the CFY strain. By 6 h after the ligation, half of the rats had died, but the survival rate was significantly higher following OPC-31260 administration. Electron microscopic examinations revealed typical ischaemic changes after the carotid ligation. The carotid ligation increased the brain contents of water and Na(+) and enhanced the plasma vasopressin level. The increased brain water and Na(+) accumulation was prevented by OPC-31260 administration, but the plasma vasopressin level was further enhanced by OPC-31260. These results demonstrate the important role of vasopressin in the development of the disturbances in brain water and electrolyte balance in response to general cerebral hypoxia. The carotid ligation-induced cerebral oedema was significantly reduced following oral OPC-31260 administration. The protective mechanism exerted by OPC-31260 stems from its influence on the renal vasopressin V(2) receptors. These observations might suggest an effective approach to the treatment of global hypoxia-induced cerebral oedema in humans.

Salt-loading increases vasopressin and vasopressin 1b receptor mRNA in the hypothalamus and choroid plexus.

PubMed

Zemo, D A; McCabe, J T

2001-01-01

The choroid plexus plays a pivotal role in the production of cerebrospinal fluid (CSF). Messenger RNA (mRNA) transcripts encoding arginine vasopressin (AVP) and the vasopressin 1b receptor (V(1b)R) are found in various structures of the central nervous system, including the choroid plexus. The present study measured AVP and V(1b)R mRNA production in response to plasma hyperosmolality. Compared to rats maintained on water, 2% salt-drinking rats had increased levels of AVP and V(1b)R mRNAs in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus and in the choroid plexus. The increase in V(1b)R mRNA in the SON and PVN as a result of plasma hyperosmolality may reflect changes in receptor production that, in turn, have a role in AVP autoregulation of hypothalamic magnocellular neurons. The increase of AVP and V(1b)R mRNAs in the choroid plexus further shows the involvement of AVP in the regulation of brain water content and cerebral edema. Copyright 2001 Harcourt Publishers Ltd.

Antidiuretic effects of a novel nonpeptide vasopressin V(2)-receptor agonist, OPC-51803, administered orally to dogs.

PubMed

Nakamura, Shigeki; Hirano, Takahiro; Onogawa, Toshiyuki; Itoh, Shuji; Hashimoto, Ayako; Yamamura, Yoshitaka; Kondo, Kazumi; Mori, Toyoki; Kambe, Toshimi

2004-04-01

We elucidated the pharmacological properties of a novel nonpeptide vasopressin V(2)-receptor agonist, OPC-51803 ((5R)-2-[1-(2-chloro-4-(1-pyrrolidinyl)benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]-N-isopropylacetamide), via both in vitro binding experiments incorporating canine kidney and platelet membrane fractions and in vivo experiments that would determine the compound's antidiuretic effects after oral administration to water-loaded dogs. OPC-51803 displaced [(3)H]arginine vasopressin (AVP) binding to canine V(2) and V(1a) receptors, as determined by resulting K(i) values of 15.2 +/- 0.6 nM (n = 4) and 653 +/- 146 nM (n = 4), respectively. These data indicate that OPC-51803 was about 43 times more selective for V(2) receptors than for V(1a) receptors. Antidiuretic studies showed that orally administered doses of OPC-51803 (0.03 to 0.3 mg x kg(-1)) decreased urine volume and increased urinary osmolality in a dose-dependent manner in water-loaded dogs. Intravenous OPC-51803 infusions (0.3 and 3 microg x kg(-1) x min(-1)) did not affect renal or systemic hemodynamics in anesthetized dogs. Since these results confirm that OPC-51803 shows antidiuretic action in dogs, the compound may be useful for treating AVP-deficient pathophysiological states.

Genetic forms of nephrogenic diabetes insipidus (NDI): Vasopressin receptor defect (X-linked) and aquaporin defect (autosomal recessive and dominant).

PubMed

Bichet, Daniel G; Bockenhauer, Detlef

2016-03-01

Nephrogenic diabetes insipidus (NDI), which can be inherited or acquired, is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of the antidiuretic hormone, arginine vasopressin (AVP). Polyuria with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. About 90% of patients with congenital NDI are males with X-linked NDI who have mutations in the vasopressin V2 receptor (AVPR2) gene encoding the vasopressin V2 receptor. In less than 10% of the families studied, congenital NDI has an autosomal recessive or autosomal dominant mode of inheritance with mutations in the aquaporin-2 (AQP2) gene. When studied in vitro, most AVPR2 and AQP2 mutations lead to proteins trapped in the endoplasmic reticulum and are unable to reach the plasma membrane. Prior knowledge of AVPR2 or AQP2 mutations in NDI families and perinatal mutation testing is of direct clinical value and can avert the physical and mental retardation associated with repeated episodes of dehydration. Copyright © 2016 Elsevier Ltd. All rights reserved.

Rapid desensitization of vasopressin-stimulated phosphatidylinositol 4,5-bisphosphate and phosphatidylcholine hydrolysis questions the role of these pathways in sustained diacylglycerol formation in A10 vascular-smooth-muscle cells.

PubMed

Plevin, R; Wakelam, M J

1992-08-01

The kinetics of vasopressin-stimulated PtdIns(4,5)P2 and phosphatidylcholine (PtdCho) hydrolysis in relation to sustained diacylglycerol (DAG) formation was investigated in A10 vascular-smooth-muscle cells in culture. Vasopressin stimulated a transient increase in Ins(1,4,5)P3 mass formation, which was mirrored by a decrease in PtdIns(4,5)P2 mass levels. Vasopressin stimulated sustained accumulation of total [3H]inositol phosphates ([3H]IP) in the presence of Li+; however, this was significantly decreased by adding a vasopressin-receptor antagonist at different times after initial stimulation. Vasopressin-stimulated phospholipase D (PLD) activity was found to be a transient phenomenon lasting approx. 2 min. Experiments involving agonist preincubation with subsequent addition of butanol confirmed that vasopressin-stimulated PLD activity was desensitized. Vasopressin stimulated an increase in formation of choline, but not of phosphocholine, suggesting that PLD was the major catalytic route of PtdCho hydrolysis in this cell line. The roles of choline and inositol phospholipid hydrolysis in the prolonged phase of DAG formation was examined by comparing vasopressin-stimulated changes in DAG levels in the presence of butanol, the protein kinase C inhibitor Ro-31-8220 or a V1a-receptor antagonist. Vasopressin-stimulated DAG formation was decreased by 40-50% in the presence of butanol between 1 and 10 min; however, during more prolonged stimulation butanol was without significant effect. In cells pretreated with Ro-31-8220, vasopressin-stimulated DAG formation was decreased by approx. 30% at 2 min, but was significantly potentiated at later times. This coincided with an enhancement of vasopressin-stimulated [3H]IP accumulation. In cells exposed to the V1a-receptor antagonist 5 min after addition of vasopressin, subsequent DAG formation was significantly decreased, indicating that sustained formation of DAG, like [3H]IP accumulation, was dependent on continual agonist receptor activation. The results are discussed in terms of different phospholipid-hydrolytic pathways providing DAG generation.

Identification of novel selective V2 receptor non-peptide agonists.

PubMed

Del Tredici, Andria L; Vanover, Kim E; Knapp, Anne E; Bertozzi, Sine M; Nash, Norman R; Burstein, Ethan S; Lameh, Jelveh; Currier, Erika A; Davis, Robert E; Brann, Mark R; Mohell, Nina; Olsson, Roger; Piu, Fabrice

2008-10-30

Peptides with agonist activity at the vasopressin V(2) receptor are used clinically to treat fluid homeostasis disorders such as polyuria and central diabetes insipidus. Of these peptides, the most commonly used is desmopressin, which displays poor bioavailability as well as potent activity at the V(1b) receptor, with possible stress-related adverse effects. Thus, there is a strong need for the development of small molecule chemistries with selective V(2) receptor agonist activity. Using the functional cell-based assay Receptor Selection and Amplification Technology (R-SAT((R))), a screening effort identified three small molecule chemotypes (AC-94544, AC-88324, and AC-110484) with selective agonist activity at the V(2) receptor. One of these compounds, AC-94544, displayed over 180-fold selectivity at the V(2) receptor compared to related vasopressin and oxytocin receptors and no activity at 28 other G protein-coupled receptors (GPCRs). All three compounds also showed partial agonist activity at the V(2) receptor in a cAMP accumulation assay. In addition, in a rat model of central diabetes insipidus, AC-94544 was able to significantly reduce urine output in a dose-dependent manner. Thus, AC-94544, AC-88324, and AC-110484 represent novel opportunities for the treatment of disorders associated with V(2) receptor agonist deficiency.

Pharmacological lineage analysis revealed the binding affinity of broad-spectrum substance P antagonists to receptors for gonadotropin-releasing peptide.

PubMed

Arai, Kazune; Kashiwazaki, Aki; Fujiwara, Yoko; Tsuchiya, Hiroyoshi; Sakai, Nobuya; Shibata, Katsushi; Koshimizu, Taka-aki

2015-02-15

A group of synthetic substance P (SP) antagonists, such as [Arg(6),D-Trp(7,9),N(Me)Phe(8)]-substance P(6-11) and [D-Arg(1),D-Phe(5),D-Trp(7,9),Leu(11)]-substance P, bind to a range of distinct G-protein-coupled receptor (GPCR) family members, including V1a vasopressin receptors, and they competitively inhibit agonist binding. This extended accessibility enabled us to identify a GPCR subset with a partially conserved binding site structure. By combining pharmacological data and amino acid sequence homology matrices, a pharmacological lineage of GPCRs that are sensitive to these two SP antagonists was constructed. We found that sensitivity to the SP antagonists was not limited to the Gq-protein-coupled V1a and V1b receptors; Gs-coupled V2 receptors and oxytocin receptors, which couple with both Gq and Gi, also demonstrated sensitivity. Unexpectedly, a dendrogram based on the amino acid sequences of 222 known GPCRs showed that a group of receptors sensitive to the SP antagonists are located in close proximity to vasopressin/oxytocin receptors. Gonadotropin-releasing peptide receptors, located near the vasopressin receptors in the dendrogram, were also sensitive to the SP analogs, whereas α1B adrenergic receptors, located more distantly from the vasopressin receptors, were not sensitive. Our finding suggests that pharmacological lineage analysis is useful in selecting subsets of candidate receptors that contain a conserved binding site for a ligand with broad-spectrum binding abilities. The knowledge that the binding site of the two broad-spectrum SP analogs partially overlaps with that of distinct peptide agonists is valuable for understanding the specificity/broadness of peptide ligands. Copyright © 2015 Elsevier B.V. All rights reserved.

Oxytocin receptors expressed and coupled to Ca2+ signalling in a human vascular smooth muscle cell line.

PubMed

Yazawa, H; Hirasawa, A; Horie, K; Saita, Y; Iida, E; Honda, K; Tsujimoto, G

1996-03-01

1. In a human vascular smooth muscle cell line (HVSMC), binding experiments with [3H]-arginine8-vasopressin (AVP) have shown the existence of a homogeneous population of binding sites with affinity (Kd value) of 0.65 nM and a maximum number of binding sites (Bmax) of 122 fmol mg-1 protein. 2. Nonlabelled compounds compete for [3H]-AVP binding in the HVSMC membrane with an order of potency of oxytocin > lyspressin > or = AVP > Thr4, Gly7-oxytocin > (beta-mercapto-beta-beta-cyclopentamethylenepropionyl-O-Me Tyr2, Arg8) vasopressin > desmopressin > OPC21268 > OPC31260. This order was markedly different from that observed in rat vascular smooth muscle cells (A10), a well-established V1A receptor system. 3. In HVSMC both oxytocin and AVP increased inositol 1,4,5-trisphosphate (IP3) production and [Ca2+]i response, but the efficacy of the responses was greater for oxytocin than AVP. 4. Reverse transcription-polymerase chain reaction (RT-PCR) assay detected only oxytocin receptor but not V1A or V2 receptors in HVSMC, whereas only V1A receptors were found in A10 cells. 5. In conclusion, in HVSMC only oxytocin receptors are expressed among the vasopressin receptor family, and they coupled to phosphatidyl inositol (PI) turnover/Ca2+ signalling. This unexpected observation should provide new insight into the functional role of the oxytocin receptor in a human vascular smooth muscle cell line.

Vasopressin V1 receptor in rat hippocampus is regulated by adrenocortical functions.

PubMed

Saito, R; Ishiharada, N; Ban, Y; Honda, K; Takano, Y; Kamiya, H

1994-05-16

Two subtypes of arginine vasopressin (AVP) receptors (V1 and V2) have been distinguished. In this study, we examined the characteristics of AVP binding in rat hippocampus and the effects of bilateral adrenalectomy and adrenal steroids on its [3H]AVP binding. [3H]AVP binding to rat liver and the hippocampal membranes was strongly inhibited by the V1 antagonist, OPC-21268. ADX resulted in a significant decrease in the Bmax of AVP binding in the hippocampus. Chronic treatment with aldosterone and corticosterone restored the ADX-induced reduction, but treatment with dexamethasone did not. These results suggest that the AVP V1 receptor in the hippocampus is regulated by adrenocortical neuroregulatory functions.

V2 Vasopressin Receptor (V2R) Mutations in Partial Nephrogenic Diabetes Insipidus Highlight Protean Agonism of V2R Antagonists*

PubMed Central

Takahashi, Kazuhiro; Makita, Noriko; Manaka, Katsunori; Hisano, Masataka; Akioka, Yuko; Miura, Kenichiro; Takubo, Noriyuki; Iida, Atsuko; Ueda, Norishi; Hashimoto, Makiko; Fujita, Toshiro; Igarashi, Takashi; Sekine, Takashi; Iiri, Taroh

2012-01-01

Inactivating mutations of the V2 vasopressin receptor (V2R) cause cross-linked congenital nephrogenic diabetes insipidus (NDI), resulting in renal resistance to the antidiuretic hormone AVP. In two families showing partial NDI, characterized by an apparently normal response to diagnostic tests and an increase in the basal ADH levels suggesting AVP resistance, we have identified two V2R mutations, Ser-333del and Y128S. Both mutant V2Rs, when expressed in COS-7 cells, show partial defects in vasopressin-stimulated cAMP accumulation and intracellular localization. The inhibition of internalization does not rescue their localization. In contrast, the non-peptide V2R antagonists OPC41061 and OPC31260 partially rescue the membrane localization and basal function of these V2R mutants, whereas they inhibit the basal activity of the wild-type V2R. These results indicate that a partial loss of function of Ser-333del and Y128S mutant V2Rs results from defective membrane trafficking. These findings further indicate that V2R antagonists can act as protean agonists, serving as pharmacological chaperones for inactivating V2R mutants and also as inverse agonists of wild-type receptors. We speculate that this protean agonism could underlie the possible dual beneficial effects of the V2R antagonist: improvement of hyponatremia with heart failure or polycystic kidney disease and potential rescue of NDI. PMID:22144672

Molecular Mechanisms of Antidiuretic Effect of Oxytocin

PubMed Central

Li, Chunling; Wang, Weidong; Summer, Sandra N.; Westfall, Timothy D.; Brooks, David P.; Falk, Sandor; Schrier, Robert W.

2008-01-01

Oxytocin is known to have an antidiuretic effect, but the mechanisms underlying this effect are not completely understood. We infused oxytocin by osmotic minipump into vasopressin-deficient Brattleboro rats for five days and observed marked antidiuresis, increased urine osmolality, and increased solute-free water reabsorption. Administration of oxytocin also significantly increased the protein levels of aquaporin-2 (AQP2), phosphorylated AQP2 (p-AQP2), and AQP3 in the inner medulla and in the outer medulla plus cortex. Immunohistochemistry demonstrated increased AQP2 and p-AQP2 expression and trafficking to the apical plasma membrane of principal cells in the collecting duct, and increased AQP3 expression in the basolateral membrane. These oxytocin-induced effects were blocked by treatment with the vasopressin V2 receptor antagonist SR121463B, but not by treatment with the oxytocin receptor antagonist GW796679X. We conclude that vasopressin V2 receptors mediate the antidiuretic effects of oxytocin, including increased expression and apical trafficking of AQP2, p-AQP2, and increased AQP3 protein expression. PMID:18057218

V3 vasopressin receptor and corticotropic phenotype in pituitary and nonpituitary tumors.

PubMed

de Keyzer, Y; René, P; Lenne, F; Auzan, C; Clauser, E; Bertagna, X

1997-01-01

Pituitary corticotropic cells express a specific vasopressin receptor, called V1b or V3, through which vasopressin stimulates corticotropin secretion. We recently cloned a cDNA coding for this receptor and showed that it belongs to the G protein-coupled receptor family. V3 mRNA is readily detected by RT-PCR in normal human pituitaries and corticotropic pituitary adenomas but not in PRL or GH-secreting adenomas, thus demonstrating that, like POMC itself and the CRH receptor, V3 is a marker of the corticotropic phenotype. Nuclease protection experiments suggest that V3 is overexpressed in some corticotropic adenomas, and thus may play a role in tumor development by activating the phospholipase C-signalling pathway. In addition analysis of its expression in nonpituitary neuroendocrine tumors showed a striking association with carcinoids of the lung responsible for the ectopic ACTH syndrome.

Body water balance and body temperature in vasopressin V1b receptor knockout mice.

PubMed

Daikoku, R; Kunitake, T; Kato, K; Tanoue, A; Tsujimoto, G; Kannan, H

2007-10-30

In an attempt to determine whether there is a specific vasopressin receptor (V(1b)) subtype involved in the regulation of body water balance and temperature, vasopressin V(1b) receptor knockout mice were used. Daily drinking behavior and renal excretory function were examined in V(1b)-deficient (V(1b)(-/-)) and control (V(1b)(+/+)) mice under the basal and stress-induced condition. In addition, body temperature and locomotor activity were measured with a biotelemetry system. The baseline daily water intake and urine volume were larger in V(1b)(-/-) mice than in V(1b)(+/+) mice. V(1b)(-/-) mice (V(1b)(-/-)) had significantly higher locomotor activity than wild-type, whereas the body temperature and oxygen consumption were lower in V(1b)(-/-) than in the V(1b)(+/+) mice. Next, the V(1b)(-/-) and V(1b)(+/+) mice were subjected to water deprivation for 48 hr. Under this condition, their body temperature decreased with the time course, which was significantly larger for V(1b)(-/-) than for V(1b)(+/+) mice. Central vasopressin has been reported to elicit drinking behavior and antipyretic action, and the V(1b) receptor has been reported to be located in the kidney. Thus, the findings suggest that the V(1b) receptor may be, at least in part, involved in body water balance and body temperature regulation.

Contractile responses of human deferential artery and vas deferens to vasopressin.

PubMed

Medina, P; Martínez, M C; Aldasoro, M; Vila, J M; Chuan, P; Lluch, S

1996-04-11

We studied the effects of vasopressin on isolated rings of human deferential artery and vas deferens (prostatic portion) obtained from patients undergoing radical cystectomy (n = 11) or prostatectomy (n = 10). Ring segments of artery or vas deferens were studied in organ bath experiments at optimal resting tension. In artery rings, vasopressin produced concentration-dependent, endothelium-independent contractions with an EC50 of 4.5 x 10(-10) M. The presence of NG-nitro-L-arginine methyl ester hydrochloride (10(-4) M), an inhibitor of nitric oxide synthase, did not change significantly (P > 0.05) the vasopressin-induced contraction. In ring preparations of the prostatic part of the vas deferens, vasopressin induced phasic contractions with an EC50 of 7.0 x 10(-9) M. The vasopressin V1 receptor antagonist, d(CH2)5Tyr(Me)AVP (10(-8) and 10(-6)), displaced to the right in parallel the control curve to vasopressin in artery and vas deferens rings. These results indicate that vasopressin exerts a powerful constrictor action on human deferential artery and vas deferens by direct stimulation of V1 receptors. It is concluded that the deferential artery may dampen the passage of blood to the vas deferens in circumstances characterized by increased plasma vasopressin levels.

Appropriate polarization following pharmacological rescue of V2 vasopressin receptors encoded by X-linked nephrogenic diabetes insipidus alleles involves a conformation of the receptor that also attains mature glycosylation.

PubMed

Tan, Christopher M; Nickols, Hilary Highfield; Limbird, Lee E

2003-09-12

To understand the mechanisms of G protein-coupled receptor delivery and steady state localization, we examined the trafficking itineraries of wild type (WT) and mutant V2 vasopressin receptors (V2Rs) in polarized Madin-Darby canine kidney II (MDCK II) cells and in COS M6 cells; the mutant V2Rs represent selected alleles responsible for X-linked nephrogenic diabetes insipidus. The WT V2R is localized on the plasma membrane and mediates arginine vasopressin (AVP)-stimulated cAMP accumulation, whereas the clinically relevant V2R mutants, L292P V2R, Delta V278 V2R, and R337X V2R, are retained intracellularly, are insensitive to extracellularly added AVP, and are not processed beyond initial immature glycosylation, manifest by their endoglycosidase H sensitivity. Reduced temperature and pharmacological, but not chemical, strategies rescue mutant V2Rs to the cell surface of COS M6 cells; surface rescue of L292P V2R and R337X V2R, but not of Delta V278 V2R, parallels acquisition of AVP-stimulated cAMP production. Pharmacological rescue of the L292P or R337X V2R by incubation with the membrane-permeant V2R antagonist, SR121463B, leads to a mature glycosylated form of the receptor that achieves localization on the basolateral surface of polarized MDCK II cells indistinguishable from that of the WT V2R. Surprisingly, however, the immature form of the mutant L292P V2R escapes to the apical, but not basolateral, surface of polarized MDCK II cells, even in the absence of SR121463B. These findings are consistent with the interpretation that the receptor conformation that allows appropriate processing through the N-linked glycosylation pathway is also essential for V2R targeting to the appropriate surface of polarized epithelial cells.

Vasopressin-induced constriction of the isolated rat occipital artery is segment-dependent

PubMed Central

Chelko, Stephen P.; Schmiedt, Chad W.; Lewis, Tristan H.; Lewis, Stephen J.; Robertson, Tom P.

2014-01-01

Background Circulating factors delivered to the nodose ganglion (NG) by the occipital artery (OA) have shown to affect vagal afferent activity, and thus the contractile state of the OA may influence blood flow to the NG. Methods OA were isolated and bisected into proximal and distal segments, relative to the external carotid artery. Results Bisection, highlighted stark differences between maximal contractile responses and OA sensitivity. Specifically, maximum responses to vasopressin and the V1 receptor agonist, were significantly higher in distal than proximal segments. Distal segments were significantly more sensitive to 5-HT and the 5-HT2 receptor agonist than proximal segments. AT2, V2 and 5-HT1B/1D receptor agonists did not elicit vascular responses. Additionally, AT1 receptor agonists elicited mild, yet not significantly different maximal responses between segments. Conclusion The results of this study are consistent with contractile properties of rat OA being mediated via AT1, V1 and 5-HT2 receptors, and are dependent upon the OA segment. Furthermore, vasopressin-induced constriction of the OA, regardless of a bolus dose or a first and second concentration response curve retained this unique segmental difference and therefore we hypothesize this may be a pathophysiological response in the regulation of blood flow through the OA. PMID:24192548

[Vasopressin V2 receptor-related pathologies: congenital nephrogenic diabetes insipidus and nephrogenic syndrome of inappropiate antidiuresis].

PubMed

Morin, Denis

2014-12-01

Congenital nephrogenic diabetes insipidus is a rare hereditary disease with mainly an X-linked inheritance (90% of the cases) but there are also autosomal recessive and dominant forms. Congenital nephrogenic diabetes insipidus is characterized by a resistance of the renal collecting duct to the action of the arginine vasopressin hormone responsible for the inability of the kidney to concentrate urine. The X-linked form is due to inactivating mutations of the vasopressin 2 receptor gene leading to a loss of function of the mutated receptors. Affected males are often symptomatic in the neonatal period with a lack of weight gain, dehydration and hypernatremia but mild phenotypes may also occur. Females carrying the mutation may be asymptomatic but, sometimes, severe polyuria is found due to the random X chromosome inactivation. The autosomal recessive and dominant forms, occurring in both genders, are linked to mutations in the aquaporin-2 gene. The treatment remains difficult, especially in infants, and is based on a low osmotic diet with increased water intake and the use of thiazides and indomethacin. The main goal is to avoid hypernatremic episodes and maintain a good hydration state. Potentially, specific treatment, in some cases of X-linked congenital nephrogenic diabetes insipidus, with pharmacological chaperones such as non-peptide vasopressin-2 receptor antagonists will be available in the future. Conversely, the nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is linked to a constitutive activation of the V(2)-receptor due to activating mutations with clinical and biological features of inappropriate antidiuresis but with low or undetectable plasma arginine vasopressin hormone levels. Copyright © 2014 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.

Molecular modeling of the human vasopressin V2 receptor/agonist complex

NASA Astrophysics Data System (ADS)

Czaplewski, Cezary; Kaźmierkiewicz, Rajmund; Ciarkowski, Jerzy

1998-05-01

The V2 vasopressin renal receptor (V2R), which controls antidiuresis in mammals, is a member of the large family of heptahelical transmembrane (7TM) G protein-coupled receptors (GPCRs). Using the automated GPCR modeling facility available via Internet (http://expasy.hcuge.ch/swissmod/SWISS-MODEL.html) for construction of the 7TM domain in accord with the bovine rhodopsin (RD) footprint, and the SYBYL software for addition of the intra- and extracellular domains, the human V2R was modeled. The structure was further refined and its conformational variability tested by the use of a version of the Constrained Simulated Annealing (CSA) protocol developed in this laboratory. An inspection of the resulting structure reveals that the V2R (likewise any GPCR modeled this way) is much thicker and accordingly forms a more spacious TM cavity than most of the hitherto modeled GPCR constructs do, typically based on the structure of bacteriorhodopsin (BRD). Moreover, in this model the 7TM helices are arranged differently than they are in any BRD-based model. Thus, the topology and geometry of the TM cavity, potentially capable of receiving ligands, is in this model quite different than it is in the earlier models. In the subsequent step, two ligands, the native [arginine8]vasopressin (AVP) and the selective agonist [d-arginine8]vasopressin (DAVP) were inserted, each in two topologically non-equivalent ways, into the TM cavity and the resulting structures were equilibrated and their conformational variabilities tested using CSA as above. The best docking was selected and justified upon consideration of ligand-receptor interactions and structure-activity data. Finally, the amino acid residues were indicated, mainly in TM helices 3-7, as potentially important in both AVP and DAVP docking. Among those Cys112, Val115-Lys116, Gln119, Met123 in helix 3; Glu174 in helix 4; Val206, Ala210, Val213-Phe214 in helix 5; Trp284, Phe287-Phe288, Gln291 in helix 6; and Phe307, Leu310, Ala314 and Asn317 in helix 7 appeared to be the most important ones. Many of these residues are invariant for either the GPCR superfamily or the neurophyseal (vasopressin V2R, V1aR and V1bR and oxytocin OR) subfamily of receptors. Moreover, some of the equivalent residues in V1aR have already been found critical for the ligand affinity [Mouillac et al., J. Biol. Chem, 270 (1995) 25771].

Vasopressin: physiology, assessment and osmosensation.

PubMed

Bankir, L; Bichet, D G; Morgenthaler, N G

2017-10-01

Vasopressin (AVP) plays a major role in the regulation of water and sodium homeostasis by its antidiuretic action on the kidney, mediated by V2 receptors. AVP secretion is stimulated by a rise in plasma osmolality, a decline in blood volume or stress. V1a receptors are expressed in vascular smooth muscle cells, but the role of vasopressin in blood pressure regulation is still a matter of debate. AVP may also play a role in some metabolic pathways, including gluconeogenesis, through its action on V1a receptors expressed in the liver. It is now understood that thirst and arginine vasopressin (AVP) release are regulated not only by the classical homeostatic, intero-sensory plasma osmolality negative feedback, but also by novel, extero-sensory, anticipatory signals. AVP measurement is time-consuming, and AVP level in the blood in the physiological range is often below the detection limit of the assays. Recently, an immunoassay has been developed for the measurement of copeptin, a fragment of the pre-provasopressin molecule that is easier to measure. It has been shown to be a good surrogate marker of AVP. © 2017 The Association for the Publication of the Journal of Internal Medicine.

Characterization of Three Vasopressin Receptor 2 Variants: An Apparent Polymorphism (V266A) and Two Loss-of-Function Mutations (R181C and M311V)

PubMed Central

Armstrong, Stephen P.; Seeber, Ruth M.; Ayoub, Mohammed Akli; Feldman, Brian J.; Pfleger, Kevin D. G.

2013-01-01

Arginine vasopressin (AVP) is released from the posterior pituitary and controls water homeostasis. AVP binding to vasopressin V2 receptors (V2Rs) located on kidney collecting duct epithelial cells triggers activation of Gs proteins, leading to increased cAMP levels, trafficking of aquaporin-2 water channels, and consequent increased water permeability and antidiuresis. Typically, loss-of-function V2R mutations cause nephrogenic diabetes insipidus (NDI), whereas gain-of-function mutations cause nephrogenic syndrome of inappropriate antidiuresis (NSIAD). Here we provide further characterization of two mutant V2Rs, R181C and M311V, reported to cause complete and partial NDI respectively, together with a V266A variant, in a patient diagnosed with NSIAD. Our data in HEK293FT cells revealed that for cAMP accumulation, AVP was about 500- or 30-fold less potent at the R181C and M311V mutants than at the wild-type receptor respectively (and about 4000- and 60-fold in COS7 cells respectively). However, in contrast to wild type V2R, the R181C mutant failed to increase inositol phosphate production, while with the M311V mutant, AVP exhibited only partial agonism in addition to a 37-fold potency decrease. Similar responses were detected in a BRET assay for β-arrestin recruitment, with the R181C receptor unresponsive to AVP, and partial agonism with a 23-fold decrease in potency observed with M311V in both HEK293FT and COS7 cells. Notably, the V266A V2R appeared functionally identical to the wild-type receptor in all assays tested, including cAMP and inositol phosphate accumulation, β-arrestin interaction, and in a BRET assay of receptor ubiquitination. Each receptor was expressed at comparable levels. Hence, the M311V V2R retains greater activity than the R181C mutant, consistent with the milder phenotype of NDI associated with this mutant. Notably, the R181C mutant appears to be a Gs protein-biased receptor incapable of signaling to inositol phosphate or recruiting β-arrestin. The etiology of NSIAD in the patient with V266A V2R remains unknown. PMID:23762448

Characterization of three vasopressin receptor 2 variants: an apparent polymorphism (V266A) and two loss-of-function mutations (R181C and M311V).

PubMed

Armstrong, Stephen P; Seeber, Ruth M; Ayoub, Mohammed Akli; Feldman, Brian J; Pfleger, Kevin D G

2013-01-01

Arginine vasopressin (AVP) is released from the posterior pituitary and controls water homeostasis. AVP binding to vasopressin V2 receptors (V2Rs) located on kidney collecting duct epithelial cells triggers activation of Gs proteins, leading to increased cAMP levels, trafficking of aquaporin-2 water channels, and consequent increased water permeability and antidiuresis. Typically, loss-of-function V2R mutations cause nephrogenic diabetes insipidus (NDI), whereas gain-of-function mutations cause nephrogenic syndrome of inappropriate antidiuresis (NSIAD). Here we provide further characterization of two mutant V2Rs, R181C and M311V, reported to cause complete and partial NDI respectively, together with a V266A variant, in a patient diagnosed with NSIAD. Our data in HEK293FT cells revealed that for cAMP accumulation, AVP was about 500- or 30-fold less potent at the R181C and M311V mutants than at the wild-type receptor respectively (and about 4000- and 60-fold in COS7 cells respectively). However, in contrast to wild type V2R, the R181C mutant failed to increase inositol phosphate production, while with the M311V mutant, AVP exhibited only partial agonism in addition to a 37-fold potency decrease. Similar responses were detected in a BRET assay for β-arrestin recruitment, with the R181C receptor unresponsive to AVP, and partial agonism with a 23-fold decrease in potency observed with M311V in both HEK293FT and COS7 cells. Notably, the V266A V2R appeared functionally identical to the wild-type receptor in all assays tested, including cAMP and inositol phosphate accumulation, β-arrestin interaction, and in a BRET assay of receptor ubiquitination. Each receptor was expressed at comparable levels. Hence, the M311V V2R retains greater activity than the R181C mutant, consistent with the milder phenotype of NDI associated with this mutant. Notably, the R181C mutant appears to be a Gs protein-biased receptor incapable of signaling to inositol phosphate or recruiting β-arrestin. The etiology of NSIAD in the patient with V266A V2R remains unknown.

Vasopressin differentially modulates aggression and anxiety in adolescent hamsters administered anabolic steroids.

PubMed

Morrison, Thomas R; Ricci, Lesley A; Melloni, Richard H

2016-11-01

Adolescent Syrian hamsters (Mesocricetus auratus) treated with anabolic/androgenic steroids display increased offensive aggression and decreased anxiety correlated with an increase in vasopressin afferent development, synthesis, and neural signaling within the anterior hypothalamus. Upon withdrawal from anabolic/androgenic steroids, this neurobehavioral relationship shifts as hamsters display decreased offensive aggression and increased anxiety correlated with a decrease in anterior hypothalamic vasopressin. This study investigated the hypothesis that alterations in anterior hypothalamic vasopressin neural signaling modulate behavioral shifting between adolescent anabolic/androgenic steroid-induced offensive aggression and anxiety. To test this, adolescent male hamsters were administered anabolic/androgenic steroids and tested for offensive aggression or anxiety following direct pharmacological manipulation of vasopressin V1A receptor signaling within the anterior hypothalamus. Blockade of anterior hypothalamic vasopressin V1A receptor signaling suppressed offensive aggression and enhanced general and social anxiety in hamsters administered anabolic/androgenic steroids during adolescence, effectively reversing the pattern of behavioral response pattern normally observed during the adolescent exposure period. Conversely, activation of anterior hypothalamic vasopressin V1A receptor signaling enhanced offensive aggression in hamsters exposed to anabolic/androgenic steroids during adolescence. Together, these findings suggest that the state of vasopressin neural development and signaling in the anterior hypothalamus plays an important role in behavioral shifting between aggression and anxiety following adolescent exposure to anabolic/androgenic steroids. Copyright © 2016 Elsevier Inc. All rights reserved.

Vasopressin Differentially Modulates Aggression and Anxiety in Adolescent Hamsters Administered Anabolic Steroids

PubMed Central

Morrison, Thomas R.; Ricci, Lesley A.; Melloni, Richard H.

2016-01-01

Adolescent Syrian hamsters (Mesocricetus auratus) treated with anabolic/androgenic steroids display increased offensive aggression and decreased anxiety correlated with an increase in vasopressin afferent development, synthesis, and neural signaling within the anterior hypothalamus. Upon withdrawal from anabolic/androgenic steroids, this neurobehavioral relationship shifts as hamsters display decreased offensive aggression and increased anxiety correlated with a decrease in anterior hypothalamic vasopressin. This study investigated the hypothesis that alterations in anterior hypothalamic vasopressin neural signaling modulate behavioral shifting between adolescent anabolic/androgenic steroid-induced offensive aggression and anxiety. To test this, adolescent male hamsters were administered anabolic/androgenic steroids and tested for offensive aggression or anxiety following direct pharmacological manipulation of vasopressin V1A receptor signaling within the anterior hypothalamus. Blockade of anterior hypothalamic vasopressin V1A receptor signaling suppressed offensive aggression and enhanced general and social anxiety in hamsters administered anabolic/androgenic steroids during adolescence, effectively reversing the pattern of behavioral response pattern normally observed during the adolescent exposure period. Conversely, activation of anterior hypothalamic vasopressin V1A receptor signaling enhanced offensive aggression in hamsters exposed to anabolic/androgenic steroids during adolescence. Together, these findings suggest that the state of vasopressin neural development and signaling in the anterior hypothalamus plays an important role in behavioral shifting between aggression and anxiety following adolescent exposure to anabolic/androgenic steroids. PMID:27149949

Nephrogenic diabetes insipidus: an X chromosome-linked dominant inheritance pattern with a vasopressin type 2 receptor gene that is structurally normal.

PubMed Central

Friedman, E; Bale, A E; Carson, E; Boson, W L; Nordenskjöld, M; Ritzén, M; Ferreira, P C; Jammal, A; De Marco, L

1994-01-01

Nephrogenic diabetes insipidus is a rare hereditary disorder, most commonly transmitted in an X chromosome-linked recessive manner and characterized by the lack of renal response to the action of antidiuretic hormone [Arg8]vasopressin. The vasopressin type 2 receptor (V2R) has been suggested to be the gene that causes the disease, and its role in disease pathogenesis is supported by mutations within this gene in affected individuals. Using the PCR, denaturing gradient gel electrophoresis, and direct DNA sequencing, we examined the V2R gene in four unrelated kindreds. In addition, linkage analysis with chromosome Xq28 markers was done in one large Brazilian kindred with an apparent unusual X chromosome-linked dominant inheritance pattern. In one family, a mutation in codon 280, causing a Tyr-->Cys substitution in the sixth transmembrane domain of the receptor, was found. In the other three additional families with nephrogenic diabetes insipidus, the V2R-coding region was normal in sequence. In one large Brazilian kindred displaying an unusual X chromosome-linked dominant mode of inheritance, the disease-related gene was localized to the same region of the X chromosome as the V2R, but no mutations were found, thus raising the possibility that this disease is caused by a gene other than V2R. Images PMID:8078903

Vasopressin-induced constriction of the isolated rat occipital artery is segment dependent.

PubMed

Chelko, Stephen P; Schmiedt, Chad W; Lewis, Tristan H; Lewis, Stephen J; Robertson, Tom P

2013-01-01

Circulating factors delivered to the nodose ganglion (NG) by the occipital artery (OA) have been shown to affect vagal afferent activity, and thus the contractile state of the OA may influence blood flow to the NG. OA were isolated and bisected into proximal and distal segments relative to the external carotid artery. Bisection highlighted stark differences between maximal contractile responses and OA sensitivity. Specifically, maximum responses to vasopressin and the V1 receptor agonist were significantly higher in distal than proximal segments. Distal segments were significantly more sensitive to 5-hydroxytryptamine (5-HT) and the 5-HT2 receptor agonist than proximal segments. Angiotensin II (AT)2, V2 and 5-HT(1B/1D) receptor agonists did not elicit vascular responses. Additionally, AT1 receptor agonists elicited mild, yet not significantly different maximal responses between segments. The results of this study are consistent with contractile properties of rat OA being mediated via AT1, V1 and 5-HT2 receptors and dependent upon the OA segment. Furthermore, vasopressin-induced constriction of the OA, regardless of a bolus dose or a first and second concentration-response curve, retained this unique segmental difference. We hypothesize that these segmental differences may be important in the regulation of blood flow through the OA in health and disease. © 2013 S. Karger AG, Basel.

Analysis of the V2 Vasopressin Receptor (V2R) Mutations Causing Partial Nephrogenic Diabetes Insipidus Highlights a Sustainable Signaling by a Non-peptide V2R Agonist.

PubMed

Makita, Noriko; Sato, Tomohiko; Yajima-Shoji, Yuki; Sato, Junichiro; Manaka, Katsunori; Eda-Hashimoto, Makiko; Ootaki, Masanori; Matsumoto, Naoki; Nangaku, Masaomi; Iiri, Taroh

2016-10-21

Disease-causing mutations in G protein-coupled receptor (GPCR) genes, including the V2 vasopressin receptor (V2R) gene, often cause misfolded receptors, leading to a defect in plasma membrane trafficking. A novel V2R mutation, T273M, identified in a boy with partial nephrogenic diabetes insipidus (NDI), shows intracellular localization and partial defects similar to the two mutants we described previously (10). Although non-peptide V2R antagonists have been shown to rescue the membrane localization of V2R mutants, their level of functional rescue is weak. Interestingly, it has been reported that a non-peptide agonist, OPC51803, activates misfolded V2R mutants intracellularly without degradation, thus potentially serving as a therapeutic agent against NDI (14). In our current experiments, however, a peptide antagonist blocked arginine vasopressin (AVP)- or OPC51803-stimulated cAMP accumulation both in COS-7 and MDCK cells, suggesting that OPC51803 mainly stimulates cell surface V2R mutants. In addition, our analyses revealed that OPC51803 works not only as a non-peptide agonist that causes activation/β-arrestin-dependent desensitization of V2R mutants expressed at the plasma membrane but also as a pharmacochaperone that promotes the endoplasmic reticulum-retained mutant maturation and trafficking to the plasma membrane. The ratio of the pharmacochaperone effect to the desensitization effect likely correlates negatively with the residual function of the tested mutants, suggesting that OPC5 has a more favorable effect on the V2R mutants with a less residual function. We speculated that the canceling of the desensitization effect of OPC51803 by the pharmacochaperone effect after long-term treatment may produce sustainable signaling, and thus pharmacochaperone agonists such as OPC51803 may serve as promising therapeutics for NDI caused by misfolded V2R mutants. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Analysis of the V2 Vasopressin Receptor (V2R) Mutations Causing Partial Nephrogenic Diabetes Insipidus Highlights a Sustainable Signaling by a Non-peptide V2R Agonist*

PubMed Central

Makita, Noriko; Sato, Tomohiko; Yajima-Shoji, Yuki; Sato, Junichiro; Manaka, Katsunori; Eda-Hashimoto, Makiko; Ootaki, Masanori; Matsumoto, Naoki; Nangaku, Masaomi; Iiri, Taroh

2016-01-01

Disease-causing mutations in G protein-coupled receptor (GPCR) genes, including the V2 vasopressin receptor (V2R) gene, often cause misfolded receptors, leading to a defect in plasma membrane trafficking. A novel V2R mutation, T273M, identified in a boy with partial nephrogenic diabetes insipidus (NDI), shows intracellular localization and partial defects similar to the two mutants we described previously (10). Although non-peptide V2R antagonists have been shown to rescue the membrane localization of V2R mutants, their level of functional rescue is weak. Interestingly, it has been reported that a non-peptide agonist, OPC51803, activates misfolded V2R mutants intracellularly without degradation, thus potentially serving as a therapeutic agent against NDI (14). In our current experiments, however, a peptide antagonist blocked arginine vasopressin (AVP)- or OPC51803-stimulated cAMP accumulation both in COS-7 and MDCK cells, suggesting that OPC51803 mainly stimulates cell surface V2R mutants. In addition, our analyses revealed that OPC51803 works not only as a non-peptide agonist that causes activation/β-arrestin-dependent desensitization of V2R mutants expressed at the plasma membrane but also as a pharmacochaperone that promotes the endoplasmic reticulum-retained mutant maturation and trafficking to the plasma membrane. The ratio of the pharmacochaperone effect to the desensitization effect likely correlates negatively with the residual function of the tested mutants, suggesting that OPC5 has a more favorable effect on the V2R mutants with a less residual function. We speculated that the canceling of the desensitization effect of OPC51803 by the pharmacochaperone effect after long-term treatment may produce sustainable signaling, and thus pharmacochaperone agonists such as OPC51803 may serve as promising therapeutics for NDI caused by misfolded V2R mutants. PMID:27601473

The V1a and V1b, but not V2, vasopressin receptor genes are expressed in the supraoptic nucleus of the rat hypothalamus, and the transcripts are essentially colocalized in the vasopressinergic magnocellular neurons.

PubMed

Hurbin, A; Boissin-Agasse, L; Orcel, H; Rabié, A; Joux, N; Desarménien, M G; Richard, P; Moos, F C

1998-11-01

We have identified and visualized the vasopressin (VP) receptors expressed by hypothalamic magnocellular neurons in supraoptic and paraventricular nuclei. To do this, we used RT-PCR on total RNA extracts from supraoptic nuclei or on single freshly dissociated supraoptic neurons, and in situ hybridization on frontal sections of hypothalamus of Wistar rats. The RT-PCR on supraoptic RNA extracts revealed that mainly V1a, but also V1b, subtypes of VP receptors are expressed from birth to adulthood. No V2 receptor messenger RNA (mRNA) was detected. Furthermore, the single-cell RT-nested PCR indicated that the V1a receptor mRNA is present in vasopressinergic magnocellular neurons. In light of these results, in situ hybridization was performed to visualize the V1a and V1b receptor mRNAs in supraoptic and paraventricular nuclei. Simultaneously, we coupled this approach to: 1) in situ hybridization detection of oxytocin or VP mRNAs; or 2) immunocytochemistry to detect the neuropeptides. This provided a way of identifying the neurons expressing perceptible amounts of V1a or V1b receptor mRNAs as vasopressinergic neurons. Here, we suggest that the autocontrol exerted specifically by VP on vasopressinergic neurons is mediated through, at least, V1a and V1b subtype receptors.

Identification, Characterization and Rescue of a Novel Vasopressin-2 Receptor Mutation Causing Nephrogenic Diabetes Insipidus

PubMed Central

Ranadive, Sayali A.; Ersoy, Baran; Favre, Helene; Cheung, Clement C.; Rosenthal, Stephen M.; Miller, Walter L.; Vaisse, Christian

2018-01-01

SUMMARY Objective X-linked nephrogenic diabetes insipidus (XNDI), caused by mutations in the V2 vasopressin receptor (V2R), is clinically distinguished from central diabetes insipidus (CDI) by elevated serum vasopressin (AVP) levels and unresponsiveness to 1-desamino-8-D-arginine vasopressin (DDAVP). We report two infants with XNDI, and present the characterization and functional rescue of a novel V2R mutation. Patients Two male infants presented with poor growth and hypernatremia. Both patients had measurable pre-treatment serum AVP and polyuria that did not respond to DDAVP, suggesting NDI. However, both also had absent posterior pituitary bright spot on MRI, which is a finding more typical of CDI. Methods The AVPR2 gene encoding V2R was sequenced. The identified novel missense mutation was re-created by site-directed mutagenesis and expressed in HEK293 cells. V2R activity was assessed by the ability of transfected cells to produce cAMP in response to stimulation with DDAVP. Membrane localization of V2R was assessed by fluorescence microscopy. Results Patient 1 had a deletion of AVPR2; patient 2 had the novel mutation L57R. In transiently transfected HEK293 cells, DDAVP induced detectable but severely impaired L57R V2R activity compared to cells expressing wild-type V2R. Fluorescence microscopy showed that myc-tagged wild-type V2R localized to the cell membrane while L57R V2R remained intracellular. A non-peptide V2R chaperone, SR121463, partially rescued L57R V2R function by allowing it to reach the cell membrane. Conclusions L57R V2R has impaired in vitro activity that can be partially improved by treatment with a V2R chaperone. The posterior pituitary hyperintensity may be absent in infants with XNDI. PMID:19170711

Regulation of the vasopressin V2 receptor by vasopressin in polarized renal collecting duct cells.

PubMed

Robben, J H; Knoers, N V A M; Deen, P M T

2004-12-01

Binding of arginine-vasopressin (AVP) to its V2 receptor (V2R) in the basolateral membrane of principal cells induces Aquaporin-2-mediated water reabsorption in the kidney. To study the regulation of the V2R by dDAVP in a proper model, a polarized renal cell line stably-expressing V2R-GFP was generated. Labeled AVP-binding studies revealed an equal basolateral vs. apical membrane distribution for V2R-GFP and endogenous V2R. In these cells, GFP-V2R was expressed in its mature form and localized for 75% in the basolateral membrane and for 25% to late endosomes/lysosomes. dDAVP caused a dose- and time-dependent internalization of V2R-GFP, which was completed within 1 h with 100 nM dDAVP, was prevented by coincubation with a V2R antagonist, and which reduced its half-life from 11.5 to 2.8 h. Semiquantification of the V2R-GFP colocalization with E-cadherin (basolateral membrane), early endosomal antigen-1 (EEA-1) and lysosome-associated membrane protein-2 (LAMP-2) in time revealed that most dDAVP-bound V2R was internalized via early endosomes to late endosomes/lysosomes, where it was degraded. The dDAVP-internalized V2R did not recycle to the basolateral membrane. In conclusion, we established the itinerary of the V2R in a polarized cell model that likely resembles the in vivo V2R localization and regulation by AVP to a great extent.

Diabetes Diminishes the Portal-Systemic Collateral Vascular Response to Vasopressin via Vasopressin Receptor and Gα Proteins Regulations in Cirrhotic Rats

PubMed Central

Lee, Jing-Yi; Huo, Teh-Ia; Wang, Sun-Sang; Lin, Han-Chieh; Chuang, Chiao-Lin; Lee, Shou-Dong

2013-01-01

Liver cirrhosis may lead to portal-systemic collateral formation and bleeding. The hemostatic effect is influenced by the response of collateral vessels to vasoconstrictors. Diabetes and glucose also influence vasoresponsiveness, but their net effect on collaterals remains unexplored. This study investigated the impact of diabetes or glucose application on portal-systemic collateral vasoresponsiveness to arginine vasopressin (AVP) in cirrhosis. Spraque-Dawley rats with bile duct ligation (BDL)-induced cirrhosis received vehicle (citrate buffer) or streptozotocin (diabetic, BDL/STZ). The in situ collateral perfusion was done after hemodynamic measurements: Both were perfused with Krebs solution, D-glucose, or D-glucose and NaF, with additional OPC-31260 for the BDL/STZ group. Splenorenal shunt vasopressin receptors and Gα proteins mRNA expressions were evaluated. The survival rate of cirrhotic rats was decreased by STZ injection. The collateral perfusion pressure changes to AVP were lower in STZ-injected groups, which were reversed by OPC-31260 (a V2R antagonist) and overcome by NaF (a G protein activator). The splenorenal shunt V2R mRNA expression was increased while Gα proteins mRNA expressions were decreased in BDL/STZ rats compared to BDL rats. The Gαq and Gα11 mRNA expressions also correlated with the maximal perfusion pressure changes to AVP. Diabetes diminished the portal-systemic collateral vascular response to AVP in rats with BDL-induced cirrhosis, probably via V2 receptor up-regulation and Gα proteins down-regulation. PMID:23874439

Diabetes diminishes the portal-systemic collateral vascular response to vasopressin via vasopressin receptor and Gα proteins regulations in cirrhotic rats.

PubMed

Lee, Jing-Yi; Huo, Teh-Ia; Wang, Sun-Sang; Huang, Hui-Chun; Lee, Fa-Yauh; Lin, Han-Chieh; Chuang, Chiao-Lin; Lee, Shou-Dong

2013-01-01

Liver cirrhosis may lead to portal-systemic collateral formation and bleeding. The hemostatic effect is influenced by the response of collateral vessels to vasoconstrictors. Diabetes and glucose also influence vasoresponsiveness, but their net effect on collaterals remains unexplored. This study investigated the impact of diabetes or glucose application on portal-systemic collateral vasoresponsiveness to arginine vasopressin (AVP) in cirrhosis. Spraque-Dawley rats with bile duct ligation (BDL)-induced cirrhosis received vehicle (citrate buffer) or streptozotocin (diabetic, BDL/STZ). The in situ collateral perfusion was done after hemodynamic measurements: Both were perfused with Krebs solution, D-glucose, or D-glucose and NaF, with additional OPC-31260 for the BDL/STZ group. Splenorenal shunt vasopressin receptors and Gα proteins mRNA expressions were evaluated. The survival rate of cirrhotic rats was decreased by STZ injection. The collateral perfusion pressure changes to AVP were lower in STZ-injected groups, which were reversed by OPC-31260 (a V2R antagonist) and overcome by NaF (a G protein activator). The splenorenal shunt V2R mRNA expression was increased while Gα proteins mRNA expressions were decreased in BDL/STZ rats compared to BDL rats. The Gαq and Gα11 mRNA expressions also correlated with the maximal perfusion pressure changes to AVP. Diabetes diminished the portal-systemic collateral vascular response to AVP in rats with BDL-induced cirrhosis, probably via V2 receptor up-regulation and Gα proteins down-regulation.

Interaction of a vasopressin antagonist with vasopressin receptors in the septum of the rat brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dorsa, D.M.; Brot, M.D.; Shewey, L.M.

1988-01-01

The ability of d(CH2)5-Tyr(Me)-arginine-8-vasopressin, an antagonist of peripheral pressoric (V1-type) vasopressin receptors, to label vasopressin binding sites in the septum of the rat brain was evaluated. Using crude membrane preparations from the septum, /sup 3/H-arginine-8-vasopressin (AVP) specifically labels a single class of binding sites with a Kd of 2.9 nM and maximum binding site concentration of 19.8 fmole/mg protein. /sup 3/H-Antag also labels a single class of membrane sites but with higher affinity (Kd = 0.47 nM) and lower capacity (10.1 fmole/mg protein) than /sup 3/H-AVP. The rank order of potency of various competitor peptides for /sup 3/H-AVP and /supmore » 3/H-Antag binding was similar. Oxytocin was 100-1,000 fold less potent than AVP in competing for binding with both ligands. /sup 3/H-AVP and /sup 3/H-Antag showed similar labeling patterns when incubated with septal tissue slices. Unlabeled Antag also effectively antagonized vasopressin-stimulated phosphatidylinositol hydrolysis in septal tissue slices.« less

Mutations of Vasopressin Receptor 2 Including Novel L312S Have Differential Effects on Trafficking.

PubMed

Tiulpakov, Anatoly; White, Carl W; Abhayawardana, Rekhati S; See, Heng B; Chan, Audrey S; Seeber, Ruth M; Heng, Julian I; Dedov, Ivan; Pavlos, Nathan J; Pfleger, Kevin D G

2016-08-01

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a genetic disease first described in 2 unrelated male infants with severe symptomatic hyponatremia. Despite undetectable arginine vasopressin levels, patients have inappropriately concentrated urine resulting in hyponatremia, hypoosmolality, and natriuresis. Here, we describe and functionally characterize a novel vasopressin type 2 receptor (V2R) gain-of-function mutation. An L312S substitution in the seventh transmembrane domain was identified in a boy presenting with water-induced hyponatremic seizures at the age of 5.8 years. We show that, compared with wild-type V2R, the L312S mutation results in the constitutive production of cAMP, indicative of the gain-of-function NSIAD profile. Interestingly, like the previously described F229V and I130N NSIAD-causing mutants, this appears to both occur in the absence of notable constitutive β-arrestin2 recruitment and can be reduced by the inverse agonist Tolvaptan. In addition, to understand the effect of various V2R substitutions on the full receptor "life-cycle," we have used and further developed a bioluminescence resonance energy transfer intracellular localization assay using multiple localization markers validated with confocal microscopy. This allowed us to characterize differences in the constitutive and ligand-induced localization and trafficking profiles of the novel L312S mutation as well as for previously described V2R gain-of-function mutants (NSIAD; R137C and R137L), loss-of-function mutants (nephrogenic diabetes insipidus; R137H, R181C, and M311V), and a putative silent V266A V2R polymorphism. In doing so, we describe differences in trafficking between unique V2R substitutions, even at the same amino acid position, therefore highlighting the value of full and thorough characterization of receptor function beyond simple signaling pathway analysis.

Sex-specific modulation of juvenile social play by vasopressin.

PubMed

Veenema, Alexa H; Bredewold, Remco; De Vries, Geert J

2013-11-01

Social play activities among juveniles are thought to contribute to the development of social and emotional skills in humans and animals. Conversely, social play deficits are observed in developmental neuropsychiatric disorders. Importantly, many of these disorders show sex differences in incidence, course of the disease, and severity of symptoms. We hypothesized that sex differences in the neural systems controlling social behavior can contribute to these differences. We therefore studied the involvement of the sexually dimorphic vasopressin and oxytocin systems, which have been implicated in these disorders, in juvenile social play behavior. Single-housed 5-week-old juvenile male and female rats were exposed in their home cage to an age-and sex-matched novel conspecific for 10 min, and social play behaviors were recorded. We found no consistent sex differences in duration or elements of social play in vehicle-treated rats. However, intracerebroventricular injection of the specific vasopressin 1a receptor (V1aR) antagonist (CH2)5Tyr(Me(2))AVP significantly reduced social play behaviors in males while increasing them in females. Intracerebroventricular injection of the specific oxytocin receptor antagonist des-Gly-NH2,d(CH2)5[Tyr(Me)(2),Thr(4)]OVT did not alter social play in either sex. To locate the effects of V1aR blockade on social play, we targeted the lateral septum, a sexually dimorphic brain region showing denser vasopressin fibers in males than in females and an abundant expression of V1aR in both sexes. Surprisingly, blockade of V1aR in the lateral septum increased social play behaviors in males, but decreased them in females. These findings suggest sex- and brain region-specific roles for vasopressin in the regulation of social play behavior in juvenile rats. Copyright © 2013 Elsevier Ltd. All rights reserved.

Sex-specific modulation of juvenile social play by vasopressin

PubMed Central

Veenema, Alexa H.; Bredewold, Remco; De Vries, Geert J.

2013-01-01

SUMMARY Social play activities among juveniles are thought to contribute to the development of social and emotional skills in humans and animals. Conversely, social play deficits are observed in developmental neuropsychiatric disorders. Importantly, many of these disorders show sex differences in incidence, course of the disease, and severity of symptoms. We hypothesized that sex differences in the neural systems controlling social behavior can contribute to these differences. We therefore studied the involvement of the sexually dimorphic vasopressin and oxytocin systems, which have been implicated in these disorders, in juvenile social play behavior. Single-housed 5-week-old juvenile male and female rats were exposed to an unknown age-and sex-matched conspecific for 10 min in their home cage and social play behaviors were recorded. We found no consistent sex differences in level or elements of social play in vehicle-treated rats. However, intracerebroventricular injection of the specific vasopressin 1a receptor (V1aR) antagonist (CH2)5Tyr(Me2) AVP significantly reduced social play behaviors in males, while increasing them in females. Intracerebroventricular injection of the specific oxytocin receptor antagonist des-Gly-NH2,d(CH2)5[Tyr(Me)2,Thr4]OVT did not alter social play in either sex. To locate the effects of V1aR blockade on social play, we targeted the lateral septum, a sexually dimorphic brain region showing denser vasopressin fibers in males than in females and abundant expression of V1aR in both sexes. Surprisingly, blockade of V1aR in the lateral septum increased social play behaviors in males, but decreased them in females. These findings suggest sex- and brain region-specific roles for vasopressin in the regulation of social play behavior in juvenile rats. PMID:23838102

Vasopressin regulates social recognition in juvenile and adult rats of both sexes, but in sex- and age-specific ways.

PubMed

Veenema, A H; Bredewold, R; De Vries, G J

2012-01-01

In adult male rats, vasopressin (AVP) facilitates social recognition via activation of V1a receptors within the lateral septum. Much less is known about how AVP affects social recognition in adult females or in juvenile animals of either sex. We found that administration of the specific V1a receptor antagonist d(CH(2))(5)[Tyr(Me)(2)]AVP into the lateral septum of adult rats impaired, whereas AVP extended, social discrimination in both sexes. In juveniles, however, we detected a sex difference, such that males but not females showed social discrimination. Interestingly, administration of the V1a receptor antagonist to juveniles (either intracerebroventricularly or locally in the lateral septum) did not prevent social discrimination, but instead significantly decreased the investigation of a novel as opposed to a familiar animal in both sexes, with stronger effects in males. V1a receptors were found to be abundantly expressed in the lateral septum with higher binding density in females than in males. These findings demonstrate that activation of V1a receptors in the lateral septum is important for social recognition in both sexes, and that the roles of septal V1a receptors in social recognition change during development. Copyright © 2011 Elsevier Inc. All rights reserved.

Binding-, intracellular transport-, and biosynthesis-defective mutants of vasopressin type 2 receptor in patients with X-linked nephrogenic diabetes insipidus.

PubMed Central

Tsukaguchi, H; Matsubara, H; Taketani, S; Mori, Y; Seido, T; Inada, M

1995-01-01

Nephrogenic diabetes insipidus (NDI) is most often an X-linked disorder in which urine is not concentrated due to renal resistance to arginine vasopressin. We recently identified four vasopressin type 2 receptor gene mutations in unrelated X-linked NDI families, including R143P, delta V278, R202C, and 804insG. All these mutations reduced ligand binding activity to < 10% of the normal without affecting mRNA accumulation. To elucidate whether the receptors are expressed on the cell surface, we analyzed biosynthesis and localization of tagged or untagged receptors stably expressed in Chinese hamster ovary (CHO) cells, using two antibodies directed against distinct termini. Whole-cell and surface labeling studies revealed that the R202C clone had both surface-localized (50-55 kD) and intracellular proteins (40 and 75 kD), similar to the wild-type AVPR2 clone, whereas the R143P and delta V278 clones lacked the surface receptors, despite relatively increased intracellular components. The 804insG mutant cell produced no proteins despite an adequate mRNA level. Immunofluorescence staining confirmed that the R202C mutant reaches the cell surface, whereas the R143P and delta V278 mutants are retained within the cytoplasmic compartment. Thus, R202C, R143P/delta V278, and 804insG result in three distinct phenotypes, that is, a simple binding impairment at the cell surface, blocked intracellular transport, and ineffective biosynthesis or/and accelerated degradation of the receptor, respectively, and therefore are responsible for NDI. This phenotypic classification will help understanding of molecular pathophysiology of this disorder. Images PMID:7560098

Decreased vasopressin-mediated renal water reabsorption in rats with compensated liver cirrhosis.

PubMed

Jonassen, T E; Nielsen, S; Christensen, S; Petersen, J S

1998-08-01

Experiments were performed to investigate vasopressin type 2 receptor (V2)-mediated renal water reabsorption and the renal expression of the vasopressin-regulated water channel aquaporin-2 (AQP-2) in cirrhotic rats with sodium retention but without ascites. In addition, the expression of the furosemide-sensitive type 1 Na-K-2Cl cotransporter (BSC-1) and the natriuretic response to an intravenous test dose furosemide (7.5 mg/kg) during acute V2-receptor blockade was measured. Acute V2-receptor blockade with the selective nonpeptide antagonist OPC-31260 (800 microg . kg-1 . h-1) was performed during conditions in which volume depletion was prevented by computer-driven, servo-controlled intravenous volume replacement with 150 mM glucose. OPC-31260 produced a significantly smaller increase in urine flow rate (-26%) and free water clearance (-18%) in cirrhotic rats than in control rats. The natriuretic response to an intravenous test dose furosemide (7.5 mg/kg) was significantly increased in cirrhotic rats (+52%), but pretreatment with OPC-31260 did not affect the natriuretic response to furosemide in neither cirrhotic nor in control rats. Semiquantitative immunoblotting showed a significant downregulation of AQP-2 in the renal cortex (-72%) and in the outer medulla (-44%). The relative expression of BSC-1 in the outer medulla was unchanged in cirrhotic rats. The corticopapillary gradient of Na was significantly increased in cirrhotic rats. Since daily urine flow rate was similar in cirrhotic and sham-operated rats, we suggest that non-vasopressin-mediated water reabsorption is increased in cirrhotic rats probably as a result of an increased corticomedullary gradient due to exaggerated NaCl reabsorption in the thick ascending limb of Henle's loop.

Neonatal oxytocin and vasopressin manipulation alter social behavior during the juvenile period in Mongolian gerbils.

PubMed

Taylor, Jack H; Cavanaugh, Jon; French, Jeffrey A

2017-07-01

Oxytocin and vasopressin are important modulators of a wide variety of social behaviors, and increasing evidence is showing that these neuropeptides are important organizational effectors of later-life behavior as well. We treated day-old gerbil pups with oxytocin, vasopressin, an oxytocin receptor antagonist, a vasopressin V1a receptor antagonist, or saline control, and then measured received parental responsiveness during the early postnatal period and juvenile social behavior during weaning. Neonatal vasopressin treatment enhanced sociality in males, but not females, at both developmental time points. When pups were individually placed outside the nest, parents were more responsive to male pups treated with vasopressin compared with littermates, and vasopressin treated male pups exhibited increased play with littermates as juveniles. These results show that vasopressin during very early life can enhance social interactions throughout early development. © 2017 Wiley Periodicals, Inc.

Molecular modeling of interactions of the non-peptide antagonist YM087 with the human vasopressin V1a, V2 receptors and with oxytocin receptors.

NASA Astrophysics Data System (ADS)

Giełdoń, Artur; Kaźmierkiewicz, Rajmund; Ślusarz, Rafał; Ciarkowski, Jerzy

2001-12-01

The nonapeptide hormones arginine vasopressin (CYFQNCPRG-NH2, AVP) and oxytocin (CYIQNCPLG-NH2, OT), control many essential functions in mammals. Their main activities include the urine concentration (via stimulation of AVP V2 receptors, V2R, in the kidneys), blood pressure regulation (via stimulation of vascular V1a AVP receptors, V1aR), ACTH control (via stimulation of V1b receptors, V1bR, in the pituitary) and labor and lactation control (via stimulation of OT receptors, OTR, in the uterus and nipples, respectively). All four receptor subtypes belong to the GTP-binding (G) protein-coupled receptor (GPCR) family. This work consists of docking of YM087, a potent non-peptide V1aR and V2R - but not OTR - antagonist, into the receptor models based on relatively new theoretical templates of rhodopsin (RD) and opiate receptors, proposed by Mosberg et al. (Univ. of Michigan, Ann Arbor, USA). It is simultaneously demonstrated that this RD template satisfactorily compares with the first historical GPCR structure of bovine rhodopsin (Palczewski et al., 2000) and that homology-modeling of V2R, V1aR and OTR using opiate receptors as templates is rational, based on relatively high (20-60%) sequence homology among the set of 4 neurophyseal and 4 opiate receptors. YM087 was computer-docked to V1aR, V2R and OTR using the AutoDock (Olson et al., Scripps Research Institute, La Jolla, USA) and subsequently relaxed using restrained simulated annealing and molecular dynamics, as implemented in AMBER program (Kollman et al., University of California, San Francisco, USA). From about 80 diverse configurations, sampled for each of the three ligand/receptor systems, 3 best energy-relaxed complexes were selected for mutual comparisons. Similar docking modes were found for the YM087/V1aR and YM087/V2R complexes, diverse from those of the YM087/OTR complexes, in agreement with the molecular affinity data.

Vasopressin and sympathetic system mediate the cardiovascular effects of the angiotensin II in the bed nucleus of the stria terminalis in rat.

PubMed

Nasimi, Ali; Kafami, Marzieh

2016-07-01

The bed nucleus of the stria terminalis (BST) is involved in cardiovascular regulation. The angiotensin II (Ang II) receptor (AT1), and angiotensinogen were found in the BST. In our previous study we found that microinjection of Ang II into the BST produced a pressor response. This study was performed to find the mechanisms mediating this response in anesthetized rats. Ang II was microinjected into the BST and the cardiovascular responses were re-tested after systemic injection of a blocker of autonomic or vasopressin V1 receptor. The ganglionic nicotinic receptor blocker, hexamethonium dichloride, attenuated the pressor response to Ang II, indicating that the cardiovascular sympathetic system is involved in the pressor effect of Ang II. A selective vasopressin V1 receptor antagonist greatly attenuated the pressor effect of Ang II, indicating that the Ang II increases the arterial pressure via stimulation of vasopressin release as well. In conclusion, in the BST, Ang II as a neurotransmitter increases blood pressure by exciting cardiovascular sympathetic system and directly or indirectly causing vasopressin to release into bloodstream by VPN. This is an interesting new finding that not only circulating Ang II but also brain Ang II makes vasopressin release. Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

Central vasopressin V1a receptor activation is independently necessary for both partner preference formation and expression in socially monogamous male prairie voles.

PubMed

Donaldson, Zoe R; Spiegel, Lauren; Young, Larry J

2010-02-01

The neuropeptide arginine vasopressin (AVP) modulates a variety of species-specific social behaviors. In socially monogamous male prairie voles, AVP acts centrally via vasopressin V1a receptor (V1aR) to facilitate mating induced partner preferences. The display of a partner preference requires at least 2 temporally distinct processes: social bond formation as well as its recall, or expression. Studies to date have not determined in which of these processes V1aR acts to promote partner preferences. Here, male prairie voles were administered intracerebroventricularly a V1aR antagonist (AVPA) at different time points to investigate the role of V1aR in social bond formation and expression. Animals receiving AVPA prior to cohabitation with mating or immediately prior to partner preference testing failed to display a partner preference, while animals receiving AVPA immediately after cohabitation with mating and control animals receiving vehicle at all 3 time points displayed partner preferences. These results suggest that V1aR signaling is necessary for both the formation and expression of partner preferences and that these processes are dissociable. (c) 2009 APA, all rights reserved.

Biological half-life and organ distribution of [3H]8-arginine vasopressin following administration of vasopressin receptor antagonist OPC-31260.

PubMed

Molnár, Andor H; Varga, Csaba; Janáky, Tamás; Tóth, Gábor; Tóth, Géza; Farkas, Judit; László, Ferenc; László, Ferenc A

2007-06-07

The effects of the antidiuretic (V(2)) non-peptide receptor antagonist OPC-31260 on the plasma vasopressin level and the biological half-life and organ distribution of radiochemically pure, biologically active [(3)H]8-arginine vasopressin [spec. act.: 15.9 mCi/mmol (588 GBq/mmol)] were studied in Wistar rats. The plasma vasopressin level increased significantly throughout the whole experimental period (24 h). There was no change in the fast phase of the curves of total radioactivity disappearance from the plasma after the administration of [(3)H]arginine vasopressin (control: 1.51+/-0.17 min, OPC-31260-treated: 1.42+/-0.12 min, n=10). The fast phase of the disappearance curves of intact [(3)H]arginine vasopressin did not change either following the administration of OPC-31260 in a dose of 30 mg/kg p.o. (control: 1.06+/-0.19 min, OPC-31260-treated: 1.00+/-0.15 min, n=6). The slow phase of the biological half-life, which is characteristic for the examined compound, proved to be significantly longer (total radioactivity control: 9.29+/-0.61 min, OPC-31260-treated: 12.33+/-0.42 min, P<0.05, n=10; [(3)H]arginine vasopressin radioactivity: control: 5.96+/-0.58 min, OPC-31260-treated: 8.90+/-0.37 min, P<0.05, n=6). In the control rats, the radioactivity was accumulated to the greatest extent in the neurohypophysis, adenohypophysis and kidney. Following OPC-31260 administration, significantly more radioactive compounds accumulated in the kidney (control: 0.30+/-0.052 total radioactivity %/100 mg organ weight, OPC-31260-treated: 0.50+/-0.133 total radioactivity %/100 mg organ weight, P<0.05, n=10) and neurohypophysis (control: 0.37+/-0.053 total radioactivity %/100 mg organ weight, OPC-31260-treated: 0.52+/-0.076 total radioactivity %/100 mg organ weight, P<0.05, n=10). Our results permit the conclusion that the antidiuretic antagonist OPC-31260 not only blocks the V(2) receptors, but also increases the biological half-life of vasopressin. The longer biological half-life of vasopressin following OPC-31260 administration may play a role in the elevation of the plasma vasopressin level.

Vasopressin regulates the growth of the biliary epithelium in polycystic liver disease

PubMed Central

Mancinelli, Romina; Franchitto, Antonio; Glaser, Shannon; Vetuschi, Antonella; Venter, Julie; Sferra, Roberta; Pannarale, Luigi; Olivero, Francesca; Carpino, Guido; Alpini, Gianfranco; Onori, Paolo; Gaudio, Eugenio

2017-01-01

The neurohypophysial hormone arginine vasopressin (AVP) acts by three distinct receptor subtypes: V1a, V1b, and V2. In the liver, AVP is involved in ureogenesis, glycogenolysis, neoglucogenesis and regeneration. No data exist about the presence of AVP in the biliary epithelium. Cholangiocytes are the target cells in a number of animal models of cholestasis, including bile duct ligation (BDL), and in several human pathologies, such as polycystic liver disease characterized by the presence of cysts that bud from the biliary epithelium. In vivo, liver fragments from normal and BDL mice and rats as well as liver samples from normal and ADPKD patients were collected to evaluate: (i) intrahepatic bile duct mass by immunohistochemistry for cytokeratin-19; and (ii) expression of V1a, V1b and V2 by immunohistochemistry, immunofluorescence and real-time PCR. In vitro, small and large mouse cholangiocytes, H69 (non-malignant human cholangiocytes) and LCDE (human cholangiocytes from the cystic epithelium) were stimulated with vasopressin in the absence/presence of AVP antagonists such as OPC-31260 and Tolvaptan, before assessing cellular growth by MTT assay and cAMP levels. Cholangiocytes express V2 receptor that was upregulated following BDL and in ADPKD liver samples. Administration of AVP increased proliferation and cAMP levels of small cholangiocytes and LCDE cells. We found no effect in the proliferation of large mouse cholangiocytes and H69 cells. Increases were blocked by preincubation with the AVP antagonists. These results showed that AVP and its receptors may be important in the modulation of the proliferation rate of the biliary epithelium. PMID:27571215

Vasopressin regulates the growth of the biliary epithelium in polycystic liver disease.

PubMed

Mancinelli, Romina; Franchitto, Antonio; Glaser, Shannon; Vetuschi, Antonella; Venter, Julie; Sferra, Roberta; Pannarale, Luigi; Olivero, Francesca; Carpino, Guido; Alpini, Gianfranco; Onori, Paolo; Gaudio, Eugenio

2016-11-01

The neurohypophysial hormone arginine vasopressin (AVP) acts by three distinct receptor subtypes: V1a, V1b, and V2. In the liver, AVP is involved in ureogenesis, glycogenolysis, neoglucogenesis and regeneration. No data exist about the presence of AVP in the biliary epithelium. Cholangiocytes are the target cells in a number of animal models of cholestasis, including bile duct ligation (BDL), and in several human pathologies, such as polycystic liver disease characterized by the presence of cysts that bud from the biliary epithelium. In vivo, liver fragments from normal and BDL mice and rats as well as liver samples from normal and ADPKD patients were collected to evaluate: (i) intrahepatic bile duct mass by immunohistochemistry for cytokeratin-19; and (ii) expression of V1a, V1b and V2 by immunohistochemistry, immunofluorescence and real-time PCR. In vitro, small and large mouse cholangiocytes, H69 (non-malignant human cholangiocytes) and LCDE (human cholangiocytes from the cystic epithelium) were stimulated with vasopressin in the absence/presence of AVP antagonists such as OPC-31260 and Tolvaptan, before assessing cellular growth by MTT assay and cAMP levels. Cholangiocytes express V2 receptor that was upregulated following BDL and in ADPKD liver samples. Administration of AVP increased proliferation and cAMP levels of small cholangiocytes and LCDE cells. We found no effect in the proliferation of large mouse cholangiocytes and H69 cells. Increases were blocked by preincubation with the AVP antagonists. These results showed that AVP and its receptors may be important in the modulation of the proliferation rate of the biliary epithelium.

Vasopressin and Diabetic Kidney Disease.

PubMed

El Boustany, Ray

2018-01-01

Diabetic nephropathy has become the most common cause of chronic kidney disease (CKD). Despite the progress accomplished in therapy, the prevalence of renal disorders remains high. Some modifiable factors driving the increase in incidence of CKD, in diabetes and other settings, might have been overlooked. Consistent evidence supports a role for vasopressin, hydration state, and urine concentration in kidney health. Plasma vasopressin is elevated in diabetes, even if metabolic control is good. Several epidemiological studies have pointed to a positive association between markers of vasopressin secretion (24-h fluid intake, urine volume, plasma copeptin concentration) and renal function decline in both the community and populations at high risk of CKD, namely, diabetic patients. Research involving animal models also supports a critical causal role of the V2 receptor antidiuretic effects of vasopressin in the early signs of kidney disease associated with type 1 or type 2 diabetes. Key Messages: Data supporting the detrimental effects of chronic vasopressin action on the kidney is consistent in animal models and human observational studies. Since vasopressin secretion can be modulated by water intake, and its actions by selective receptor antagonists, the vasopressin-hydration system could be a potential therapeutic target for the prevention and treatment of diabetic nephropathy. Intervention studies are needed to examine the relevance of lifestyle or pharmacological interventions. © 2018 The Author(s) Published by S. Karger AG, Basel.

OPC-41061, a highly potent human vasopressin V2-receptor antagonist: pharmacological profile and aquaretic effect by single and multiple oral dosing in rats.

PubMed

Yamamura, Y; Nakamura, S; Itoh, S; Hirano, T; Onogawa, T; Yamashita, T; Yamada, Y; Tsujimae, K; Aoyama, M; Kotosai, K; Ogawa, H; Yamashita, H; Kondo, K; Tominaga, M; Tsujimoto, G; Mori, T

1998-12-01

The pharmacological profile and the acute and chronic aquaretic effects of OPC-41061, a novel nonpeptide human arginine vasopressin (AVP) V2-receptor antagonist, were respectively characterized in HeLa cells expressing cloned human AVP receptors and in conscious male rats. OPC-41061 antagonized [3H]-AVP binding to human V2-receptors (Ki = 0.43 +/- 0.06 nM) more potently than AVP (Ki = 0. 78 +/- 0.08 nM) or OPC-31260 (Ki = 9.42 +/- 0.90 nM). OPC-41061 also inhibited [3H]-AVP binding to human V1a-receptors (Ki = 12.3 +/- 0.8 nM) but not to human V1b-receptors, indicating that OPC-41061 was 29 times more selective for V2-receptors than for V1a-receptors. OPC-41061 inhibited cAMP production induced by AVP with no intrinsic agonist activity. In rats, OPC-41061 inhibited [3H]-AVP binding to V1a-receptors (Ki = 325 +/- 41 nM) and V2-receptors (Ki = 1.33 +/- 0. 30 nM), showing higher receptor selectivity (V1a/V2 = 244) than with human receptors. A single oral administration of OPC-41061 in rats clearly produced dose-dependent aquaresis. In treatment by multiple OPC-41061 dosing for 28 days at 1 and 10 mg/kg p.o. in rats, significant aquaretic effects were seen throughout the study period. As the result of aquaresis, hemoconcentration was seen at 4 hr postdosing although, no differences were seen in serum osmolality, sodium, creatinine and urea nitrogen concentrations at 24 hr postdosing. Furthermore, there was no difference in serum AVP concentration, pituitary AVP content or the number and affinity of AVP receptors in the kidney and liver at trough throughout the study period. These results demonstrate that OPC-41061 is a highly potent human AVP V2-receptor antagonist and produces clear aquaresis after single and multiple dosing, suggesting the usefulness in the treatment of various water retaining states.

Characterization of a novel aquaretic agent, OPC-31260, as an orally effective, nonpeptide vasopressin V2 receptor antagonist.

PubMed

Yamamura, Y; Ogawa, H; Yamashita, H; Chihara, T; Miyamoto, H; Nakamura, S; Onogawa, T; Yamashita, T; Hosokawa, T; Mori, T

1992-04-01

1. OPC-31260, a benzazepine derivative, has been studied for its ability to antagonize the binding of arginine vasopressin (AVP) to receptors in rat liver (V1) and kidney (V2) plasma membranes, for antagonism of the antidiuretic action of AVP in alcohol-anaesthetized rats and for diuretic action in conscious normal rats. 2. OPC-31260 caused a competitive displacement of [3H]-AVP binding to both V1 and V2 receptors with IC50 values of 1.2 +/- 0.2 x 10(-6) M and 1.4 +/- 0.2 x 10(-8) M, respectively. 3. OPC-31260 at doses of 10 to 100 micrograms kg-1, i.v., inhibited the antidiuretic action of exogenously administered AVP in water-loaded, alcohol-anaesthetized rats in a dose-dependent manner. OPC-31260 did not exert an antidiuretic activity suggesting that it is not a partial V2 receptor agonist. 4. After oral administration at doses of 1 to 30 mg kg-1 in normal conscious rats, OPC-31260 dose-dependently increased urine flow and decreased urine osmolality. The diuretic action of OPC-31260 was characterized as aquaresis, the mode of diuretic action being different from previously known diuretic agents such as furosemide, hydrochlorothiazide and spironolactone. 5. The results indicate that OPC-31260 is a selective V2 receptor antagonist and behaves as an aquaretic agent. OPC-31260 will be a useful tool in studying the physiological role of AVP and in the treatment of various conditions characterized by water retention.

Characterization of a novel aquaretic agent, OPC-31260, as an orally effective, nonpeptide vasopressin V2 receptor antagonist

PubMed Central

Yamamura, Yoshitaka; Ogawa, Hidenori; Yamashita, Hiroshi; Chihara, Tomihiko; Miyamoto, Hisashi; Nakamura, Shigeki; Onogawa, Toshiyuki; Yamashita, Tatsuya; Hosokawa, Tetsumi; Mori, Toyoki; Tominaga, Michiaki; Yabuuchi, Youichi

1992-01-01

1 OPC-31260, a benzazepine derivative, has been studied for its ability to antagonize the binding of arginine vasopressin (AVP) to receptors in rat liver (V1) and kidney (V2) plasma membranes, for antagonism of the antidiuretic action of AVP in alcohol-anaesthetized rats and for diuretic action in conscious normal rats. 2 OPC-31260 caused a competitive displacement of [3H]-AVP binding to both V1 and V2 receptors with IC50 values of 1.2 ± 0.2 × 10-6 M and 1.4 ± 0.2 × 10-8 M, respectively. 3 OPC-31260 at doses of 10 to 100 μg kg-1, i.v., inhibited the antidiuretic action of exogenously administered AVP in water-loaded, alcohol-anaesthetized rats in a dose-dependent manner. OPC-31260 did not exert an antidiuretic activity suggesting that it is not a partial V2 receptor agonist. 4 After oral administration at doses of 1 to 30 mg kg-1 in normal conscious rats, OPC-31260 dose-dependently increased urine flow and decreased urine osmolality. The diuretic action of OPC-31260 was characterized as aquaresis, the mode of diuretic action being different from previously known diuretic agents such as furosemide, hydrochlorothiazide and spironolactone. 5 The results indicate that OPC-31260 is a selective V2 receptor antagonist and behaves as an aquaretic agent. OPC-31260 will be a useful tool in studying the physiological role of AVP and in the treatment of various conditions characterized by water retention. PMID:1387020

β-Adrenergic Receptor-Mediated Cardiac Contractility is Inhibited via Vasopressin Type 1A-Receptor-Dependent Signaling

PubMed Central

Tilley, Douglas G.; Zhu, Weizhong; Myers, Valerie D.; Barr, Larry A.; Gao, Erhe; Li, Xue; Song, Jianliang; Carter, Rhonda L.; Makarewich, Catherine A.; Yu, Daohai; Troupes, Constantine D.; Grisanti, Laurel A.; Coleman, Ryan C.; Koch, Walter J.; Houser, Steven R.; Cheung, Joseph Y.; Feldman, Arthur M.

2014-01-01

Background Enhanced arginine vasopressin (AVP) levels are associated with increased mortality during end-stage human heart failure (HF), and cardiac AVP type 1A receptor (V1AR) expression becomes increased. Additionally, mice with cardiac-restricted V1AR overexpression develop cardiomyopathy and decreased β-adrenergic receptor (βAR) responsiveness. This led us to hypothesize that V1AR signaling regulated βAR responsiveness and in doing so contributes to HF development. Methods and Results Transaortic constriction resulted in decreased cardiac function and βAR density and increased cardiac V1AR expression, effects reversed by a V1AR-selective antagonist. Molecularly, V1AR stimulation led to decreased βAR ligand affinity, as well as βAR-induced Ca2+ mobilization and cAMP generation in isolated adult cardiomyocytes, effects recapitulated via ex vivo Langendorff analysis. V1AR-mediated regulation of βAR responsiveness was demonstrated to occur in a previously unrecognized Gq protein-independent/GRK-dependent manner. Conclusions This newly discovered relationship between cardiac V1AR and βAR may be informative for the treatment of patients with acute decompensated HF and elevated AVP. PMID:25205804

Vasopressin regulates social recognition in juvenile and adult rats of both sexes, but in sex- and age-specific ways

PubMed Central

Veenema, AH; Bredewold, R; De Vries, GJ

2011-01-01

In adult male rats, vasopressin (AVP) facilitates social recognition via activation of V1a receptors within the lateral septum. Much less is known about how AVP affects social recognition in adult females or in juvenile animals of either sex. We found that administration of the specific V1a receptor antagonist (CH2)5Tyr(Me)AVP into the lateral septum of adult rats impaired, whereas AVP extended, social discrimination in both sexes. In juveniles, however, we detected a sex difference, such that males but not females showed social discrimination. Interestingly, administration of the V1a receptor antagonist to juveniles (either intracerebroventricularly or locally in the lateral septum) did not prevent social discrimination, but instead significantly decreased the investigation of a novel as opposed to a familiar animal in both sexes, with stronger effects in males. V1a receptors were found to be abundantly expressed in the lateral septum with higher binding density in females than in males at both ages. These findings demonstrate that activation of V1a receptors in the septum is important for social recognition in both sexes, and that the roles of septal V1a receptors in social recognition change during development. PMID:22033278

Restoration of peripheral V2 receptor vasopressin signaling fails to correct behavioral changes in Brattleboro rats.

PubMed

Balázsfi, Diána; Pintér, Ottó; Klausz, Barbara; Kovács, Krisztina B; Fodor, Anna; Török, Bibiána; Engelmann, Mario; Zelena, Dóra

2015-01-01

Beside its hormonal function in salt and water homeostasis, vasopressin released into distinct brain areas plays a crucial role in stress-related behavior resulting in the enhancement of an anxious/depressive-like state. We aimed to investigate whether correction of the peripheral symptoms of congenital absence of AVP also corrects the behavioral alterations in AVP-deficient Brattleboro rats. Wild type (WT) and vasopressin-deficient (KO) male Brattleboro rats were tested. Half of the KO animals were treated by desmopressin (V2-receptor agonist) via osmotic minipump (subcutaneous) to eliminate the peripheral symptoms of vasopressin-deficiency. Anxiety was studied by elevated plus maze (EPM), defensive withdrawal (DW) and marble burying (MB) tests, while depressive-like changes were monitored in forced swimming (FS) and anhedonia by sucrose preference test. Cell activity was examined in septum and amygdala by c-Fos immunohistochemistry after 10 min FS. KO rats spent more time in the open arm of the EPM, spent less time at the periphery of DW and showed less burying behavior in MB suggesting a reduced anxiety state. KO animals showed less floating behavior during FS revealing a less depressive phenotype. Desmopressin treatment compensated the peripheral effects of vasopressin-deficiency without a significant influence on the behavior. The FS-induced c-Fos immunoreactivity in the medial amygdala was different in WT and KO rats, with almost identical levels in KO and desmopressin treated animals. There were no differences in central and basolateral amygdala as well as in lateral septum. Our data confirmed the role of vasopressin in the development of affective disorders through central mechanisms. The involvement of the medial amygdala in the behavioral alterations of vasopressin deficient animals deserves further attention. Copyright © 2014 Elsevier Ltd. All rights reserved.

A selective EP4 PGE2 receptor agonist alleviates disease in a new mouse model of X-linked nephrogenic diabetes insipidus

PubMed Central

Li, Jian Hua; Chou, Chung-Lin; Li, Bo; Gavrilova, Oksana; Eisner, Christoph; Schnermann, Jürgen; Anderson, Stasia A.; Deng, Chu-Xia; Knepper, Mark A.; Wess, Jürgen

2009-01-01

X-linked nephrogenic diabetes insipidus (XNDI) is a severe kidney disease caused by inactivating mutations in the V2 vasopressin receptor (V2R) gene that result in the loss of renal urine-concentrating ability. At present, no specific pharmacological therapy has been developed for XNDI, primarily due to the lack of suitable animal models. To develop what we believe to be the first viable animal model of XNDI, we generated mice in which the V2R gene could be conditionally deleted during adulthood by administration of 4-OH-tamoxifen. Radioligand-binding studies confirmed the lack of V2R-binding sites in kidneys following 4-OH-tamoxifen treatment, and further analysis indicated that upon V2R deletion, adult mice displayed all characteristic symptoms of XNDI, including polyuria, polydipsia, and resistance to the antidiuretic actions of vasopressin. Gene expression analysis suggested that activation of renal EP4 PGE2 receptors might compensate for the lack of renal V2R activity in XNDI mice. Strikingly, both acute and chronic treatment of the mutant mice with a selective EP4 receptor agonist greatly reduced all major manifestations of XNDI, including changes in renal morphology. These physiological improvements were most likely due to a direct action on EP4 receptors expressed on collecting duct cells. These findings illustrate the usefulness of the newly generated V2R mutant mice for elucidating and testing new strategies for the potential treatment of humans with XNDI. PMID:19729836

The physiological and pathophysiological functions of renal and extrarenal vasopressin V2 receptors.

PubMed

Juul, Kristian Vinter; Bichet, Daniel G; Nielsen, Søren; Nørgaard, Jens Peter

2014-05-01

The arginine vasopressin (AVP) type 2 receptor (V2R) is unique among AVP receptor subtypes in signaling through cAMP. Its key function is in the kidneys, facilitating the urine concentrating mechanism through the AVP/V2 type receptor/aquaporin 2 system in the medullary and cortical collecting ducts. Recent clinical and research observations strongly support the existence of an extrarenal V2R. The clinical importance of the extrarenal V2R spans widely from stimulation of coagulation factor in the endothelium to as yet untested potential therapeutic targets. These include V2R-regulated membranous fluid turnover in the inner ear, V2R-regulated mitogensis and apoptosis in certain tumor tissues, and numerous other cell types where the physiological role of V2Rs still requires further research. Here, we review current evidence on the physiological and pathophysiological functions of renal and extrarenal V2Rs. These functions of V2R are important, not only in rare diseases with loss or gain of function of V2R but also in relation to the recent use of nonpeptide V2R antagonists to treat hyponatremia and possibly retard the growth of cysts and development of renal failure in autosomal dominant polycystic kidney disease. The main functions of V2R in principal cells of the collecting duct are water, salt, and urea transport by modifying the trafficking of aquaporin 2, epithelial Na(+) channels, and urea transporters and vasodilation and stimulation of coagulation factor properties, mainly seen with pharmacological doses of 1-desamino-8-D-AVP. The AVPR2 gene is located on the X chromosome, in a region with high probability of escape from inactivation; this may lead to phenotypic sex differences, with females expressing higher levels of transcript than males.

Adenylyl cyclase 6 enhances NKCC2 expression and mediates vasopressin-induced phosphorylation of NKCC2 and NCC.

PubMed

Rieg, Timo; Tang, Tong; Uchida, Shinichi; Hammond, H Kirk; Fenton, Robert A; Vallon, Volker

2013-01-01

Arginine vasopressin (AVP) affects kidney function via vasopressin V2 receptors that are linked to activation of adenylyl cyclase (AC) and an increase in cyclic adenosine monophosphate formation. AVP/cyclic adenosine monophosphate enhance the phosphorylation of the Na-K-2Cl cotransporter (NKCC2) at serine residue 126 (pS126 NKCC2) and of the Na-Cl cotransporter (NCC) at threonine 58 (pT58 NCC). The isoform(s) of AC involved in these responses, however, were unknown. Phosphorylation of S126 NKCC2 and T58 NCC, induced by the V2 receptor agonist (1-desamino-8-D-arginine vasopressin) in wild-type mice, is lacking in knockout mice for AC isoform 6 (AC6). With regard to NKCC2 phosphorylation, the stimulatory effect of 1-desamino-8-D-AVP and the defect in AC6(-/-) mice seem to be restricted to the medullary portion of the thick ascending limb. AC6 is also a stimulator of total renal NKCC2 protein abundance in medullary and cortical thick ascending limb. Consequently, mice lacking AC6 have lower NKCC2 expression and a mild Bartter syndrome-like phenotype, including lower plasma concentrations of K+ and H+ and compensatory upregulation of NCC. Increased AC6-independent phosphorylation of NKCC2 at S126 might help to stabilize NKCC2 activity in the absence of AC6. Renal AC6 determines total NKCC2 expression and mediates vasopressin-induced NKCC2/NCC phosphorylation. These regulatory mechanisms, which are defective in AC knockout mice, are likely responsible for the observed mild Bartter syndrome. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Oxytocin and Vasopressin Agonists and Antagonists as Research Tools and Potential Therapeutics

PubMed Central

Manning, M; Misicka, A; Olma, A; Bankowski, K; Stoev, S; Chini, B; Durroux, T; Mouillac, B; Corbani, M; Guillon, G

2012-01-01

We recently reviewed the status of peptide and nonpeptide agonists and antagonists for the V1a, V1b and V2 receptors for arginine vasopressin (AVP) and the oxytocin receptor for oxytocin (OT). In the present review, we update the status of peptides and nonpeptides as: (i) research tools and (ii) therapeutic agents. We also present our recent findings on the design of fluorescent ligands for V1b receptor localisation and for OT receptor dimerisation. We note the exciting discoveries regarding two novel naturally occurring analogues of OT. Recent reports of a selective VP V1a agonist and a selective OT agonist point to the continued therapeutic potential of peptides in this field. To date, only two nonpeptides, the V2/V1a antagonist, conivaptan and the V2 antagonist tolvaptan have received Food and Drug Administration approval for clinical use. The development of nonpeptide AVP V1a, V1b and V2 antagonists and OT agonists and antagonists has recently been abandoned by Merck, Sanofi and Pfizer. A promising OT antagonist, Retosiban, developed at Glaxo SmithKline is currently in a Phase II clinical trial for the prevention of premature labour. A number of the nonpeptide ligands that were not successful in clinical trials are proving to be valuable as research tools. Peptide agonists and antagonists continue to be very widely used as research tools in this field. In this regard, we present receptor data on some of the most widely used peptide and nonpeptide ligands, as a guide for their use, especially with regard to receptor selectivity and species differences. PMID:22375852

The effect of aspartate-lysine-isoleucine and aspartate-arginine-tyrosine mutations on the expression and activity of vasopressin V2 receptor gene.

PubMed

Najafzadeh, Hossein; Safaeian, Leila; Mirmohammad Sadeghi, Hamid; Rabbani, Mohammad; Jafarian, Abbas

2010-01-01

Vasopressin type 2 receptor (V2R) plays an important role in the water reabsorption in the kidney collecting ducts. V2R is a G protein coupled receptor (GPCR) and the triplet of amino acids aspartate-arginine-histidine (DRH) in this receptor might significantly influence its activity similar to other GPCR. However, the role of this motif has not been fully confirmed. Therefore, the present study attempted to shed some more light on the role of DRH motif in G protein coupling and V2R function with the use of site-directed mutagenesis. Nested PCR using specific primers was used to produce DNA fragments containing aspartate-lysine-isoleucine and aspartate-arginine-tyrosine mutations with replacements of the arginine to lysine and histidine to tyrosine, respectively. After digestion, these inserts were ligated into the pcDNA3 vector and transformation into E. coli HB101 was performed using heat shock method. The obtained colonies were analyzed for the presence and orientation of the inserts using proper restriction enzymes. After transient transfection of COS-7 cells using diethylaminoethyl-dextran method, the adenylyl cyclase activity assay was performed for functional study. The cell surface expression was analyzed by indirect ELISA method. The functional assay indicated that none of these mutations significantly altered cAMP production and cell surface expression of V2R in these cells. Since some substitutions in arginine residue have shown to lead to the inactive V2 receptor, further studies are required to define the role of this residue more precisely. However, it seems that the role of the histidine residue is not critical in the V2 receptor function.

Vasopressin-independent targeting of aquaporin-2 by selective E-prostanoid receptor agonists alleviates nephrogenic diabetes insipidus.

PubMed

Olesen, Emma T B; Rützler, Michael R; Moeller, Hanne B; Praetorius, Helle A; Fenton, Robert A

2011-08-02

In the kidney, the actions of vasopressin on its type-2 receptor (V2R) induce increased water reabsorption alongside polyphosphorylation and membrane targeting of the water channel aquaporin-2 (AQP2). Loss-of-function mutations in the V2R cause X-linked nephrogenic diabetes insipidus. Treatment of this condition would require bypassing the V2R to increase AQP2 membrane targeting, but currently no specific pharmacological therapy is available. The present study examined specific E-prostanoid receptors for this purpose. In vitro, prostaglandin E2 (PGE2) and selective agonists for the E-prostanoid receptors EP2 (butaprost) or EP4 (CAY10580) all increased trafficking and ser-264 phosphorylation of AQP2 in Madin-Darby canine kidney cells. Only PGE2 and butaprost increased cAMP and ser-269 phosphorylation of AQP2. Ex vivo, PGE2, butaprost, or CAY10580 increased AQP2 phosphorylation in isolated cortical tubules, whereas PGE2 and butaprost selectively increased AQP2 membrane accumulation in kidney slices. In vivo, a V2R antagonist caused a severe urinary concentrating defect in rats, which was greatly alleviated by treatment with butaprost. In conclusion, EP2 and EP4 agonists increase AQP2 phosphorylation and trafficking, likely through different signaling pathways. Furthermore, EP2 selective agonists can partially compensate for a nonfunctional V2R, providing a rationale for new treatment strategies for hereditary nephrogenic diabetes insipidus.

Vasopressin-independent targeting of aquaporin-2 by selective E-prostanoid receptor agonists alleviates nephrogenic diabetes insipidus

PubMed Central

Olesen, Emma T. B.; Rützler, Michael R.; Moeller, Hanne B.; Praetorius, Helle A.; Fenton, Robert A.

2011-01-01

In the kidney, the actions of vasopressin on its type-2 receptor (V2R) induce increased water reabsorption alongside polyphosphorylation and membrane targeting of the water channel aquaporin-2 (AQP2). Loss-of-function mutations in the V2R cause X-linked nephrogenic diabetes insipidus. Treatment of this condition would require bypassing the V2R to increase AQP2 membrane targeting, but currently no specific pharmacological therapy is available. The present study examined specific E-prostanoid receptors for this purpose. In vitro, prostaglandin E2 (PGE2) and selective agonists for the E-prostanoid receptors EP2 (butaprost) or EP4 (CAY10580) all increased trafficking and ser-264 phosphorylation of AQP2 in Madin-Darby canine kidney cells. Only PGE2 and butaprost increased cAMP and ser-269 phosphorylation of AQP2. Ex vivo, PGE2, butaprost, or CAY10580 increased AQP2 phosphorylation in isolated cortical tubules, whereas PGE2 and butaprost selectively increased AQP2 membrane accumulation in kidney slices. In vivo, a V2R antagonist caused a severe urinary concentrating defect in rats, which was greatly alleviated by treatment with butaprost. In conclusion, EP2 and EP4 agonists increase AQP2 phosphorylation and trafficking, likely through different signaling pathways. Furthermore, EP2 selective agonists can partially compensate for a nonfunctional V2R, providing a rationale for new treatment strategies for hereditary nephrogenic diabetes insipidus. PMID:21768374

Increase in sensitivity of the baroreceptor reflex following microinjection of carbachol into the posterior hypothalamic nucleus of awake rats.

PubMed

Newey, C R; Martin, J R

2016-01-01

In a rat model, the baroreceptor reflex can be assessed by graded infusions of either phenylephrine or sodium nitroprusside with continuous hemodynamic monitoring. Microinjection of the cholinergic agonist carbachol (CCh) into the posterior hypothalamic nucleus (PHN) evokes an increase in mean arterial pressure and a change in heart rate. Lower doses of CCh evoke only tachycardia, whereas middle and higher doses evoke a biphasic change in heart rate of tachycardia followed by bradycardia. The bradycardia following the microinjection of CCh into the PHN can be attenuated by the previous administration of the vasopressin V1 receptor antagonist [d(CH2 )5 Tyr(Me)] arginine vasopressin (AVPX). Circulating arginine vasopressin (AVP) has been shown to increase the sensitivity of the baroreceptor reflex by stimulating vasopressin V1 receptors in the area postrema. The attenuation by AVPX of the bradycardia that results following the high doses of CCh suggests that AVP is released into the circulation following stimulation of cholinergic systems within the PHN. Thus, microinjection of a high dose of CCh (11 nmol) into the PHN alters the sensitivity of the baroreceptor reflex by increasing peripheral levels of AVP. © 2016 John Wiley & Sons Ltd.

Oxytocin and vasopressin: distinct receptors in myometrium

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guillon, G.; Balestre, M.N.; Roberts, J.M.

1987-06-01

The binding characteristics of (/sup 3/H)oxytocin (( /sup 3/H)OT) and (/sup 3/H)lysine vasopressin (( /sup 3/H)LVP) to nonpregnant human myometrium were investigated. Binding of both radioligands was saturable, time dependent, and reversible. Whereas (/sup 3/H)OT was found to bind to a single class of sites with high affinity (Kd, 1.5 +/- 0.4 (+/- SEM) nM) and low capacity (maximum binding (Bmax), 34 +/- 6 fmol/mg protein), (/sup 3/H)LVP bound to two classes of sites, one with high affinity (Kd, 2.2 +/- 0.1 nM) and low capacity (Bmax, 198 +/- 7 fmol/mg protein) and another with low affinity (Kd, 655 +/-more » 209 nM) and high capacity (Bmax, 5794 +/- 1616 fmol/mg protein). The binding of the labeled peptides also displayed a marked difference in sensitivity to Mg2+ and guanine nucleotides. These differences in binding characteristics as well as the differences in potency of analogs in competing for (/sup 3/H)OT and (/sup 3/H)LVP binding indicate the presence of distinct receptors for OT and vasopressin in human myometrium. Pharmacological characterization of the high affinity binding sites for (/sup 3/H)LVP indicated that these are of the V1 subtype. Although, as suggested by others, vasopressin and OT can bind to the same sites, the presence of distinct receptors for both peptides provides an explanation for the previously reported difference in myometrial responsiveness to OT and vasopressin.« less

An intrinsic vasopressin system in the olfactory bulb is involved in social recognition

PubMed Central

Tobin, Vicky A.; Hashimoto, Hirofumi; Wacker, Douglas W.; Takayanagi, Yuki; Langnaese, Kristina; Caquineau, Celine; Noack, Julia; Landgraf, Rainer; Onaka, Tatsushi; Leng, Gareth; Meddle, Simone L.; Engelmann, Mario; Ludwig, Mike

2010-01-01

Many peptides, when released as chemical messengers within the brain, have powerful influences on complex behaviours. Most strikingly, vasopressin and oxytocin, once thought of as circulating hormones whose actions were confined to peripheral organs, are now known to be released in the brain where they play fundamentally important roles in social behaviours1. In humans, disruptions of these peptide systems have been linked to several neurobehavioural disorders, including Prader-Willi syndrome, affective disorders, and obsessive-compulsive disorder, and polymorphisms of the vasopressin V1a receptor have been linked to autism2,3. Here we report that the rat olfactory bulb contains a large population of interneurones which express vasopressin, that blocking the actions of vasopressin in the olfactory bulb impairs the social recognition abilities of rats, and that vasopressin agonists and antagonists can modulate the processing of information by olfactory bulb neurones. The findings indicate that social information is processed in part by a vasopressin system intrinsic to the olfactory system. PMID:20182426

A Minireview on Vasopressin-regulated Aquaporin-2 in Kidney Collecting Duct Cells.

PubMed

Park, Eui-Jung; Kwon, Tae-Hwan

2015-06-01

The kidney collecting duct is an important renal tubular segment for the regulation of body water and salt homeostasis. Water reabsorption in the collecting duct cells is regulated by arginine vasopressin (AVP) via the vasopressin V2-receptor (V2R). AVP increases the osmotic water permeability of the collecting duct cells through aquaporin-2 (AQP2) and aquaporin-3 (AQP3). AVP induces the apical targeting of AQP2 and transcription of AQP2 gene in the kidney collecting duct principal cells. The signaling transduction pathways resulting in the AQP2 trafficking to the apical plasma membrane of the collecting duct principal cells, include AQP2 phosphorylation, RhoA phosphorylation, actin depolymerization and calcium mobilization, and the changes of AQP2 protein abundance in water balance disorders have been extensively studied. These studies elucidate the underlying cellular and molecular mechanisms of body water homeostasis and provide the basis for the treatment of body water balance disorders.

Mechanism of the cardiovascular effects of the GABAA receptors of the ventral tegmental area of the rat brain.

PubMed

Yeganeh, Fahimeh; Ranjbar, Afsaneh; Hatam, Masoumeh; Nasimi, Ali

2015-07-23

The ventral tegmental area (VTA) contains GABA terminals involved in the regulation of the cardiovascular system. Previously, we demonstrated that blocking GABAA but not GABAB receptors produced a pressor response accompanied by marked bradycardia. This study was performed to find the possible mechanisms involved in these responses by blocking ganglionic nicotinic receptors, peripheral muscarinic receptors or peripheral V1 vasopressin receptors. Experiments were performed on urethane anesthetized male Wistar rats. Drugs were microinjected unilaterally into the VTA (100 nl). The average changes in mean arterial pressure (MAP) and heart rate (HR) were compared between pre- and post-treatment using paired t-test. Injection of bicuculline methiodide (BMI), a GABAA antagonist, into the VTA caused a significant increase in MAP and a decrease in HR. Administration (i.v.) of the nicotinic receptor blocker, hexamethonium, enhanced the pressor response but abolished the bradycardic response to BMI, which ruled out involvement of the sympathetic nervous system. Blockade of the peripheral muscarinic receptors by homatropine (i.v.) abolished the bradycardic effect of BMI, but had no effect on the pressor response, indicating that bradycardia was produced by the parasympathetic outflow to the heart. Both the pressor and bradycardic responses to BMI were blocked by V1 receptor antagonist (i.v.), indicating that administration of BMI in the VTA disinhibited the release of vasopressin into the circulation. In conclusion, we demonstrated that GABAergic mechanism of the VTA exerts a tonic inhibition on vasopressin release through activation of GABAA receptors. The sympathetic system is not involved in the decrease of blood pressure by GABA of the VTA. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Structural insights into biased G protein-coupled receptor signaling revealed by fluorescence spectroscopy.

PubMed

Rahmeh, Rita; Damian, Marjorie; Cottet, Martin; Orcel, Hélène; Mendre, Christiane; Durroux, Thierry; Sharma, K Shivaji; Durand, Grégory; Pucci, Bernard; Trinquet, Eric; Zwier, Jurriaan M; Deupi, Xavier; Bron, Patrick; Banères, Jean-Louis; Mouillac, Bernard; Granier, Sébastien

2012-04-24

G protein-coupled receptors (GPCRs) are seven-transmembrane proteins that mediate most cellular responses to hormones and neurotransmitters, representing the largest group of therapeutic targets. Recent studies show that some GPCRs signal through both G protein and arrestin pathways in a ligand-specific manner. Ligands that direct signaling through a specific pathway are known as biased ligands. The arginine-vasopressin type 2 receptor (V2R), a prototypical peptide-activated GPCR, is an ideal model system to investigate the structural basis of biased signaling. Although the native hormone arginine-vasopressin leads to activation of both the stimulatory G protein (Gs) for the adenylyl cyclase and arrestin pathways, synthetic ligands exhibit highly biased signaling through either Gs alone or arrestin alone. We used purified V2R stabilized in neutral amphipols and developed fluorescence-based assays to investigate the structural basis of biased signaling for the V2R. Our studies demonstrate that the Gs-biased agonist stabilizes a conformation that is distinct from that stabilized by the arrestin-biased agonists. This study provides unique insights into the structural mechanisms of GPCR activation by biased ligands that may be relevant to the design of pathway-biased drugs.

Green mamba peptide targets type-2 vasopressin receptor against polycystic kidney disease

PubMed Central

Ciolek, Justyna; Reinfrank, Helen; Quinton, Loïc; Viengchareun, Say; Vera, Laura; Sigismeau, Sabrina; Mouillac, Bernard; Orcel, Hélène; Peigneur, Steve; Tytgat, Jan; Droctové, Laura; Beau, Fabrice; Nevoux, Jerome; Lombès, Marc; Mourier, Gilles; De Pauw, Edwin; Servent, Denis; Mendre, Christiane; Witzgall, Ralph; Gilles, Nicolas

2017-01-01

Polycystic kidney diseases (PKDs) are genetic disorders that can cause renal failure and death in children and adults. Lowering cAMP in cystic tissues through the inhibition of the type-2 vasopressin receptor (V2R) constitutes a validated strategy to reduce disease progression. We identified a peptide from green mamba venom that exhibits nanomolar affinity for the V2R without any activity on 155 other G-protein–coupled receptors or on 15 ionic channels. Mambaquaretin-1 is a full antagonist of the V2R activation pathways studied: cAMP production, beta-arrestin interaction, and MAP kinase activity. This peptide adopts the Kunitz fold known to mostly act on potassium channels and serine proteases. Mambaquaretin-1 interacts selectively with the V2R through its first loop, in the same manner that aprotinin inhibits trypsin. Injected in mice, mambaquaretin-1 increases in a dose-dependent manner urine outflow with concomitant reduction of urine osmolality, indicating a purely aquaretic effect associated with the in vivo blockade of V2R. CD1-pcy/pcy mice, a juvenile model of PKD, daily treated with 13 𝝁g of mambaquaretin-1 for 99 d, developed less abundant (by 33%) and smaller (by 47%) cysts than control mice. Neither tachyphylaxis nor apparent toxicity has been noted. Mambaquaretin-1 represents a promising therapeutic agent against PKDs. PMID:28630289

Vasopressin Mediates the Renal Damage Induced by Limited Fructose Rehydration in Recurrently Dehydrated Rats.

PubMed

García-Arroyo, Fernando E; Tapia, Edilia; Blas-Marron, Mónica G; Gonzaga, Guillermo; Silverio, Octaviano; Cristóbal, Magdalena; Osorio, Horacio; Arellano-Buendía, Abraham S; Zazueta, Cecilia; Aparicio-Trejo, Omar Emiliano; Reyes-García, Juan G; Pedraza-Chaverri, José; Soto, Virgilia; Roncal-Jiménez, Carlos; Johnson, Richard J; Sánchez-Lozada, Laura G

2017-01-01

Recurrent dehydration and heat stress cause chronic kidney damage in experimental animals. The injury is exacerbated by rehydration with fructose-containing beverages. Fructose may amplify dehydration-induced injury by directly stimulating vasopressin release and also by acting as a substrate for the aldose reductase-fructokinase pathway, as both of these systems are active during dehydration. The role of vasopressin in heat stress associated injury has not to date been explored. Here we show that the amplification of renal damage mediated by fructose in thermal dehydration is mediated by vasopressin. Fructose rehydration markedly enhanced vasopressin (copeptin) levels and activation of the aldose reductase-fructokinase pathway in the kidney. Moreover, the amplification of the renal functional changes (decreased creatinine clearance and tubular injury with systemic inflammation, renal oxidative stress, and mitochondrial dysfunction) were prevented by the blockade of V1a and V2 vasopressin receptors with conivaptan. On the other hand, there are also other operative mechanisms when water is used as rehydration fluid that produce milder renal damage that is not fully corrected by vasopressin blockade. Therefore, we clearly showed evidence of the cross-talk between fructose, even at small doses, and vasopressin that interact to amplify the renal damage induced by dehydration. These data may be relevant for heat stress nephropathy as well as for other renal pathologies due to the current generalized consumption of fructose and deficient hydration habits.

Binding of [3H] SR 49059, a potent nonpeptide vasopressin V1a antagonist, to rat and human liver membranes.

PubMed

Serradeil-Le Gal, C; Raufaste, D; Marty, E; Garcia, C; Maffrand, J P; Le Fur, G

1994-02-28

The new potent and selective nonpeptide vasopressin V1a antagonist, SR 49059, was tritiated and used for the characterization of rat and human liver AVP V1a receptors. Binding of [3H] SR 49059 was time-dependent, reversible and saturable. A single class of high affinity binding sites was identified with Kd values of 0.63 +/- 0.13 and 2.95 +/- 0.64 nM, in rat and human liver membranes, respectively. The maximal binding capacity (Bmax) was about 7 times higher in rat than in human liver preparations. The relative potencies of several AVP/oxytocin agonists or antagonists to inhibit [3H] SR 49059 binding confirmed that this ligand labeled a homogeneous population of sites with the expected AVP V1a profile. Furthermore, [3H] SR 49059 or unlabeled SR 49059 displayed only slight species differences between rat and human V1a receptors, whereas OPC-21268, another nonpeptide V1a antagonist, exhibited a high species-related potency with more than 500 fold higher affinity for rat than for human liver V1a receptors. Thus, [3H] SR 49059 is the first nonpeptide AVP V1a ligand reported having highly specific activity, stability, specificity and affinity. This makes it a suitable probe for labeling AVP V1a receptors in rat and also in human tissues.

Nonpeptide vasopressin receptor antagonists: development of selective and orally active V1a, V2 and V1b receptor ligands.

PubMed

Serradeil-Le Gal, C; Wagnon, J; Valette, G; Garcia, G; Pascal, M; Maffrand, J P; Le Fur, G

2002-01-01

The involvement of vasopressin (AVP) in several pathological states has been reported recently and the selective blockade of the different AVP receptors could offer new clinical perspectives. During the past few years, various selective, orally active AVP V1a (OPC-21268, SR49059 (Relcovaptan)), V2 (OPC-31260, OPC-41061 (Tolvaptan), VPA-985 (Lixivaptan), SR121463, VP-343, FR-161282) and mixed V1a/V2 (YM-087 (Conivaptan), JTV-605, CL-385004) receptor antagonists have been intensively studied in various animal models and have reached, Phase IIb clinical trials for some of them. For many years now, our laboratory has focused on the identification of nonpeptide vasopressin antagonists with suitable oral bioavailability. Using random screening on small molecule libraries, followed by rational SAR and modelization, we identified a chemical series of 1-phenylsulfonylindolines which first yielded SR49059, a V1a receptor antagonist prototype. This compound displayed high affinity for animal and human V1a receptors and antagonized various V1a AVP-induced effects in vitro and in vivo (intracellular [Ca2+] increase, platelet aggregation, vascular smooth muscle cell proliferation, hypertension and coronary vasospasm). We and others have used this compound to study the role of AVP in various animal models. Recent findings from clinical trials show a potential interest for SR49059 in the treatment of dysmenorrhea and in Raynaud's disease. Structural modifications and simplifications performed in the SR49059 chemical series yielded highly specific V2 receptor antagonists (N-arylsulfonyl-oxindoles), amongst them SR121463 which possesses powerful oral aquaretic properties in various animal species and in man. SR121463 is well-tolerated and dose-dependently increases urine output and decreases urine osmolality. It induces free water-excretion without affecting electrolyte balance in contrast to classical diuretics (e.g. furosemide and hydrochlorothiazide). Notably, in cirrhotic rats with ascites and impaired renal function, a 10-day oral treatment with SR121463 (0.5 mg/kg) totally corrected hyponatremia and restored normal urine excretion. This compound also displayed interesting new properties in a rabbit model of ocular hypertension, decreasing intraocular pressure after single or repeated instillation. Thus, V2 receptor blockade could be of interest in several water-retaining diseases such as the syndrome of inappropriate antidiuretic hormone secretion (SIADH), liver cirrhosis and congestive heart failure and deserves to be widely explored. Finally, further chemical developments in the oxindole family have led to the first specific and orally active V1b receptor antagonists (with SSR149415 as a representative), an awaited class of drugs with expected therapeutic interest mainly in ACTH-secreting tumors and various emotional diseases such as stress-related disorders, anxiety and depression. However, from the recently described tissue localization for this receptor, we could also speculate on other unexpected uses. In conclusion, the development of AVP receptor antagonists is a field of intensive pharmacological and clinical investigation. Selective and orally active compounds are now available to give new insight into the pathophysiological role of AVP and to provide promising drugs.

Arginine vasopressin antagonizes the effects of prostaglandin E2 on the spontaneous activity of warm-sensitive and temperature-insensitive neurons in the medial preoptic area in rats.

PubMed

Xu, Jian-Hui; Hou, Xiao-Yu; Tang, Yu; Luo, Rong; Zhang, Jie; Liu, Chang; Yang, Yong-Lu

2018-01-01

Arginine vasopressin (AVP) plays an important role in thermoregulation and antipyresis. We have demonstrated that AVP could change the spontaneous activity of thermosensitive and temperature insensitive neurons in the preoptic area. However, whether AVP influences the effects of prostaglandin E 2 (PGE 2 ) on the spontaneous activity of neurons in the medial preoptic area (MPO) remains unclear. Our experiment showed that PGE 2 decreased the spontaneous activity of warm-sensitive neurons, and increased that of low-slope temperature-insensitive neurons in the MPO. AVP attenuated the inhibitory effect of PGE 2 on warm-sensitive neurons, and reversed the excitatory effect of PGE 2 on low-slope temperature-insensitive neurons, demonstrating that AVP antagonized the effects of PGE 2 on the spontaneous activity of these neurons. The effect of AVP was suppressed by an AVP V 1a receptor antagonist, suggesting that V 1a receptor mediated the action of AVP. We also demonstrated that AVP attenuated the PGE 2 -induced decrease in the prepotential's rate of rise in warm-sensitive neurons and the PGE 2 -induced increase in that in low-slope temperature-insensitive neurons through the V 1a receptor. Together, these data indicated that AVP antagonized the PGE 2 -induced change in the spontaneous activity of warm-sensitive and low-slope temperature-insensitive neurons in the MPO partly by reducing the PGE 2 -induced change in the prepotential of these neurons in a V 1a receptor-dependent manner. Copyright © 2017 Elsevier B.V. All rights reserved.

Characterization of rodent liver and kidney AVP receptors: pharmacologic evidence for species differences.

PubMed

Tahara, A; Tsukada, J; Ishii, N; Tomura, Y; Wada, K; Kusayama, T; Yatsu, T; Uchida, W; Tanaka, A

1999-10-22

Radioligand binding studies with [3H]vasopressin (AVP) were used to determine the affinities of AVP receptor agonists and antagonists for mouse liver and kidney plasma membrane preparations. Both membrane preparations exhibited one class of high-affinity binding site. AVP ligand binding inhibition studies confirmed that mouse liver binding sites belong to the V1A subtype while kidney binding sites belong to the V2 receptor subtype. The affinity of each ligand for mouse V1A receptors was very similar to that for rat V1A receptors, showing differences in Ki values of less than 3-fold. In contrast, several peptide (d(CH2)5Tyr(Me)AVP) and nonpeptide (OPC-21268 and SR 49059) ligands had different affinities for mouse and rat kidney V2 receptors, with differences in Ki values ranging from 14- to 17-fold. These results indicate that mouse and rat kidney V2 receptors show significant pharmacologic differences.

Nephrogenic diabetes insipidus.

PubMed

Bockenhauer, D; Bichet, Daniel G

2017-04-01

In nephrogenic diabetes insipidus (NDI), the kidney is unable to concentrate urine despite elevated concentrations of the antidiuretic hormone arginine-vasopressin. In congenital NDI, polyuria and polydipsia are present from birth and should be immediately recognized to avoid severe episodes of dehydration. Unfortunately, NDI is still often recognized late after a 'diagnostic odyssey' involving false leads and dangerous treatments.Once diagnosed, appropriate treatment can be started. Moreover, laboratory studies have identified promising new compounds, which may help achieve urinary concentration independent of vasopressin. MAGED2 mutations caused X-linked polyhydramnios with prematurity and a severe but transient form of antenatal Bartter's syndrome.We distinguish two types of hereditary NDI: a 'pure' type with loss of water only and a complex type with loss of water and ions. Mutations in the AVPR2 or AQP2 genes, encoding the vasopressin V2 receptor and the water channel Aquaporin2, respectively, lead to a 'pure' NDI with loss of water but normal conservation of ions. Mutations in genes that encode membrane proteins involved in sodium chloride reabsorption in the thick ascending limb of Henle's loop lead to Bartter syndrome, a complex polyuric-polydipsic disorder often presenting with polyhydramnios. A new variant of this was recently identified: seven families were described with transient antenatal Bartter's syndrome, polyhydramnios and MAGED2 mutations.Multiple compounds have been identified experimentally that may stimulate urinary concentration independently of the vasopressin V2 receptor. These compounds may provide new treatments for patients with X-linked NDI. A plea for early consideration of the diagnosis of NDI, confirmation by phenotypic and/or genetic testing and appropriate adjustment of treatment in affected patients.

Body temperature and cardiac changes induced by peripherally administered oxytocin, vasopressin and the non-peptide oxytocin receptor agonist WAY 267,464: a biotelemetry study in rats

PubMed Central

Hicks, C; Ramos, L; Reekie, T; Misagh, G H; Narlawar, R; Kassiou, M; McGregor, I S

2014-01-01

Background and Purpose There is current interest in oxytocin (OT) as a possible therapeutic in psychiatric disorders. However, the usefulness of OT may be constrained by peripheral autonomic effects, which may involve an action at both OT and vasopressin V1A receptors. Here, we characterized the cardiovascular and thermoregulatory effects of OT, vasopressin (AVP) and the non-peptide OT receptor agonist WAY 267,464 in rats, and assessed the relative involvement of the OT and V1A receptors in these effects. Experimental Approach Biotelemetry in freely moving male Wistar rats was used to examine body temperature and heart rate after OT (0.01 – 1 mg kg−1; i.p.), AVP (0.001 – 0.1 mg kg−1; i.p.) or WAY 267,464 (10 and 100 mg kg−1; i.p.). The actions of the OT receptor antagonist Compound 25 (C25, 5 and 10 mg kg−1) and V1A receptor antagonist SR49059 (1 and 10 mg kg−1) were studied, as well as possible V1A receptor antagonist effects of WAY 267,464. Key Results OT and AVP dose-dependently reduced body temperature and heart rate. WAY 267,464 had similar, but more modest, effects. SR49059, but not C25, prevented the hypothermia and bradycardia induced by OT and AVP. WAY 267,464 (100 mg·kg−1) prevented the effects of OT, and to some extent AVP. Conclusions and Implications Peripherally administered OT and AVP have profound cardiovascular and thermoregulatory effects that appear to principally involve the V1A receptor rather than the OT receptor. Additionally, WAY 267,464 is not a simple OT receptor agonist, as it has functionally relevant V1A antagonist actions. PMID:24641248

Body temperature and cardiac changes induced by peripherally administered oxytocin, vasopressin and the non-peptide oxytocin receptor agonist WAY 267,464: a biotelemetry study in rats.

PubMed

Hicks, C; Ramos, L; Reekie, T; Misagh, G H; Narlawar, R; Kassiou, M; McGregor, I S

2014-06-01

There is current interest in oxytocin (OT) as a possible therapeutic in psychiatric disorders. However, the usefulness of OT may be constrained by peripheral autonomic effects, which may involve an action at both OT and vasopressin V1A receptors. Here, we characterized the cardiovascular and thermoregulatory effects of OT, vasopressin (AVP) and the non-peptide OT receptor agonist WAY 267,464 in rats, and assessed the relative involvement of the OT and V1A receptors in these effects. Biotelemetry in freely moving male Wistar rats was used to examine body temperature and heart rate after OT (0.01 - 1 mg kg(-1); i.p.), AVP (0.001 - 0.1 mg kg(-1); i.p.) or WAY 267,464 (10 and 100 mg kg(-1); i.p.). The actions of the OT receptor antagonist Compound 25 (C25, 5 and 10 mg kg(-1)) and V1A receptor antagonist SR49059 (1 and 10 mg kg(-1)) were studied, as well as possible V1A receptor antagonist effects of WAY 267,464. OT and AVP dose-dependently reduced body temperature and heart rate. WAY 267,464 had similar, but more modest, effects. SR49059, but not C25, prevented the hypothermia and bradycardia induced by OT and AVP. WAY 267,464 (100 mg·kg(-1)) prevented the effects of OT, and to some extent AVP. Peripherally administered OT and AVP have profound cardiovascular and thermoregulatory effects that appear to principally involve the V1A receptor rather than the OT receptor. Additionally, WAY 267,464 is not a simple OT receptor agonist, as it has functionally relevant V1A antagonist actions. © 2014 The British Pharmacological Society.

Gonadotrophin-releasing activity of neurohypophysial hormones: II. The pituitary oxytocin receptor mediating gonadotrophin release differs from that of corticotrophs.

PubMed

Evans, J J; Catt, K J

1989-07-01

Neurohypophysial hormones stimulate gonadotrophin release from dispersed rat anterior pituitary cells in vitro, acting through receptors distinct from those which mediate the secretory response to gonadotrophin-releasing hormone (GnRH). The LH response to oxytocin was not affected by the presence of the phosphodiesterase inhibitor, methyl isobutylxanthine, but was diminished in the absence of extracellular calcium and was progressively increased as the calcium concentration in the medium was raised to normal. In addition, the calcium channel antagonist, nifedipine, suppressed oxytocin-stimulated secretion of LH. It is likely that the mechanisms of LH release induced by GnRH and neurohypophysial hormones are similar, although stimulation of gonadotrophin secretion is mediated by separate receptor systems. Oxytocin was more active than vasopressin in releasing LH, but less active in releasing ACTH. The highly selective oxytocin agonist, [Thr4,Gly7]oxytocin, elicited concentration-dependent secretion of LH but had little effect on corticotrophin secretion. The neurohypophysial hormone antagonist analogues, [d(CH2)5Tyr(Me)2]vasopressin, [d(CH2)5Tyr(Me)2,Orn8]vasotocin and [d(CH2)5D-Tyr(Et)2Val4,Cit8]vasopressin, inhibited the LH response to both oxytocin and vasopressin. However, [d(CH2)5Tyr(Me)2]vasopressin was much less effective in inhibiting the ACTH response to the neurohypophysial hormones, and [d(CH2)5Tyr-(Me)2,Orn8]vasotocin and [d(CH2)5D-Tyr(Et)2,Val4,Cit8]vasopressin exhibited no inhibitory activity against ACTH release. Thus, agonist and antagonist analogues of neurohypophysial hormones display divergent activities with regard to LH and ACTH responses, and the neuropeptide receptor mediating gonadotroph activation is clearly different from that on the corticotroph. Whereas the corticotroph receptor is a vasopressin-type receptor an oxytocin-type receptor is responsible for gonadotrophin release by neurohypophysial hormones.

Overexpression of vasopressin (V3) and corticotrophin-releasing hormone receptor genes in corticotroph tumours.

PubMed

de Keyzer, Y; René, P; Beldjord, C; Lenne, F; Bertagna, X

1998-10-01

The molecular mechanisms underlying ACTH-secreting tumour formation remain unknown. Transmembrane signalling pathways play an important role in several endocrine disorders including pituitary tumours. To investigate the role of the pituitary vasopressin (V3) receptor (R) in ACTH-secreting tumours we have qualitatively and quantitatively analysed its mRNA. RT-PCR, denaturing gradient gel electrophoresis and S1 nuclease protection experiments were used to analyse V3 mRNA structure in ACTH-secreting tumours. We also developed a competitive RT-PCR system to compare the levels of expression of POMC, V3 and CRH-R genes. This system used as competitor a single mutant template (termed multi-mutant) containing primers for the three genes flanking an unrelated core sequence allowing multiple quantifications from the same cDNA preparations. We analysed 12 normal pituitaries, 15 corticotroph pituitary adenomas and 6 ACTH-secreting bronchial carcinoids. The V3 mRNA structure and sequence were found to be identical in normal and tumoural pituitary indicating that the tumoural Vs mRNA codes for a normal receptor. POMC RT-PCR signals in the pituitary tumour group were approximately 7-fold higher than in the normal pituitary group. Similarly, V3 and CRH-R signal were increased in pituitary tumors (mean +/- SEM: 5.87 x 10(-6) +/- 1.73 x 10(-6), and 2.33 x 10(-4) +/- 1.4 x 10(-4), respectively), when compared to normal pituitaries (1.19 x 10(-7) +/- 2.39 x 10(-8), and 1.7 x 10(-6) +/- 4.65 x 10(-7), respectively) suggesting that these two genes are expressed at very high levels in corticotroph tumours. When expressed relative to the corresponding POMC signals, increases in V3 and CRH-R signals reached 49-fold and 137-fold, respectively, in pituitary tumours. In ACTH-secreting bronchial carcinoids V3 gene expression level was also higher than in normal pituitary, whereas CRH-R signals were detected in only 4 of the 6 tumours with wide variations. Our results show that both vasopressin and CRH receptor genes are overexpressed in ACTH-secreting pituitary tumours. They suggest that overexpression of G protein-coupled receptors may be an additional mechanism through which membrane receptors may play a role in human tumours.

Long-term aquaretic efficacy of a selective nonpeptide V(2)-vasopressin receptor antagonist, SR121463, in cirrhotic rats.

PubMed

Jiménez, W; Gal, C S; Ros, J; Cano, C; Cejudo, P; Morales-Ruiz, M; Arroyo, V; Pascal, M; Rivera, F; Maffrand, J P; Rodés, J

2000-10-01

Water retention in experimental cirrhosis can be reversed by blocking V(2)-vasopressin (AVP) receptors with the nonpeptide antagonist OPC-31260 or by using the kappa-opioid receptor agonist niravoline, a compound inhibiting central AVP release. However, reluctance to use these drugs in human beings has emerged because the former loses aquaretic efficacy in rats after 2 days of treatment and the latter may have adverse effects in humans. Recently, a new potent and selective nonpeptide V(2)-AVP receptor antagonist, SR121463, has been developed that could be useful for the treatment of dilutional hyponatremia in human cirrhosis. The current study assessed the aquaretic efficacy of 10-day chronic oral administration of SR121463 (0.5 mg/kg/day) in cirrhotic rats with ascites and impaired water excretion after a water load (minimum urinary osmolality >160 mOsm/kg and percentage of water load excreted <60%). Urine volume (UV), osmolality (U(Osm)V), and sodium excretion (U(Na)V) were measured daily. At the end of the 10-day treatment, mean arterial pressure also was measured. In basal conditions cirrhotic rats showed ascites, sodium retention, and impaired water excretion. UV, U(Osm)V, and U(Na)V did not change throughout the study in cirrhotic rats receiving the vehicle. In contrast, SR121463 increased UV and reduced U(Osm)V during the 10-day treatment. This resulted in a greater renal ability to excrete a water load and normalization in serum sodium and osmolality. During the first 6 days of treatment, SR121463 also increased U(Na)V without affecting mean arterial pressure. These data suggest that SR121463 could be of therapeutical value for chronic management of human cirrhosis.

Antidiuretic effects of a nonpeptide vasopressin V(2)-receptor agonist, OPC-51803, administered orally to rats.

PubMed

Nakamura, S; Hirano, T; Tsujimae, K; Aoyama, M; Kondo, K; Yamamura, Y; Mori, T; Tominaga, M

2000-12-01

OPC-51803 is the first nonpeptide vasopressin (AVP) V(2)-receptor-selective agonist. Its pharmacological profile, including antidiuretic action and receptor binding, was characterized using conscious Brattleboro rats with hereditary diabetes insipidus and Sprague-Dawley rats. In membrane preparations from the liver and kidney, OPC-51803 displaced the [(3)H]AVP binding to V(2)-receptors (K(i) = 49.8 +/- 8.1 nM) more greatly than that to V(1a)-receptors (K(i) = 1061 +/- 60 nM), showing a 21 times higher affinity for V(2)-receptors. At single oral doses of 0.003 to 0.3 mg/kg in female Brattleboro rats, OPC-51803 decreased urine volume (from 10.8 +/- 1.1 to 0.5 +/- 0.2 ml during 0-2 h postdosing) and increased urinary osmolality (from 114 +/- 9 to 432 +/- 114 mOsm/kg) in a dose-dependent manner. During the period of 4-week treatment with OPC-51803, significant and constant antidiuresis was observed. In male Sprague-Dawley rats with normal plasma AVP levels, OPC-51803 at 0.03 to 0.3 mg/kg also produced a dose-dependent antidiuretic action (urine volume: from 2.6 +/- 0.6 to 1.1 +/- 0.2 ml at 0-4 h postdosing). Few changes in urinary parameters, serum parameters, or plasma hormone levels were observed. OPC-51803 did not change blood pressure or heart rate, or inhibit AVP-induced pressor response even at 30 mg/kg p.o. These results demonstrate that OPC-51803 is a V(2)-selective agonist that produces a significant antidiuretic action after single and multiple oral dosing in AVP-deficient and normal AVP states. The data suggest that OPC-51803 is a useful therapeutic drug in the treatment of hypothalamic diabetes insipidus, nocturnal enuresis, and some kinds of urinary incontinence.

Biochemical and pharmacological properties of SR 49059, a new, potent, nonpeptide antagonist of rat and human vasopressin V1a receptors.

PubMed

Serradeil-Le Gal, C; Wagnon, J; Garcia, C; Lacour, C; Guiraudou, P; Christophe, B; Villanova, G; Nisato, D; Maffrand, J P; Le Fur, G

1993-07-01

SR 49059, a new potent and selective orally active, nonpeptide vasopressin (AVP) antagonist has been characterized in several in vitro and in vivo models. SR 49059 showed high affinity for V1a receptors from rat liver (Ki = 1.6 +/- 0.2) and human platelets, adrenals, and myometrium (Ki ranging from 1.1 to 6.3 nM). The previously described nonpeptide V1 antagonist, OPC-21268, was almost inactive in human tissues at concentrations up to 100 microM. SR 49059 exhibited much lower affinity (two orders of magnitude or more) for AVP V2 (bovine and human), V1b (human), and oxytocin (rat and human) receptors and had no measurable affinity for a great number of other receptors. In vitro, AVP-induced contraction of rat caudal artery was competitively antagonized by SR 49059 (pA2 = 9.42). Furthermore, SR 49059 inhibited AVP-induced human platelet aggregation with an IC50 value of 3.7 +/- 0.4 nM, while OPC-21268 was inactive up to 20 microM. In vivo, SR 49059 inhibited the pressor response to exogenous AVP in pithed rats (intravenous) and in conscious normotensive rats (intravenous and per os) with a long duration of action (> 8 h at 10 mg/kg p.o). In all the biological assays used, SR 49059 was devoid of any intrinsic agonistic activity. Thus, SR 49059 is the most potent and selective nonpeptide AVP V1a antagonist described so far, with marked affinity, selectivity, and efficacy toward both animal and human receptors. With this original profile, SR 49059 constitutes a powerful tool for exploring the therapeutical usefulness of a selective V1a antagonist.

The Challenge of Translation in Social Neuroscience: A Review of Oxytocin, Vasopressin, and Affiliative Behavior

PubMed Central

Insel, Thomas R.

2010-01-01

Social neuroscience is rapidly exploring the complex territory between perception and action where recognition, value, and meaning are instantiated. This review follows the trail of research on oxytocin and vasopressin as an exemplar of one path for exploring the “dark matter” of social neuroscience. Studies across vertebrate species suggest that these neuropeptides are important for social cognition, with gender and steroid-dependent effects. Comparative research in voles yields a model based on inter-species and intra-species variation of the geography of oxytocin receptors and vasopressin V1a receptors in the forebrain. Highly affiliative species have receptors in brain circuits related to reward or reinforcement. The neuroanatomical distribution of these receptors may be guided by variations in the regulatory regions of their respective genes. This review describes the promises and problems of extrapolating these findings to human social cognition, with specific reference to the social deficits of autism. PMID:20346754

Gene transfer of heterologous G protein-coupled receptors to cardiomyocytes: differential effects on contractility.

PubMed

Laugwitz, K L; Weig, H J; Moretti, A; Hoffmann, E; Ueblacker, P; Pragst, I; Rosport, K; Schömig, A; Ungerer, M

2001-04-13

In heart failure, reduced cardiac contractility is accompanied by blunted cAMP responses to beta-adrenergic stimulation. Parathyroid hormone (PTH)-related peptide and arginine vasopressin are released from the myocardium in response to increased wall stress but do not stimulate contractility or adenylyl cyclase at physiological concentrations. To bypass the defective beta-adrenergic signaling cascade, recombinant P1 PTH/PTH-related peptide receptors (rPTH1-Rs) and V(2) vasopressin receptors (rV(2)-Rs), which are normally not expressed in the myocardium and which are both strongly coupled to adenylyl cyclase, and recombinant beta(2)-adrenergic receptors (rbeta(2)-ARs) were overexpressed in cardiomyocytes by viral gene transfer. The capacity of endogenous hormones to increase contractility via the heterologous, recombinant receptors was compared. Whereas V(2)-Rs are uniquely coupled to Gs, PTH1-Rs and beta(2)-ARs are also coupled to other G proteins. Gene transfer of rPTH1-Rs or rbeta(2)-ARs to adult cardiomyocytes resulted in maximally increased basal contractility, which could not be further stimulated by adding receptor agonists. Agonists at rPTH1-Rs induced increased cAMP formation and phospholipase C activity. In contrast, healthy or failing rV(2)-R-expressing cardiomyocytes showed unaltered basal contractility. Their contractility and cAMP formation increased only at agonist exposure, which did not activate phospholipase C. In summary, we found that gene transfer of PTH1-Rs to cardiomyocytes results in constitutive activity of the transgene, as does that of beta(2)-ARS: In the absence of receptor agonists, rPTH1-Rs and rbeta(2)-ARs increase basal contractility, coupling to 2 G proteins simultaneously. In contrast, rV(2)-Rs are uniquely coupled to Gs and are not constitutively active, retaining their property to be activated exclusively on agonist stimulation. Therefore, gene transfer of V(2)-Rs might be more suited to test the effects of cAMP-stimulating receptors in heart failure than that of PTH1-Rs or beta(2)-ARS:

Orally active, nonpeptide vasopressin V1 antagonists. A novel series of 1-(1-substituted 4-piperidyl)-3,4-dihdyro-2(1H)-quinolinone.

PubMed

Ogawa, H; Yamamura, Y; Miyamoto, H; Kondo, K; Yamashita, H; Nakaya, K; Chihara, T; Mori, T; Tominaga, M; Yabuuchi, Y

1993-07-09

A series of compounds has been synthesized and demonstrated to be antagonists of V1 receptors both in vitro and in vivo. These compounds are structurally related to the 1-(4-piperidyl)-2(1H)-quinolinones, including OPC-21268, an orally bioavailable AVP V1 antagonist with high V1 specificity. It has been found that the introduction of an acetamide group on the terminal alkoxy chain of 41-44 leads to an increase in oral activity. Certain of these compounds may have efficacy in the study of AVP V1 receptors.

Effect of SR-49059, a vasopressin V1a antagonist, on human vascular smooth muscle cells.

PubMed

Serradeil-Le Gal, C; Herbert, J M; Delisee, C; Schaeffer, P; Raufaste, D; Garcia, C; Dol, F; Marty, E; Maffrand, J P; Le Fur, G

1995-01-01

The effects of SR-49059, a new nonpeptide and selective arginine vasopressin (AVP) V1a antagonist, were investigated in binding and functional studies on cultured human aortic vascular smooth muscle cells (VSMC). Characterization of human vascular V1a receptors, using a specific V1a radioiodinated ligand, showed that [125I]-linear AVP antagonist binding to human VSMC membranes was time dependent, reversible, and saturable. A single population of high-affinity binding sites (apparent equilibrium dissociation constant = 15 +/- 6 pM; maximum binding density = 36 +/- 5 fmol/mg protein, i.e., approximately 3,000 sites/cell) with the expected V1a profile was identified. Exposure of these cells to AVP dose-dependently produced cytosolic free [Ca2+] increase [AVP concentration required to obtain a half-maximal response (EC50) = 23 +/- 9 nM] and proliferation (EC50 = 3.2 +/- 0.5 nM). SR-49059 strongly and stereospecifically inhibited [125I]-linear AVP antagonist binding to VSMC V1a receptors [inhibition constant (Ki) = 1.4 +/- 0.3 nM], AVP-evoked Ca2+ increase [concentration of inhibitor required to obtain 50% inhibition of specific binding (IC50) = 0.41 +/- 0.06 nM], and the mitogenic effects induced by 100 nM AVP (IC50 = 0.83 +/- 0.04 nM). OPC-21268, another nonpeptide V1a antagonist, was more than two orders of magnitude less potent than SR-49059 in these models. However, the consistent affinity (Ki = 138 +/- 21 nM) and activity found with OPC-21268 on human VSMC in comparison with the inactivity already observed for other human V1a receptors (liver, platelets, adrenals, and uterus) strongly suggested the existence of human AVP V1a-receptor subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)

The selective V1a receptor agonist selepressin (FE 202158) blocks vascular leak in ovine severe sepsis

PubMed Central

Wiśniewska, Halina; Traber, Lillian D.; Lin, ChiiDean; Fan, Juanjuan; Hawkins, Hal K.; Cox, Robert A.; Wiśniewski, Kazimierz; Schteingart, Claudio D.; Landry, Donald W.; Rivière, Pierre J.-M.; Traber, Daniel L.

2014-01-01

Objective To determine if the selective vasopressin type 1a receptor (V1aR) agonist selepressin (FE 202158) is as effective as the mixed V1a/V2 receptor (V1aR/V2R) agonist vasopressor hormone arginine vasopressin (AVP) when used as a titrated first-line vasopressor therapy in an ovine model of Pseudomonas aeruginosa pneumonia-induced severe sepsis. Design Prospective, randomized, controlled laboratory experiment. Setting University animal research facility. Subjects Forty-five chronically instrumented sheep. Interventions Sheep were anesthetized, insufflated with cooled cotton smoke via tracheostomy, and P. aeruginosa were instilled into their airways. They were then placed on assisted ventilation, awakened, and resuscitated with lactated Ringer's solution titrated to maintain hematocrit ± 3% from baseline levels. If, despite fluid management, mean arterial pressure (MAP) fell by > 10 mm Hg from baseline levels, a continuous i.v. infusion of AVP or selepressin was titrated to raise and maintain MAP within 10 mm Hg of baseline. Effects of combination treatment of selepressin with the selective V2R agonist desmopressin were similarly investigated. Measurements and Main Results In septic sheep, MAP fell by ~30 mm Hg, systemic vascular resistance index (SVRI) decreased by ~50%, and ~7 L of fluid were retained over 24 h; this fluid accumulation was partially reduced by AVP and almost completely blocked by selepressin; combined infusion of selepressin and desmopressin increased fluid accumulation to levels similar to AVP treatment. Conclusions Resuscitation with the selective V1aR agonist selepressin blocked vascular leak more effectively than the mixed V1aR/V2R agonist AVP because of its lack of agonist activity at the V2R. PMID:24674922

Vasopressin V1a receptors are present in the carotid body and contribute to the control of breathing in male Sprague-Dawley rats.

PubMed

Żera, Tymoteusz; Przybylski, Jacek; Grygorowicz, Tomasz; Kasarełło, Kaja; Podobińska, Martyna; Mirowska-Guzel, Dagmara; Cudnoch-Jędrzejewska, Agnieszka

2018-04-01

Vasopressin (AVP) maintains body homeostasis by regulating water balance, cardiovascular system and stress response. AVP inhibits breathing through central vasopressin 1a receptors (V1aRs). Chemoreceptors within carotid bodies (CBs) detect chemical and hormonal signals in the bloodstream and provide sensory input to respiratory and cardiovascular centers of the brainstem. In the study we investigated if CBs contain V1aRs and how the receptors are involved in the regulation of ventilation by AVP. We first immunostained CBs for V1aRs and tyrosine hydroxylase, a marker of chemoreceptor type I (glomus) cells. In urethane-anesthetized adult Sprague-Dawley male rats, we then measured hemodynamic and respiratory responses to systemic (intravenous) or local (carotid artery) administration of AVP prior and after systemic blockade of V1aRs. Immunostaining of CBs showed colocalization of V1aRs and tyrosine hydroxylase within glomus cells. Systemic administration of AVP increased mean arterial blood pressure (MABP) and decreased respiratory rate (RR) and minute ventilation (MV). Local administration of AVP increased MV and RR without significant changes in MABP or heart rate. Pretreatment with V1aR antagonist abolished responses to local and intravenous AVP administration. Our findings show that chemosensory cells within CBs express V1aRs and that local stimulation of the CB with AVP increases ventilation, which is contrary to systemic effects of AVP manifested by decreased ventilation. The responses are mediated by V1aRs, as blockade of the receptors prevents changes in ventilation. We hypothesize that excitatory effects of AVP within the CB provide a counterbalancing mechanism for the inhibitory effects of systemically acting AVP on the respiration. Copyright © 2018 Elsevier Inc. All rights reserved.

Combined sodium ion sensitivity in agonist binding and internalization of vasopressin V1b receptors.

PubMed

Koshimizu, Taka-Aki; Kashiwazaki, Aki; Taniguchi, Junichi

2016-05-03

Reducing Na(+) in the extracellular environment may lead to two beneficial effects for increasing agonist binding to cell surface G-protein coupled receptors (GPCRs): reduction of Na(+)-mediated binding block and reduce of receptor internalization. However, such combined effects have not been explored. We used Chinese Hamster Ovary cells expressing vasopressin V1b receptors as a model to explore Na(+) sensitivity in agonist binding and receptor internalization. Under basal conditions, a large fraction of V1b receptors is located intracellularly, and a small fraction is in the plasma membrane. Decreases in external Na(+) increased cell surface [(3)H]AVP binding and decreased receptor internalization. Substitution of Na(+) by Cs(+) or NH4(+) inhibited agonist binding. To suppress receptor internalization, the concentration of NaCl, but not of CsCl, had to be less than 50 mM, due to the high sensitivity of the internalization machinery to Na(+) over Cs(+). Iso-osmotic supplementation of glucose or NH4Cl maintained internalization of the V1b receptor, even in a low-NaCl environment. Moreover, iodide ions, which acted as a counter anion, inhibited V1b agonist binding. In summary, we found external ionic conditions that could increase the presence of high-affinity state receptors at the cell surface with minimum internalization during agonist stimulations.

Combined sodium ion sensitivity in agonist binding and internalization of vasopressin V1b receptors

PubMed Central

Koshimizu, Taka-aki; Kashiwazaki, Aki; Taniguchi, Junichi

2016-01-01

Reducing Na+ in the extracellular environment may lead to two beneficial effects for increasing agonist binding to cell surface G-protein coupled receptors (GPCRs): reduction of Na+-mediated binding block and reduce of receptor internalization. However, such combined effects have not been explored. We used Chinese Hamster Ovary cells expressing vasopressin V1b receptors as a model to explore Na+ sensitivity in agonist binding and receptor internalization. Under basal conditions, a large fraction of V1b receptors is located intracellularly, and a small fraction is in the plasma membrane. Decreases in external Na+ increased cell surface [3H]AVP binding and decreased receptor internalization. Substitution of Na+ by Cs+ or NH4+ inhibited agonist binding. To suppress receptor internalization, the concentration of NaCl, but not of CsCl, had to be less than 50 mM, due to the high sensitivity of the internalization machinery to Na+ over Cs+. Iso-osmotic supplementation of glucose or NH4Cl maintained internalization of the V1b receptor, even in a low-NaCl environment. Moreover, iodide ions, which acted as a counter anion, inhibited V1b agonist binding. In summary, we found external ionic conditions that could increase the presence of high-affinity state receptors at the cell surface with minimum internalization during agonist stimulations. PMID:27138239

Distributions of oxytocin and vasopressin 1a receptors in the Taiwan vole and their role in social monogamy.

PubMed

Chappell, A R; Freeman, S M; Lin, Y K; LaPrairie, J L; Inoue, K; Young, L J; Hayes, L D

2016-06-01

Social monogamy is a mating strategy rarely employed by mammalian species. Laboratory studies in socially monogamous prairie voles ( Microtus ochrogaster ) demonstrate that oxytocin and vasopressin act within the mesolimbic dopamine pathway to facilitate pair-bond formation. Species differences in oxytocin receptor (OTR) and vasopressin 1a receptor (V1aR) distribution in this pathway are associated with species differences in mating strategy. Here we characterize the neuroanatomical distribution of OTR and V1aR binding sites in naturally occurring populations of Taiwan voles ( M. kikuchii ), which purportedly display social monogamy. Live trapping was conducted at two sites in 2009-2010 and receptor autoradiography for OTR and V1aR was performed on brains from 24 animals. OTR binding in two brain regions where OTR signaling regulates pair-bonding were directly compared with that of prairie voles. Our results show that like prairie voles, Taiwan voles exhibit OTR in the prefrontal cortex, insular cortex, claustrum, nucleus accumbens, caudate-putamen, dorsal lateral septal nucleus, central amygdala, and ventromedial hypothalamus. Unlike prairie voles, Taiwan voles exhibit OTR binding in the CA3 pathway of the hippocampus, as well as the indusium griseum, which has only previously been documented in tuco-tucos ( Ctenomys haigi, C. sociabilis ), Syrian hamsters ( Mesocricetus auratus ) and naked mole-rats ( Heterocephalus glaber ). V1aR binding was present in the ventral pallidum, lateral septum, nucleus basalis, bed nucleus of the stria terminalis, hippocampus, medial amygdala, and anterior, ventromedial and dorsomedial hypothalamus. Marked individual differences in V1aR binding were noted in the cingulate cortex and several thalamic nuclei, remarkably similar to prairie voles. While pharmacological studies are needed to determine whether oxytocin and vasopressin are involved in pair-bond formation in this species, our results lay a foundation for future investigations into the role of these neuropeptides in Taiwan vole social behavior.

Distributions of oxytocin and vasopressin 1a receptors in the Taiwan vole and their role in social monogamy

PubMed Central

Chappell, A. R.; Freeman, S. M.; Lin, Y. K.; LaPrairie, J. L.; Inoue, K.; Young, L. J.; Hayes, L. D.

2016-01-01

Social monogamy is a mating strategy rarely employed by mammalian species. Laboratory studies in socially monogamous prairie voles (Microtus ochrogaster) demonstrate that oxytocin and vasopressin act within the mesolimbic dopamine pathway to facilitate pair-bond formation. Species differences in oxytocin receptor (OTR) and vasopressin 1a receptor (V1aR) distribution in this pathway are associated with species differences in mating strategy. Here we characterize the neuroanatomical distribution of OTR and V1aR binding sites in naturally occurring populations of Taiwan voles (M. kikuchii), which purportedly display social monogamy. Live trapping was conducted at two sites in 2009–2010 and receptor autoradiography for OTR and V1aR was performed on brains from 24 animals. OTR binding in two brain regions where OTR signaling regulates pair-bonding were directly compared with that of prairie voles. Our results show that like prairie voles, Taiwan voles exhibit OTR in the prefrontal cortex, insular cortex, claustrum, nucleus accumbens, caudate-putamen, dorsal lateral septal nucleus, central amygdala, and ventromedial hypothalamus. Unlike prairie voles, Taiwan voles exhibit OTR binding in the CA3 pathway of the hippocampus, as well as the indusium griseum, which has only previously been documented in tuco-tucos (Ctenomys haigi, C. sociabilis), Syrian hamsters (Mesocricetus auratus) and naked mole-rats (Heterocephalus glaber). V1aR binding was present in the ventral pallidum, lateral septum, nucleus basalis, bed nucleus of the stria terminalis, hippocampus, medial amygdala, and anterior, ventromedial and dorsomedial hypothalamus. Marked individual differences in V1aR binding were noted in the cingulate cortex and several thalamic nuclei, remarkably similar to prairie voles. While pharmacological studies are needed to determine whether oxytocin and vasopressin are involved in pair-bond formation in this species, our results lay a foundation for future investigations into the role of these neuropeptides in Taiwan vole social behavior. PMID:27453637

Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat.

PubMed

Wang, Xiaofang; Gattone, Vincent; Harris, Peter C; Torres, Vicente E

2005-04-01

cAMP plays a major role in cystogenesis. Recent in vitro studies suggested that cAMP stimulates B-Raf/ERK activation and proliferation of cyst-derived cells in a Ca(2+) inhibitable, Ras-dependent manner. OPC-31260, a vasopressin V2 receptor (VPV2) antagonist, was shown to lower renal cAMP and inhibit renal disease development and progression in models orthologous to human cystic diseases. Here it is shown that OPC-41061, an antagonist chosen for its potency and selectivity for human VPV2, is effective in PCK rats. PCK kidneys have increased Ras-GTP and phosphorylated ERK levels and 95-kD/68-kD B-Raf ratios, changes that are corrected by the administration of OPC-31260 or OPC-41061. These results support the importance of cAMP in the pathogenesis of polycystic kidney disease, confirm the effectiveness of a VPV2 antagonist to be used in clinical trials for this disease, and suggest that OPC-31260 and OPC-41061 inhibit Ras/mitogen-activated protein kinase signaling in polycystic kidneys.

Metformin, an AMPK activator, stimulates the phosphorylation of aquaporin 2 and urea transporter A1 in inner medullary collecting ducts.

PubMed

Klein, Janet D; Wang, Yanhua; Blount, Mitsi A; Molina, Patrick A; LaRocque, Lauren M; Ruiz, Joseph A; Sands, Jeff M

2016-05-15

Nephrogenic diabetes insipidus (NDI) is characterized by production of very large quantities of dilute urine due to an inability of the kidney to respond to vasopressin. Congenital NDI results from mutations in the type 2 vasopressin receptor (V2R) in ∼90% of families. These patients do not have mutations in aquaporin-2 (AQP2) or urea transporter UT-A1 (UT-A1). We tested adenosine monophosphate kinase (AMPK) since it is known to phosphorylate another vasopressin-sensitive transporter, NKCC2 (Na-K-2Cl cotransporter). We found AMPK expressed in rat inner medulla (IM). AMPK directly phosphorylated AQP2 and UT-A1 in vitro. Metformin, an AMPK activator, increased phosphorylation of both AQP2 and UT-A1 in rat inner medullary collecting ducts (IMCDs). Metformin increased the apical plasma membrane accumulation of AQP2, but not UT-A1, in rat IM. Metformin increased both osmotic water permeability and urea permeability in perfused rat terminal IMCDs. These findings suggest that metformin increases osmotic water permeability by increasing AQP2 accumulation in the apical plasma membrane but increases urea permeability by activating UT-A1 already present in the membrane. Lastly, metformin increased urine osmolality in mice lacking a V2R, a mouse model of congenital NDI. We conclude that AMPK activation by metformin mimics many of the mechanisms by which vasopressin increases urine-concentrating ability. These findings suggest that metformin may be a novel therapeutic option for congenital NDI due to V2R mutations. Copyright © 2016 the American Physiological Society.

Metformin, an AMPK activator, stimulates the phosphorylation of aquaporin 2 and urea transporter A1 in inner medullary collecting ducts

PubMed Central

Wang, Yanhua; Blount, Mitsi A.; Molina, Patrick A.; LaRocque, Lauren M.; Ruiz, Joseph A.

2016-01-01

Nephrogenic diabetes insipidus (NDI) is characterized by production of very large quantities of dilute urine due to an inability of the kidney to respond to vasopressin. Congenital NDI results from mutations in the type 2 vasopressin receptor (V2R) in ∼90% of families. These patients do not have mutations in aquaporin-2 (AQP2) or urea transporter UT-A1 (UT-A1). We tested adenosine monophosphate kinase (AMPK) since it is known to phosphorylate another vasopressin-sensitive transporter, NKCC2 (Na-K-2Cl cotransporter). We found AMPK expressed in rat inner medulla (IM). AMPK directly phosphorylated AQP2 and UT-A1 in vitro. Metformin, an AMPK activator, increased phosphorylation of both AQP2 and UT-A1 in rat inner medullary collecting ducts (IMCDs). Metformin increased the apical plasma membrane accumulation of AQP2, but not UT-A1, in rat IM. Metformin increased both osmotic water permeability and urea permeability in perfused rat terminal IMCDs. These findings suggest that metformin increases osmotic water permeability by increasing AQP2 accumulation in the apical plasma membrane but increases urea permeability by activating UT-A1 already present in the membrane. Lastly, metformin increased urine osmolality in mice lacking a V2R, a mouse model of congenital NDI. We conclude that AMPK activation by metformin mimics many of the mechanisms by which vasopressin increases urine-concentrating ability. These findings suggest that metformin may be a novel therapeutic option for congenital NDI due to V2R mutations. PMID:26962099

Transmission disequilibrium testing of arginine vasopressin receptor 1A (AVPR1A) polymorphisms in autism.

PubMed

Kim, S-J; Young, L J; Gonen, D; Veenstra-VanderWeele, J; Courchesne, R; Courchesne, E; Lord, C; Leventhal, B L; Cook, E H; Insel, T R

2002-01-01

Impairment in social reciprocity is a central component of autism. In preclinical studies, arginine vasopressin (AVP) has been shown to increase a range of social behaviors, including affiliation and attachment, via the V(1a) receptor (AVPR1A) in the brain. Both the behavioral effects of AVP and the neural distribution of the V1a receptor vary greatly across mammalian species. This difference in regional receptor expression as well as differences in social behavior may result from a highly variable repetitive sequence in the 5' flanking region of the V1a gene (AVPR1A). Given this comparative evidence for a role in inter-species variation in social behavior, we explored whether within our own species, variation in the human AVPR1A may contribute to individual variations in social behavior, with autism representing an extreme form of social impairment. We genotyped two microsatellite polymorphisms from the 5' flanking region of AVPR1A for 115 autism trios and found nominally significant transmission disequilibrium between autism and one of the microsatellite markers by Multiallelic Transmission/Disequilibrium test (MTDT) that was not significant after Bonferroni correction. We also screened approximately 2 kb of the 5' flanking region and the coding region and identified 10 single nucleotide polymorphisms.

Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia.

PubMed

Palm, Catrin; Pistrosch, Frank; Herbrig, Kay; Gross, Peter

2006-07-01

Hyponatremia is the most frequent electrolyte disorder encountered in hospitalized patients. It is a state of relative water excess due to stimulated arginine vasopressin (AVP) and fluid intake greater than obligatory losses. This kind of hyponatremia occurs in the syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure, and liver cirrhosis. Fluid restriction is the presently recommended treatment for hyponatremia. However, fluid restriction may be very difficult for patients to achieve, is slow to work, and does not allow a graded therapeutic approach. More efficient and specific treatments of hyponatremia are needed. In this respect, pharmacologic research has yielded a number of compounds exhibiting antagonistic qualities at the vasopressin V2 receptor. Among these agents, peptidic derivatives of AVP turned out to have intrinsic antidiuretic properties in vivo when given over days or weeks. The development of such agents for use in patients has not been pursued. However, several promising nonpeptide, vasopressin receptor antagonists have been described; these agents are VPA-985 (lixivaptan), YM-087 (conivaptan), OPC-41061 (tolvaptan), and SR-121463. Prospective, randomized, placebo-controlled trials performed with these agents found that they corrected hyponatremia efficiently and safely. Most of the studies were conducted over a 4- to 28-day period. Long-term studies will be needed in the future to address such issues as the eventual benefit to patients and the effects of vasopressin antagonists on morbidity and mortality of patients with hyponatremia.

Systems-level identification of PKA-dependent signaling in epithelial cells.

PubMed

Isobe, Kiyoshi; Jung, Hyun Jun; Yang, Chin-Rang; Claxton, J'Neka; Sandoval, Pablo; Burg, Maurice B; Raghuram, Viswanathan; Knepper, Mark A

2017-10-17

G protein stimulatory α-subunit (G αs )-coupled heptahelical receptors regulate cell processes largely through activation of protein kinase A (PKA). To identify signaling processes downstream of PKA, we deleted both PKA catalytic subunits using CRISPR-Cas9, followed by a "multiomic" analysis in mouse kidney epithelial cells expressing the G αs -coupled V2 vasopressin receptor. RNA-seq (sequencing)-based transcriptomics and SILAC (stable isotope labeling of amino acids in cell culture)-based quantitative proteomics revealed a complete loss of expression of the water-channel gene Aqp2 in PKA knockout cells. SILAC-based quantitative phosphoproteomics identified 229 PKA phosphorylation sites. Most of these PKA targets are thus far unannotated in public databases. Surprisingly, 1,915 phosphorylation sites with the motif x-(S/T)-P showed increased phosphooccupancy, pointing to increased activity of one or more MAP kinases in PKA knockout cells. Indeed, phosphorylation changes associated with activation of ERK2 were seen in PKA knockout cells. The ERK2 site is downstream of a direct PKA site in the Rap1GAP, Sipa1l1, that indirectly inhibits Raf1. In addition, a direct PKA site that inhibits the MAP kinase kinase kinase Map3k5 (ASK1) is upstream of JNK1 activation. The datasets were integrated to identify a causal network describing PKA signaling that explains vasopressin-mediated regulation of membrane trafficking and gene transcription. The model predicts that, through PKA activation, vasopressin stimulates AQP2 exocytosis by inhibiting MAP kinase signaling. The model also predicts that, through PKA activation, vasopressin stimulates Aqp2 transcription through induction of nuclear translocation of the acetyltransferase EP300, which increases histone H3K27 acetylation of vasopressin-responsive genes (confirmed by ChIP-seq).

Variation in vasopressin receptor Avpr1a) expression creates diversity in behaviors related to monogamy in prairie voles

PubMed Central

Barrett, Catherine E.; Keebaugh, Alaine C.; Ahern, Todd H.; Bass, Caroline E.; Terwilliger, Ernest F.; Young, Larry J.

2013-01-01

Polymorphisms in noncoding regions of the vasopressin 1a receptor gene (Avpr1a) are associated with a variety of socioemotional characteristics in humans, chimpanzees, and voles, and may impact behavior through site-specific variation in gene expression. The socially monogamous prairie vole offers a unique opportunity to study such neurobiological control of individual differences in complex behavior. Vasopressin 1a receptor (V1aR) signaling is necessary for the formation of the pair bond in males, and prairie voles exhibit greater V1aR binding in the reward-processing ventral pallidum than do asocial voles of the same genus. Diversity in social behavior within prairie voles has been correlated to natural variation in neuropeptide receptor expression in specific brain regions. Here we use RNA interference to examine the causal relationship between intraspecific variation in V1aR and behavioral outcomes, by approximating the degree of naturalistic variation in V1aR expression. Juvenile male prairie voles were injected with viral vectors expressing shRNA sequences targeting Avpr1a mRNA into the ventral pallidum. Down-regulation of pallidal V1aR density resulted in a significant impairment in the preference for a mated female partner and a reduction in anxiety-like behavior in adulthood. No effect on alloparenting was detected. These data demonstrate that within-species naturalistic-like variation in V1aR expression has a profound effect on individual differences in social attachment and emotionality. RNA interference may prove a useful technique to unite the fields of behavioral ecology and neurogenetics to perform ethologically relevant studies of the control of individual variation and offer insight into the evolutionary mechanisms leading to behavioral diversity. PMID:23370363

Renal water handling in rats with decompensated liver cirrhosis.

PubMed

Jonassen, T E; Christensen, S; Kwon, T H; Langhoff, S; Salling, N; Nielsen, S

2000-12-01

The present study was performed to investigate the renal handling of water in rats with decompensated liver cirrhosis. Liver cirrhosis was induced by intraperitoneal administration of carbon tetrachloride twice weekly for 16 wk. Control rats were treated with vehicle. The cirrhotic rats developed severe disturbances in water homeostasis: urine production was decreased and hyperosmotic, the rats had significantly decreased plasma sodium concentration and ascites, and the ability to excrete an intravenous water load was significantly impaired. Plasma concentrations of vasopressin and aldosterone were increased. Mean arterial pressure, glomerular filtration rate (GFR), and fractional lithium excretion were decreased. Acute vasopressin type 2-receptor blockade with the selective nonpeptide antagonist OPC-31260 (800 microg. kg(-1). h(-1)) was performed during conditions whereby volume depletion was prevented by computer-driven, servo-controlled intravenous volume replacement with 150 mM glucose. The aquaretic response to OPC-31260 was similar in cirrhotic and control rats. However, the OPC 31260-induced rises in fractional water excretion (delta V/GFR; +24%) and fractional distal water excretion (delta V/C(Li); +46%) were significantly increased in the cirrhotic rats, where V is flow rate and delta is change. This suggests that vasopressin-mediated renal water reabsorption capacity was increased in the cirrhotic rats. Semiquantitative immunoblotting revealed that the expression of the vasopressin-regulated water channel aquaporin-2 was unchanged in membrane fractions of both whole kidney and inner medulla from cirrhotic rats. Together, these results suggest a relative escape from vasopressin on collecting duct water reabsorption in rats with decompensated liver cirrhosis.

The pituitary V3 vasopressin receptor and the corticotroph phenotype in ectopic ACTH syndrome.

PubMed Central

de Keyzer, Y; Lenne, F; Auzan, C; Jégou, S; René, P; Vaudry, H; Kuhn, J M; Luton, J P; Clauser, E; Bertagna, X

1996-01-01

Ectopic ACTH secretion occurs in highly differentiated and rather indolent tumors like bronchial carcinoids or, in contrast, in various types of aggressive and poorly differentiated neuroendocrine tumors. We explored this phenomenon using the recently cloned human pituitary V3 vasopressin receptor as an alternate molecular marker of the corticotroph phenotype. Expression of V3 receptor, corticotrophin releasing hormone (CRH) receptor, and proopiomelanocortin (POMC) genes was examined in tumors of pituitary and nonpituitary origin. A comparative RT-PCR approach revealed signals for both V3 receptor and CHR receptor mRNAs in 17 of 18 ACTH-secreting pituitary adenomas, and 6 of 6 normal pituitaries; in six growth hormone- or prolactin-secreting adenomas, a very faint V3 receptor signal was observed in three cases, and CRH receptor signal was undetected in all. Six of eight bronchial carcinoids responsible for the ectopic ACTH syndrome had both POMC and V3 receptor signals as high as those in ACTH-secreting pituitary adenomas; in contrast, no POMC signal and only a very faint V3 receptor signal were detected in six of eight nonsecreting bronchial carcinoids. Northern blot analysis showed V3 receptor mRNA of identical size in ACTH-secreting bronchial carcinoids and pituitary tumors. Other types of nonpituitary tumors responsible for ectopic ACTH syndrome presented much lower levels of both POMC and V3 receptor gene expression than those found in ACTH-secreting bronchial carcinoids. In contrast with the V3 receptor, CRH receptor mRNA was detected in the majority of neuroendocrine tumors irrespective of their POMC status. These results show that expression of the V3 receptor gene participates in the corticotroph phenotype. Its striking association with ACTH-secreting bronchial carcinoids defines a subset of nonpituitary tumors in which ectopic POMC gene expression is but one aspect of a wider process of corticotroph cell differentiation, and opens new possibilities of pharmacological investigations and even manipulations of this peculiar ACTH hypersecretory syndrome. PMID:8636444

The pituitary V3 vasopressin receptor and the corticotroph phenotype in ectopic ACTH syndrome.

PubMed

de Keyzer, Y; Lenne, F; Auzan, C; Jégou, S; René, P; Vaudry, H; Kuhn, J M; Luton, J P; Clauser, E; Bertagna, X

1996-03-01

Ectopic ACTH secretion occurs in highly differentiated and rather indolent tumors like bronchial carcinoids or, in contrast, in various types of aggressive and poorly differentiated neuroendocrine tumors. We explored this phenomenon using the recently cloned human pituitary V3 vasopressin receptor as an alternate molecular marker of the corticotroph phenotype. Expression of V3 receptor, corticotrophin releasing hormone (CRH) receptor, and proopiomelanocortin (POMC) genes was examined in tumors of pituitary and nonpituitary origin. A comparative RT-PCR approach revealed signals for both V3 receptor and CHR receptor mRNAs in 17 of 18 ACTH-secreting pituitary adenomas, and 6 of 6 normal pituitaries; in six growth hormone- or prolactin-secreting adenomas, a very faint V3 receptor signal was observed in three cases, and CRH receptor signal was undetected in all. Six of eight bronchial carcinoids responsible for the ectopic ACTH syndrome had both POMC and V3 receptor signals as high as those in ACTH-secreting pituitary adenomas; in contrast, no POMC signal and only a very faint V3 receptor signal were detected in six of eight nonsecreting bronchial carcinoids. Northern blot analysis showed V3 receptor mRNA of identical size in ACTH-secreting bronchial carcinoids and pituitary tumors. Other types of nonpituitary tumors responsible for ectopic ACTH syndrome presented much lower levels of both POMC and V3 receptor gene expression than those found in ACTH-secreting bronchial carcinoids. In contrast with the V3 receptor, CRH receptor mRNA was detected in the majority of neuroendocrine tumors irrespective of their POMC status. These results show that expression of the V3 receptor gene participates in the corticotroph phenotype. Its striking association with ACTH-secreting bronchial carcinoids defines a subset of nonpituitary tumors in which ectopic POMC gene expression is but one aspect of a wider process of corticotroph cell differentiation, and opens new possibilities of pharmacological investigations and even manipulations of this peculiar ACTH hypersecretory syndrome.

Angiotensin II in the paraventricular nucleus stimulates sympathetic outflow to the cardiovascular system and make vasopressin release in rat.

PubMed

Khanmoradi, Mehrangiz; Nasimi, Ali

2016-10-06

The hypothalamic paraventricular nucleus (PVN) plays essential roles in neuroendocrine and autonomic functions, including cardiovascular regulation. It was shown that microinjection of angiotensin II (AngII) into the PVN produced a pressor response. In this study, we explored the probable mechanisms of this pressor response. AngII was microinjected into the PVN and cardiovascular responses were recorded. Then, the responses were re-tested after systemic injection of a ganglionic blocker, Hexamethonium, or a vasopressin V1 receptor blocker. Hexamethonium pretreatment (i.v.) greatly and significantly attenuated the pressor response to AngII, with no significant effect on heart rate, indicating that the sympathetic system is involved in the cardiovascular effect of AngII in the PVN. Systemic pretreatment (i.v.) with V1 antagonist greatly and significantly attenuated the pressor response to AngII, with no significant effect on heart rate, indicating that vasopressin release is involved in the cardiovascular effect of AngII in the PVN. Overall, we found that AngII microinjected into the PVN produced a pressor response mediated by the sympathetic system and vasopressin release, indicating that other than circulating AngII, endogenous AngII of the PVN increases the vasopressin release from the PVN. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The amphiphilic action of vasopressin and analogues on the plasma membrane of Amoeba proteus.

PubMed

Mayers, P; Couillard, P

1990-10-01

Arginine (AVP) and lysine vasopressin induce a weak but statistically significant increase in the water permeability of Amoeba proteus plasmalemma. Vasotocin and deaminovasopressin, which share the hydroosmotic properties of AVP on classical vertebrate systems, are without effects on Amoeba while SKF 101926, a synthetic AVP antagonist, is even more effective than the parent compound. Theophyllin and dibutyryl-cAMP do not affect AVP action on Amoeba. Lithium, oxytocin, and carbachol are also without effect. Thus, it is unlikely that either V2 (cAMP) or V1 (phosphatidylinositol choline) receptors are involved. A clear correlation has been found between the amphiphilic character of tested peptides and their effect on Amoeba water permeability. Classical amphiphilic peptides, melittin, mastoparan, and fragment 1-8 of alpha-neoendorphin, also increased water permeability in Amoeba. It is known that vasopressin can interact with artificial lipid membranes, increasing their permeability to water. We propose that amphiphilic members of the AVP family interact directly with the lipid phase of the Amoeba membrane. Their incorporation within the lipid bilayer may cause local disruptions or may create micellar water channels as shown for other amphiphilic proteins. Our observations provide a model for the early evolution of peptide hormone systems, preceding the appearance of specific membrane receptors and associated second messenger amplifying mechanisms.

Through the central V2, not V1 receptors influencing the endogenous opiate peptide system, arginine vasopressin, not oxytocin in the hypothalamic paraventricular nucleus involves in the antinociception in the rat.

PubMed

Yang, Jun; Chen, Jian-min; Song, Cao-You; Liu, Wen-Yan; Wang, Gen; Wang, Cheng-hai; Lin, Bao-Chen

2006-01-19

Our previous study has proven that hypothalamic paraventricular nucleus (PVN) played a role in the antinociception. The central bioactive substances involving in the PVN regulating antinociception were investigated in the rat. The results showed that electrical stimulation of the PVN increased the pain threshold, and L-glutamate sodium injection into the PVN elevated the pain threshold, but the PVN cauterization decreased the pain threshold; pain stimulation raised the arginine vasopressin (AVP), not oxytocin (OXT), leucine-enkephalin (L-Ek), beta-endorphin (beta-Ep) and DynorphinA1-13 (DynA1-13) concentrations in the PVN tissue using micropunch method, heightened AVP, L-Ek, beta-Ep and DynA1-13, not OXT concentrations in the PVN perfuse liquid, and reduced the number of AVP-, not OXT, L-Ek, beta-Ep and DynA1-13-immunoreactive neurons in the PVN especially in the posterior magnocellular part of the PVN using immunocytochemistry. There was a negative relationship between the PVN AVP concentration and the pain threshold; pain stimulation enhanced the AVP, not OXT mRNA expression in the PVN using in situ hybridization and RT-PCR; intraventricular injection of anti-AVP serum completely reversed L-glutamate sodium injection into the PVN-induced antinociception, and administration of naloxone - the opiate peptide antagonist, partly blocked this L-glutamate sodium effect, but anti-OXT serum pretreatment did not influence this L-glutamate sodium effect; L-glutamate sodium injection into the PVN-induced analgesia was inhibited by V2 receptor antagonist - d(CH2)5[D-Ile2, Ile4, Ala-NH2(9)]AVP, not V1 receptor antagonist - d(CH2)5Tyr(Me)AVP. The data suggested that the PVN was limited to the central AVP, not OXT, which was through V2, not V1 receptors influencing the endogenous opiate peptide system, to regulate antinociception.

Social Novelty Investigation in the Juvenile Rat: Modulation by the μ-Opioid System.

PubMed

Smith, C J W; Wilkins, K B; Mogavero, J N; Veenema, A H

2015-10-01

The drive to approach and explore novel conspecifics is inherent to social animals and may promote optimal social functioning. Juvenile animals seek out interactions with novel peers more frequently and find these interactions to be more rewarding than their adult counterparts. In the present study, we aimed to establish a behavioural paradigm to measure social novelty-seeking in juvenile rats and to determine the involvement of the opioid, dopamine, oxytocin and vasopressin systems in this behaviour. To this end, we developed the social novelty preference test to assess the preference of a juvenile rat to investigate a novel over a familiar (cage mate) conspecific. We show that across the juvenile period both male and female rats spend more time investigating a novel conspecific than a cage mate, independent of subject sex or repeated exposure to the test. We hypothesised that brain systems subserving social information processing and social motivation/reward (i.e. the opioid, dopamine, oxytocin, vasopressin systems) might support social novelty preference. To test this, receptor antagonists of each of these systems were administered i.c.v. prior to exposure to the social novelty preference test and, subsequently, to the social preference test, to examine the specificity of these effects. We find that μ-opioid receptor antagonism reduces novel social investigation in both the social novelty preference and social preference tests while leaving the investigation of a cage mate (social novelty preference test) or an object (social preference test) unaffected. In contrast, central blockade of dopamine D2 receptors (with eticlopride), oxytocin receptors (with des-Gly-NH2,d(CH2)5[Tyr(Me)2,Thr4]OVT) or vasopressin V1a receptors [with (CH2)5Tyr(Me2)AVP] failed to alter social novelty preference or social preference. Overall, we have established a new behavioural test to study social novelty-seeking behaviour in the juvenile rat and show that the μ-opioid system facilitates this behaviour, possibly by reducing risk avoidance and enhancing the hedonic and/or motivational value of social novelty. © 2015 British Society for Neuroendocrinology.

Novel AVPR2 mutation causing partial nephrogenic diabetes insipidus in a Japanese family.

PubMed

Yamashita, Sumie; Hata, Astuko; Usui, Takeshi; Oda, Hirotsugu; Hijikata, Atsushi; Shirai, Tsuyoshi; Kaneko, Naoto; Hata, Daisuke

2016-05-01

X-linked recessive congenital nephrogenic diabetes insipidus (NDI) is caused by mutations of the arginine vasopressin type 2 receptor gene (AVPR2). More than 200 mutations of the AVPR2 gene with complete NDI have been reported although only 15 mutations with partial NDI has been reported to date. We herein report a Japanese kindred with partial NDI. The proband is an 8-year-old boy who was referred to our hospital for nocturnal enuresis. Water deprivation test and hypertonic saline test suggested partial renal antidiuretic hormone arginine vasopressin (AVP) resistance. Analysis of genomic DNA revealed a novel missense mutation (p.L161P) in the patient. The patient's mother was heterozygous for the mutation. Three-dimensional (3-D) modeling study showed that L161P possibly destabilizes the transmembrane domain of the V2 receptor, resulting in its misfolding or mislocalization. Distinguishing partial NDI from nocturnal enuresis is important. A clinical clue for diagnosis of partial NDI is an incompatibly high level of AVP despite normal serum osmolality.

Cyclotides Isolated from an Ipecac Root Extract Antagonize the Corticotropin Releasing Factor Type 1 Receptor

PubMed Central

Fahradpour, Mohsen; Keov, Peter; Tognola, Carlotta; Perez-Santamarina, Estela; McCormick, Peter J.; Ghassempour, Alireza; Gruber, Christian W.

2017-01-01

Cyclotides are plant derived, cystine-knot stabilized peptides characterized by their natural abundance, sequence variability and structural plasticity. They are abundantly expressed in Rubiaceae, Psychotrieae in particular. Previously the cyclotide kalata B7 was identified to modulate the human oxytocin and vasopressin G protein-coupled receptors (GPCRs), providing molecular validation of the plants’ uterotonic properties and further establishing cyclotides as valuable source for GPCR ligand design. In this study we screened a cyclotide extract derived from the root powder of the South American medicinal plant ipecac (Carapichea ipecacuanha) for its GPCR modulating activity of the corticotropin-releasing factor type 1 receptor (CRF1R). We identified and characterized seven novel cyclotides. One cyclotide, caripe 8, isolated from the most active fraction, was further analyzed and found to antagonize the CRF1R. A nanomolar concentration of this cyclotide (260 nM) reduced CRF potency by ∼4.5-fold. In contrast, caripe 8 did not inhibit forskolin-, or vasopressin-stimulated cAMP responses at the vasopressin V2 receptor, suggesting a CRF1R-specific mode-of-action. These results in conjunction with our previous findings establish cyclotides as modulators of both classes A and B GPCRs. Given the diversity of cyclotides, our data point to other cyclotide-GPCR interactions as potentially important sources of drug-like molecules. PMID:29033832

The role of the vasopressin system and dopamine D1 receptors in the effects of social housing condition on morphine reward.

PubMed

Bates, M L Shawn; Hofford, Rebeca S; Emery, Michael A; Wellman, Paul J; Eitan, Shoshana

2018-07-01

The association with opioid-abusing individuals or even the perception of opioid abuse by peers are risk factors for the initiation and escalation of abuse. Similarly, we demonstrated that morphine-treated animals housed with only morphine-treated animals (referred to as morphine only) acquire morphine conditioned place-preference (CPP) more readily than morphine-treated animals housed with drug-naïve animals (referred to as morphine cage-mates). However, the molecular mechanisms underlying these effects are still elusive. Mice received repeated morphine or saline while housed as saline only, morphine only, or cage-mates. Then, they were examined for the expression levels of D1 dopamine receptor (D1DR), D2 dopamine receptor (D2DR), dopamine transporter (DAT), oxytocin, and Arginine-vasopressin (AVP) in the striatum using qPCR. Additionally, we examined the effects of the AVP-V1b receptor antagonist, SSR149415, on the acquisition of morphine conditioned place-preference (CPP). Increased striatal expression of D1DR and AVP was observed in morphine only animals, but not morphine cage-mates. No significant effects were observed on the striatal expression of D2DR, DAT, or oxytocin. Antagonizing the AVP-V1b receptors decreased the acquisition of morphine CPP in the morphine only mice, but did not alter the acquisition of morphine CPP in the morphine cage-mate mice. Housing with drug-naïve animals protects against the increase in striatal expression of D1DR and AVP elicited by morphine exposure. Moreover, our studies suggest that the protective effect of housing with drug-naïve animals on the acquisition of morphine reward might be, at least partially, mediated by AVP. Copyright © 2018 Elsevier B.V. All rights reserved.

Vasopressin and angiotensin II in reflex regulation of ACTH, glucocorticoids, and renin: effect of water deprivation

NASA Technical Reports Server (NTRS)

Brooks, V. L.; Keil, L. C.

1992-01-01

Angiotensin II (ANG II) and vasopressin participate in baroreflex regulation of adrenocorticotropic hormone (ACTH), glucocorticoid, and renin secretion. The purpose of this study was to determine whether this participation is enhanced in water-deprived dogs, with chronically elevated plasma ANG II and vasopressin levels, compared with water-replete dogs. The baroreflex was assessed by infusing increasing doses of nitroprusside (0.3, 0.6, 1.5, and 3.0 micrograms.kg-1.min-1) in both groups of animals. To quantitate the participation of ANG II and vasopressin, the dogs were untreated or pretreated with the competitive ANG II antagonist saralasin, a V1-vasopressin antagonist, or combined V1/V2-vasopressin antagonist, either alone or in combination. The findings were as follows. 1) Larger reflex increases in ANG II, vasopressin, and glucocorticoids, but not ACTH, were produced in water-deprived dogs compared with water-replete dogs. 2) ANG II blockade blunted the glucocorticoid and ACTH responses to hypotension in water-deprived dogs, but not water-replete dogs. In contrast, vasopressin blockade reduced the ACTH response only in water-replete dogs. 3) Vasopressin or combined vasopressin and ANG II blockade reduced the plasma level of glucocorticoids related either to the fall in arterial pressure or to the increase in plasma ACTH concentration in water-replete dogs, and this effect was enhanced in water-deprived dogs. 4) In both water-deprived and water-replete animals, saralasin and/or a V1-antagonist increased the renin response to hypotension, but a combined V1/V2-antagonist did not. These results reemphasize the importance of endogenous ANG II and vasopressin in the regulation of ACTH, glucocorticoid, and renin secretion.(ABSTRACT TRUNCATED AT 250 WORDS).

Bench-to-bedside review: Vasopressin in the management of septic shock

PubMed Central

2011-01-01

This review of vasopressin in septic shock differs from previous reviews by providing more information on the physiology and pathophysiology of vasopressin and vasopressin receptors, particularly because of recent interest in more specific AVPR1a agonists and new information from the Vasopressin and Septic Shock Trial (VASST), a randomized trial of vasopressin versus norepinephrine in septic shock. Relevant literature regarding vasopressin and other AVPR1a agonists was reviewed and synthesized. Vasopressin, a key stress hormone in response to hypotension, stimulates a family of receptors: AVPR1a, AVPR1b, AVPR2, oxytocin receptors and purinergic receptors. Rationales for use of vasopressin in septic shock are as follows: first, a deficiency of vasopressin in septic shock; second, low-dose vasopressin infusion improves blood pressure, decreases requirements for norepinephrine and improves renal function; and third, a recent randomized, controlled, concealed trial of vasopressin versus norepinephrine (VASST) suggests low-dose vasopressin may decrease mortality of less severe septic shock. Previous clinical studies of vasopressin in septic shock were small or not controlled. There was no difference in 28-day mortality between vasopressin-treated versus norepinephrine-treated patients (35% versus 39%, respectively) in VASST. There was potential benefit in the prospectively defined stratum of patients with less severe septic shock (5 to 14 μg/minute norepinephrine at randomization): vasopressin may have lowered mortality compared with norepinephrine (26% versus 36%, respectively, P = 0.04 within stratum). The result was robust: vasopressin also decreased mortality (compared with norepinephrine) if less severe septic shock was defined by the lowest quartile of arterial lactate or by use of one (versus more than one) vasopressor at baseline. Other investigators found greater hemodynamic effects of higher dose of vasopressin (0.06 units/minute) but also unique adverse effects (elevated liver enzymes and serum bilirubin). Use of higher dose vasopressin requires further evaluation of efficacy and safety. There are very few studies of interactions of therapies in critical care - or septic shock - and effects on mortality. Therefore, the interaction of vasopressin infusion, corticosteroid treatment and mortality of septic shock was evaluated in VASST. Low-dose vasopressin infusion plus corticosteroids significantly decreased 28-day mortality compared with corticosteroids plus norepinephrine (44% versus 35%, respectively, P = 0.03; P = 0.008 interaction statistic). Prospective randomized controlled trials would be necessary to confirm this interesting interaction. In conclusion, low-dose vasopressin may be effective in patients who have less severe septic shock already receiving norepinephrine (such as patients with modest norepinephrine infusion (5 to 15 μg/minute) or low serum lactate levels). The interaction of vasopressin infusion and corticosteroid treatment in septic shock requires further study. PMID:21892977

Nucleotide sequence and structural organization of the human vasopressin pituitary receptor (V3) gene.

PubMed

René, P; Lenne, F; Ventura, M A; Bertagna, X; de Keyzer, Y

2000-01-04

In the pituitary, vasopressin triggers ACTH release through a specific receptor subtype, termed V3 or V1b. We cloned the V3 cDNA and showed that its expression was almost exclusive to pituitary corticotrophs and some corticotroph tumors. To study the determinants of this tissue specificity, we have now cloned the gene for the human (h) V3 receptor and characterized its structure. It is composed of two exons, spanning 10kb, with the coding region interrupted between transmembrane domains 6 and 7. We established that the transcription initiation site is located 498 nucleotides upstream of the initiator codon and showed that two polyadenylation sites may be used, while the most frequent is the most downstream. Sequence analysis of the promoter region showed no TATA box but identified consensus binding motifs for Sp1, CREB, and half sites of the estrogen receptor binding site. However comparison with another corticotroph-specific gene, proopiomelanocortin, did not identify common regulatory elements in the two promoters except for a short GC-rich region. Unexpectedly, hV3 gene analysis revealed that a formerly cloned 'artifactual' hV3 cDNA indeed corresponded to a spliced antisense transcript, overlapping the 5' part of the coding sequence in exon 1 and the promoter region. This transcript, hV3rev, was detected in normal pituitary and in many corticotroph tumors expressing hV3 sense mRNA and may therefore play a role in hV3 gene expression.

Associations between Vocal Symptoms and Genetic Variants in the Oxytocin Receptor and Arginine Vasopressin 1A Receptor Gene

ERIC Educational Resources Information Center

Jämsen, Sofia Holmqvist; Johansson, Ada; Westberg, Lars; Santtila, Pekka; von der Pahlen, Bettina; Simberg, Susanna

2017-01-01

Purpose: Oxytocin and arginine vasopressin are associated with different aspects of the stress response. As stress is regarded as a risk factor for vocal symptoms, we wanted to explore the association between the oxytocin receptor gene ("OXTR") and arginine vasopressin 1A receptor gene ("AVPR1A") single-nucleotide polymorphisms…

WAY 267,464, a non-peptide oxytocin receptor agonist, impairs social recognition memory in rats through a vasopressin 1A receptor antagonist action.

PubMed

Hicks, Callum; Ramos, Linnet; Reekie, Tristan A; Narlawar, Rajeshwar; Kassiou, Michael; McGregor, Iain S

2015-08-01

Recent in vitro studies suggest that the oxytocin receptor (OTR) agonist WAY 267,464 has vasopressin 1A receptor (V1AR) antagonist effects. This might limit its therapeutic potential due to the positive involvement of the V1AR in social behavior. The objective of this study was to assess functional V1AR antagonist-like effects of WAY 267,464 in vivo using a test of social recognition memory. Adult experimental rats were tested for their recognition of a juvenile conspecific rat that they had briefly met 30 or 120 min previously. The modulatory effects of vasopressin (AVP), the selective V1AR antagonist SR49059, and WAY 267,464 were examined together with those of the selective OTR antagonist Compound 25 (C25). Drugs were administered immediately after the first meeting. Control rats showed recognition of juveniles at a 30 min, but not a 120 min retention interval. AVP (0.005, but not 0.001 mg/kg intraperitoneal (i.p.)) improved memory such that recognition was evident after 120 min. This was prevented by pretreatment with SR49059 (1 mg/kg) and WAY 267,464 (10, 30, and 100 mg/kg). Given alone, SR49059 (1 mg/kg) and WAY 267,464 (30 and 100 mg/kg) impaired memory at a 30 min retention interval. The impairment with WAY 267,464 was not prevented by C25 (5 mg/kg), suggesting V1AR rather than OTR mediation of the effect. Given alone, C25 also impaired memory. These results highlight a tonic role for endogenous AVP (and oxytocin) in social recognition memory and indicate that WAY 267,464 functions in vivo as a V1AR antagonist to prevent the memory-enhancing effects of AVP.

Effects of YM471, a nonpeptide AVP V1A and V2 receptor antagonist, on human AVP receptor subtypes expressed in CHO cells and oxytocin receptors in human uterine smooth muscle cells

PubMed Central

Tsukada, Junko; Tahara, Atsuo; Tomura, Yuichi; Wada, Koh-ichi; Kusayama, Toshiyuki; Ishii, Noe; Yatsu, Takeyuki; Uchida, Wataru; Taniguchi, Nobuaki; Tanaka, Akihiro

2001-01-01

YM471, (Z)-4′-{4,4-difluoro-5-[2-(4-dimethylaminopiperidino)-2-oxoethylidene]-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl}-2-phenylbenzanilide monohydrochloride, is a newly synthesized potent vasopressin (AVP) receptor antagonist. Its effects on binding to and signal transduction by cloned human AVP receptors (V1A, V1B and V2) stably expressed in Chinese hamster ovary (CHO) cells, and oxytocin receptors in human uterine smooth muscle cells (USMC) were studied. YM471 potently inhibited specific [3H]-AVP binding to V1A and V2 receptors with Ki values of 0.62 nM and 1.19 nM, respectively. In contrast, YM471 exhibited much lower affinity for V1B and oxytocin receptors with Ki values of 16.4 μM and 31.6 nM, respectively. In CHO cells expressing V1A receptors, YM471 potently inhibited AVP-induced intracellular Ca2+ concentration ([Ca2+]i) increase, exhibiting an IC50 value of 0.56 nM. However, in human USMC expressing oxytocin receptors, YM471 exhibited much lower potency in inhibiting oxytocin-induced [Ca2+]i increase (IC50=193 nM), and did not affect AVP-induced [Ca2+]i increase in CHO cells expressing V1B receptors. Furthermore, in CHO cells expressing V2 receptors, YM471 potently inhibited the production of cyclic AMP stimulated by AVP with an IC50 value of 1.88 nM. In all assays, YM471 showed no agonistic activity. These results demonstrate that YM471 is a potent, nonpeptide human V1A and V2 receptor antagonist which will be a valuable tool in defining the physiologic and pharmacologic actions of AVP. PMID:11429400

Effects of YM471, a nonpeptide AVP V(1A) and V(2) receptor antagonist, on human AVP receptor subtypes expressed in CHO cells and oxytocin receptors in human uterine smooth muscle cells.

PubMed

Tsukada, J; Tahara, A; Tomura, Y; Wada Ki; Kusayama, T; Ishii, N; Yatsu, T; Uchida, W; Taniguchi, N; Tanaka, A

2001-07-01

YM471, (Z)-4'-[4,4-difluoro-5-[2-(4-dimethylaminopiperidino)-2-oxoethylidene]-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl]-2-phenylbenzanilide monohydrochloride, is a newly synthesized potent vasopressin (AVP) receptor antagonist. Its effects on binding to and signal transduction by cloned human AVP receptors (V(1A), V(1B) and V(2)) stably expressed in Chinese hamster ovary (CHO) cells, and oxytocin receptors in human uterine smooth muscle cells (USMC) were studied. YM471 potently inhibited specific [(3)H]-AVP binding to V(1A) and V(2) receptors with K(i) values of 0.62 nM and 1.19 nM, respectively. In contrast, YM471 exhibited much lower affinity for V(1B) and oxytocin receptors with K(i) values of 16.4 microM and 31.6 nM, respectively. In CHO cells expressing V(1A) receptors, YM471 potently inhibited AVP-induced intracellular Ca(2+) concentration ([Ca(2+)](i)) increase, exhibiting an IC(50) value of 0.56 nM. However, in human USMC expressing oxytocin receptors, YM471 exhibited much lower potency in inhibiting oxytocin-induced [Ca(2+)](i) increase (IC(50)=193 nM), and did not affect AVP-induced [Ca(2+)](i) increase in CHO cells expressing V(1B) receptors. Furthermore, in CHO cells expressing V(2) receptors, YM471 potently inhibited the production of cyclic AMP stimulated by AVP with an IC(50) value of 1.88 nM. In all assays, YM471 showed no agonistic activity. These results demonstrate that YM471 is a potent, nonpeptide human V(1A) and V(2) receptor antagonist which will be a valuable tool in defining the physiologic and pharmacologic actions of AVP.

A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling

NASA Astrophysics Data System (ADS)

Beautrait, Alexandre; Paradis, Justine S.; Zimmerman, Brandon; Giubilaro, Jenna; Nikolajev, Ljiljana; Armando, Sylvain; Kobayashi, Hiroyuki; Yamani, Lama; Namkung, Yoon; Heydenreich, Franziska M.; Khoury, Etienne; Audet, Martin; Roux, Philippe P.; Veprintsev, Dmitry B.; Laporte, Stéphane A.; Bouvier, Michel

2017-04-01

In addition to G protein-coupled receptor (GPCR) desensitization and endocytosis, β-arrestin recruitment to ligand-stimulated GPCRs promotes non-canonical signalling cascades. Distinguishing the respective contributions of β-arrestin recruitment to the receptor and β-arrestin-promoted endocytosis in propagating receptor signalling has been limited by the lack of selective analytical tools. Here, using a combination of virtual screening and cell-based assays, we have identified a small molecule that selectively inhibits the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP2 without interfering with the formation of receptor/β-arrestin complexes. This selective β-arrestin/β2-adaptin inhibitor (Barbadin) blocks agonist-promoted endocytosis of the prototypical β2-adrenergic (β2AR), V2-vasopressin (V2R) and angiotensin-II type-1 (AT1R) receptors, but does not affect β-arrestin-independent (transferrin) or AP2-independent (endothelin-A) receptor internalization. Interestingly, Barbadin fully blocks V2R-stimulated ERK1/2 activation and blunts cAMP accumulation promoted by both V2R and β2AR, supporting the concept of β-arrestin/AP2-dependent signalling for both G protein-dependent and -independent pathways.

A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling.

PubMed

Beautrait, Alexandre; Paradis, Justine S; Zimmerman, Brandon; Giubilaro, Jenna; Nikolajev, Ljiljana; Armando, Sylvain; Kobayashi, Hiroyuki; Yamani, Lama; Namkung, Yoon; Heydenreich, Franziska M; Khoury, Etienne; Audet, Martin; Roux, Philippe P; Veprintsev, Dmitry B; Laporte, Stéphane A; Bouvier, Michel

2017-04-18

In addition to G protein-coupled receptor (GPCR) desensitization and endocytosis, β-arrestin recruitment to ligand-stimulated GPCRs promotes non-canonical signalling cascades. Distinguishing the respective contributions of β-arrestin recruitment to the receptor and β-arrestin-promoted endocytosis in propagating receptor signalling has been limited by the lack of selective analytical tools. Here, using a combination of virtual screening and cell-based assays, we have identified a small molecule that selectively inhibits the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP2 without interfering with the formation of receptor/β-arrestin complexes. This selective β-arrestin/β2-adaptin inhibitor (Barbadin) blocks agonist-promoted endocytosis of the prototypical β2-adrenergic (β2AR), V2-vasopressin (V2R) and angiotensin-II type-1 (AT1R) receptors, but does not affect β-arrestin-independent (transferrin) or AP2-independent (endothelin-A) receptor internalization. Interestingly, Barbadin fully blocks V2R-stimulated ERK1/2 activation and blunts cAMP accumulation promoted by both V2R and β2AR, supporting the concept of β-arrestin/AP2-dependent signalling for both G protein-dependent and -independent pathways.

A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling

PubMed Central

Beautrait, Alexandre; Paradis, Justine S.; Zimmerman, Brandon; Giubilaro, Jenna; Nikolajev, Ljiljana; Armando, Sylvain; Kobayashi, Hiroyuki; Yamani, Lama; Namkung, Yoon; Heydenreich, Franziska M.; Khoury, Etienne; Audet, Martin; Roux, Philippe P.; Veprintsev, Dmitry B.; Laporte, Stéphane A.; Bouvier, Michel

2017-01-01

In addition to G protein-coupled receptor (GPCR) desensitization and endocytosis, β-arrestin recruitment to ligand-stimulated GPCRs promotes non-canonical signalling cascades. Distinguishing the respective contributions of β-arrestin recruitment to the receptor and β-arrestin-promoted endocytosis in propagating receptor signalling has been limited by the lack of selective analytical tools. Here, using a combination of virtual screening and cell-based assays, we have identified a small molecule that selectively inhibits the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP2 without interfering with the formation of receptor/β-arrestin complexes. This selective β-arrestin/β2-adaptin inhibitor (Barbadin) blocks agonist-promoted endocytosis of the prototypical β2-adrenergic (β2AR), V2-vasopressin (V2R) and angiotensin-II type-1 (AT1R) receptors, but does not affect β-arrestin-independent (transferrin) or AP2-independent (endothelin-A) receptor internalization. Interestingly, Barbadin fully blocks V2R-stimulated ERK1/2 activation and blunts cAMP accumulation promoted by both V2R and β2AR, supporting the concept of β-arrestin/AP2-dependent signalling for both G protein-dependent and -independent pathways. PMID:28416805

Identification of Potential Pharmacoperones Capable of Rescuing the Functionality of Misfolded Vasopressin 2 Receptor Involved in Nephrogenic Diabetes Insipidus.

PubMed

Smith, Emery; Janovick, Jo Ann; Bannister, Thomas D; Shumate, Justin; Scampavia, Louis; Conn, P Michael; Spicer, Timothy P

2016-09-01

Pharmacoperones correct the folding of otherwise misfolded protein mutants, restoring function (i.e., providing "rescue") by correcting their trafficking. Currently, most pharmacoperones possess intrinsic antagonist activity because they were identified using methods initially aimed at discovering such functions. Here, we describe an ultra-high-throughput homogeneous cell-based assay with a cAMP detection system, a method specifically designed to identify pharmacoperones of the vasopressin type 2 receptor (V2R), a GPCR that, when mutated, is associated with nephrogenic diabetes insipidus. Previously developed methods to identify compounds capable of altering cellular trafficking of V2R were modified and used to screen a 645,000 compound collection by measuring the ability of library compounds to rescue a mutant hV2R [L83Q], using a cell-based luminescent detection system. The campaign initially identified 3734 positive modulators of cAMP. The confirmation and counterscreen identified only 147 of the active compounds with an EC50 of ≤5 µM. Of these, 83 were reconfirmed as active through independently obtained pure samples and were also inactive in a relevant counterscreen. Active and tractable compounds within this set can be categorized into three predominant structural clusters, described here, in the first report detailing the results of a large-scale pharmacoperone high-throughput screening campaign. © 2016 Society for Laboratory Automation and Screening.

Biased agonist pharmacochaperones of the AVP V2 receptor may treat congenital nephrogenic diabetes insipidus.

PubMed

Jean-Alphonse, Frédéric; Perkovska, Sanja; Frantz, Marie-Céline; Durroux, Thierry; Méjean, Catherine; Morin, Denis; Loison, Stéphanie; Bonnet, Dominique; Hibert, Marcel; Mouillac, Bernard; Mendre, Christiane

2009-10-01

X-linked congenital nephrogenic diabetes insipidus (cNDI) results from inactivating mutations of the human arginine vasopressin (AVP) V2 receptor (hV(2)R). Most of these mutations lead to intracellular retention of the hV(2)R, preventing its interaction with AVP and thereby limiting water reabsorption and concentration of urine. Because the majority of cNDI-hV(2)Rs exhibit protein misfolding, molecular chaperones hold promise as therapeutic agents; therefore, we sought to identify pharmacochaperones for hV(2)R that also acted as agonists. Here, we describe high-affinity nonpeptide compounds that promoted maturation and membrane rescue of L44P, A294P, and R337X cNDI mutants and restored a functional AVP-dependent cAMP signal. Contrary to pharmacochaperone antagonists, these compounds directly activated a cAMP signal upon binding to several cNDI mutants. In addition, these molecules displayed original functionally selective properties (biased agonism) toward the hV(2)R, being unable to recruit arrestin, trigger receptor internalization, or stimulate mitogen-activated protein kinases. These characteristics make these hV(2)R agonist pharmacochaperones promising therapeutic candidates for cNDI.

Biased Agonist Pharmacochaperones of the AVP V2 Receptor May Treat Congenital Nephrogenic Diabetes Insipidus

PubMed Central

Jean-Alphonse, Frédéric; Perkovska, Sanja; Frantz, Marie-Céline; Durroux, Thierry; Méjean, Catherine; Morin, Denis; Loison, Stéphanie; Bonnet, Dominique; Hibert, Marcel

2009-01-01

X-linked congenital nephrogenic diabetes insipidus (cNDI) results from inactivating mutations of the human arginine vasopressin (AVP) V2 receptor (hV2R). Most of these mutations lead to intracellular retention of the hV2R, preventing its interaction with AVP and thereby limiting water reabsorption and concentration of urine. Because the majority of cNDI-hV2Rs exhibit protein misfolding, molecular chaperones hold promise as therapeutic agents; therefore, we sought to identify pharmacochaperones for hV2R that also acted as agonists. Here, we describe high-affinity nonpeptide compounds that promoted maturation and membrane rescue of L44P, A294P, and R337X cNDI mutants and restored a functional AVP-dependent cAMP signal. Contrary to pharmacochaperone antagonists, these compounds directly activated a cAMP signal upon binding to several cNDI mutants. In addition, these molecules displayed original functionally selective properties (biased agonism) toward the hV2R, being unable to recruit arrestin, trigger receptor internalization, or stimulate mitogen-activated protein kinases. These characteristics make these hV2R agonist pharmacochaperones promising therapeutic candidates for cNDI. PMID:19729439

Selective Vasopressin-1a receptor antagonist prevents brain edema, reduces astrocytic cell swelling and GFAP, V1aR and AQP4 expression after focal traumatic brain injury

PubMed Central

Marmarou, Christina R.; Liang, Xiuyin; Abidi, Naqeeb H.; Parveen, Shanaz; Taya, Keisuke; Henderson, Scott C.; Young, Harold F.; Filippidis, Aristotelis S.; Baumgarten, Clive M.

2014-01-01

A secondary and often lethal consequence of traumatic brain injury is cellular edema that we posit is due to astrocytic swelling caused by transmembrane water fluxes augmented by vasopressin-regulated aquaporin-4 (AQP4). We therefore tested whether vasopressin 1a receptor (V1aR) inhibition would suppress astrocyte AQP4, reduce astrocytic edema, and thereby diminish TBI-induced edematous changes. V1aR inhibition by SR49059 significantly reduced brain edema after cortical contusion injury (CCI) in rat 5 h post-injury. Injured-hemisphere brain water content (n=6 animals/group) and astrocytic area (n=3/group) were significantly higher in CCI-vehicle (80.5±0.3%; 18.0±1.4 µm2) versus sham groups (78.3±0.1%; 9.5±0.9 µm2), and SR49059 blunted CCI-induced increases in brain edema (79.0±0.2%; 9.4±0.8 µm2). CCI significantly up-regulated GFAP, V1aR and AQP4 protein levels and SR49059 suppressed injury induced up regulation (n=6/group). In CCI-vehicle, sham and CCI-SR49059 groups, GFAP was 1.58±0.04, 0.47±0.02, and 0.81±0.03, respectively; V1aR was 1.00±0.06, 0.45±0.05, and 0.46±0.09; and AQP4 was 2.03± 0.34, 0.49±0.04, and 0.92±0.22. Confocal immunohistochemistry gave analogous results. In CCI-vehicle, sham and CCI-SR49059 groups, fluorescence intensity of GFAP was 349±38, 56±5, and 244±30, respectively, V1aR was 601±71, 117.8±14, and 390±76, and AQP4 was 818±117, 158±5, and 458±55 (n=3/group). The results support that edema was predominantly cellular following CCI and documented that V1aR inhibition with SR49059 suppressed injury-induced up regulation of GFAP, V1A and AQP4, blunting edematous changes. Our findings suggest V1aR inhibitors may be potential therapeutic tools to prevent cellular swelling and provide treatment for post-traumatic brain edema. PMID:24933327

AV3V lesions attenuate the cardiovascular responses produced by blood-borne excitatory amino acid analogs

NASA Technical Reports Server (NTRS)

Whalen, E. J.; Beltz, T. G.; Lewis, S. J.; Johnson, A. K.

1999-01-01

Systemic injections of the excitatory amino acid (EAA) analogs, kainic acid (KA) and N-methyl-D-aspartate (NMDA), produce a pressor response in conscious rats that is caused by a centrally mediated activation of sympathetic drive and the release of arginine vasopressin (AVP). This study tested the hypothesis that the tissue surrounding the anteroventral part of the third ventricle (AV3V) plays a role in the expression of the pressor responses produced by systemically injected EAA analogs. Specifically, we examined whether prior electrolytic ablation of the AV3V region would affect the pressor responses to KA and NMDA (1 mg/kg iv) in conscious rats. The KA-induced pressor response was smaller in AV3V-lesioned than in sham-lesioned rats (11 +/- 2 vs. 29 +/- 2 mmHg; P < 0.05). After ganglion blockade, KA produced a pressor response in sham-lesioned but not AV3V-lesioned rats (+27 +/- 3 vs. +1 +/- 2 mmHg; P < 0.05). The KA-induced pressor response in ganglion-blocked sham-lesioned rats was abolished by a vasopressin V1-receptor antagonist. Similar results were obtained with NMDA. The pressor response to AVP (10 ng/kg iv) was slightly smaller in AV3V-lesioned than in sham-lesioned ganglion-blocked rats (45 +/- 3 vs. 57 +/- 4 mmHg; P < 0.05). This study demonstrates that the pressor responses to systemically injected EAA analogs are smaller in AV3V-lesioned rats. The EAA analogs may produce pressor responses by stimulation of EAA receptors in the AV3V region, or the AV3V region may play an important role in the expression of these responses.

Diabetes Insipidus in Mice with a Mutation in Aquaporin-2

PubMed Central

Lloyd, David J; Hall, Frank Wesley; Tarantino, Lisa M; Gekakis, Nicholas

2005-01-01

Congenital nephrogenic diabetes insipidus (NDI) is a disease characterized by failure of the kidney to concentrate urine in response to vasopressin. Human kindreds with nephrogenic diabetes insipidus have been found to harbor mutations in the vasopressin receptor 2 (Avpr2) gene or the vasopressin-sensitive water channel aquaporin-2 (Aqp2) gene. Development of a treatment is rendered difficult due to the lack of a viable animal model. Through forward genetic screening of ethylnitrosourea-mutagenized mice, we report the identification and characterization of a mouse model of NDI, with an F204V mutation in the Aqp2 gene. Unlike previously attempted murine models of NDI, our mice survive to adulthood and more exactly recapitulate the human disorder. Previous in vitro experiments using renal cell lines suggest recessive Aqp2 mutations result in improper trafficking of the mutant water pore. Using these animals, we have directly proven this hypothesis of improper AQP2 translocation as the molecular defect in nephrogenic diabetes insipidus in the intact organism. Additionally, using a renal cell line we show that the mutated protein, AQP2-F204V, is retained in the endoplasmic reticulum and that this abnormal localization can be rescued by wild-type protein. This novel mouse model allows for further mechanistic studies as well as testing of pharmacological and gene therapies for NDI. PMID:16121255

Neuropeptides and the social brain: potential rodent models of autism.

PubMed

Lim, Miranda M; Bielsky, Isadora F; Young, Larry J

2005-01-01

Conducting basic scientific research on a complex psychiatric disorder, such as autism, is a challenging prospect. It is difficult to dissociate the fundamental neurological and psychological processes that are disturbed in autism and, therefore, it is a challenge to discover accurate and reliable animal models of the disease. Because of their role in animal models of social processing and social bonding, the neuropeptides oxytocin and vasopressin are strong candidates for dysregulation in autism. In this review, we discuss the current animal models which have investigated oxytocin and vasopressin systems in the brain and their effects on social behavior. For example, mice lacking the oxytocin gene have profound deficits in social processing and social recognition, as do rats lacking vasopressin or mice lacking the vasopressin V1a receptor (V1aR). In another rodent model, monogamous prairie voles are highly social and form strong pair bonds with their mates. Pair bonds can be facilitated or disrupted by perturbing the oxytocin and vasopressin systems. Non-monogamous vole species that do not pair bond have different oxytocin and V1aR distribution patterns in the brain than monogamous vole species. Potential ties from these rodent models to the human autistic condition are then discussed. Given the hallmark disturbances in social function, the study of animal models of social behavior may provide novel therapeutic targets for the treatment of autism.

The Vasopressin 1b Receptor Antagonist A-988315 Blocks Stress Effects on the Retrieval of Object-Recognition Memory

PubMed Central

Barsegyan, Areg; Atsak, Piray; Hornberger, Wilfried B; Jacobson, Peer B; van Gaalen, Marcel M; Roozendaal, Benno

2015-01-01

Stress-induced activation of the hypothalamo–pituitary–adrenocortical (HPA) axis and high circulating glucocorticoid levels are well known to impair the retrieval of memory. Vasopressin can activate the HPA axis by stimulating vasopressin 1b (V1b) receptors located on the pituitary. In the present study, we investigated the effect of A-988315, a selective and highly potent non-peptidergic V1b-receptor antagonist with good pharmacokinetic properties, in blocking stress effects on HPA-axis activity and memory retrieval. To study cognitive performance, male Sprague-Dawley rats were trained on an object-discrimination task during which they could freely explore two identical objects. Memory for the objects and their location was tested 24 h later. A-988315 (20 or 60 mg/kg) or water was administered orally 90 min before retention testing, followed 60 min later by stress of footshock exposure. A-988315 dose-dependently dampened stress-induced increases in corticosterone plasma levels, but did not significantly alter HPA-axis activity of non-stressed control rats. Most importantly, A-988315 administration prevented stress-induced impairment of memory retrieval on both the object-recognition and the object-location tasks. A-988315 did not alter the retention of non-stressed rats and did not influence the total time spent exploring the objects or experimental context in either stressed or non-stressed rats. Thus, these findings indicate that direct antagonism of V1b receptors is an effective treatment to block stress-induced activation of the HPA axis and the consequent impairment of retrieval of different aspects of recognition memory. PMID:25669604

Oxytocin receptor mRNA expression in rat brain: implications for behavioral integration and reproductive success.

PubMed

Ostrowski, N L

1998-11-01

The nonapeptide, oxytocin (OT), has been implicated in a wide range of physiological, behavioral and pharmacological effects related to learning and memory, parturition and lactation, maternal and sexual behavior, and the formation of social attachments. Specific G-protein linked membrane bound OT receptors mediate OTs effects. The unavailability of highly selective pharmacological ligands that discriminate the OT receptor from the highly homologous vasopressin receptors (V1a, V1b and V2 subtypes) has made it difficult to confirm specific effects of oxytocin, particularly in brain regions where OT and multiple AVP receptor subtypes may be coexpressed. Here, data on the oxytocin receptor (OTR) messenger ribonucleic acid (mRNA) localization in brain are presented in the context of a model that proposes a reproductive state-dependent role for steroid-hormone restructuring of neural circuits, and a role for oxytocin in the integration of neural transmission in pathways subserving: (1) steroid-sensitive reproductive behaviors; (2) learning; and (3) reinforcement. It is hypothesized that social attachments emerge as a consequence of a conditioned association between OT-related activity in these pathways and the eliciting stimulus.

A Single Dose, Randomized, Controlled Proof-Of-Mechanism Study of a Novel Vasopressin 1a Receptor Antagonist (RG7713) in High-Functioning Adults with Autism Spectrum Disorder.

PubMed

Umbricht, Daniel; Del Valle Rubido, Marta; Hollander, Eric; McCracken, James T; Shic, Frederick; Scahill, Lawrence; Noeldeke, Jana; Boak, Lauren; Khwaja, Omar; Squassante, Lisa; Grundschober, Christophe; Kletzl, Heidemarie; Fontoura, Paulo

2017-08-01

The core symptoms of autism spectrum disorder (ASD) include impaired social communication, repetitive behaviors, and restricted interests. No effective pharmacotherapy for these core deficits exists. Within the domain of social communication, the vasopressin system is implicated in social cognition and social signaling deficits of ASD, and represents a potential therapeutic target. We assessed the effects of a single 20 mg intravenous dose of the arginine vasopressin receptor 1A (V1a) antagonist, RG7713, on exploratory biomarkers (eye tracking), behavioral and clinical measures of social cognition and communication (affective speech recognition (ASR), reading the mind in the eyes, olfactory identification, scripted interaction), and safety and tolerability in a multicenter, randomized, double-blind, placebo-controlled, cross-over study of 19 high-functioning adult male subjects with DSM-IV Autistic Disorder (age 18-45 years; full scale IQ >70; ABC-Irritability subscale ⩽13). Eye-tracking showed an increase in biological motion orienting preference with RG7713 (ES=0.8, p=0.047) and a non-significant improvement in the composite score (ES=0.2, p=0.29). RG7713 reduced ability to detect lust (ES=-0.8, p=0.03) and fear (ES=-0.7, p=0.07) in ASR. However, when all eight individual emotion subscales were combined into an overall ASR performance score, the reduction was non-significant (ES=-0.1, p=0.59). Thirteen adverse events were reported in 10 subjects; all were of mild (11/13) or moderate (2/13) severity. Although interpretation should be cautious due to multiple comparisons and small sample size, these results provide preliminary evidence from experimental and behavioral biomarkers, that blockade of the V1a receptor may improve social communication in adults with high-functioning ASD. ClinicalTrials.gov identifier: NCT01474278 A Study of RO5028442 in Adult Male High-Functioning Autistic Patients. Available at: https://clinicaltrials.gov/ct2/show/NCT01474278.

The effect of vasopressin 1b receptor (V1bR) blockade on HPA axis activity in rats exposed to acute heat stress.

PubMed

Jasnic, Nebojsa; Djordjevic, Jelena; Vujovic, Predrag; Lakic, Iva; Djurasevic, Sinisa; Cvijic, Gordana

2013-06-15

Thermal stressors such as low and high ambient temperature elicit an abundance of neuroendocrine responses including activation of the hypothalamo-pituitary-adrenal (HPA) axis and arginine vasopressin (AVP) release. The exposure to heat is a particularly interesting model for studying AVP action because this kind of stressor represents not only an unpleasant experience but also a threat to osmotic homeostasis. As AVP has long been recognized as a hormone involved in the modulation of HPA axis activity, the aim of this study was to elucidate the role of AVP in acutely heat-exposed rats using Nelivaptan, a selective vasopressin 1b receptor (V1bR) antagonist. Rats were exposed to high ambient temperature (38°C) for 60 min. The circulating hormones were determined by ELISA or chemiluminescence, and intrapituitary adrenocorticotropic hormone (ACTH) and V1bR level were determined by western blot. The results obtained show that V1bR blockade negatively affected the increase in blood ACTH caused by heat exposure. This treatment alone, or in combination with Nelivaptan, decreased intrapituitary V1bR levels while circulating AVP concentration was increased under the same conditions. Furthermore, a strong correlation was observed between blood ACTH and corticosterone concentration. In conclusion, our results directly confirm the positive role of AVP in the regulation of ACTH secretion from the pituitary in animals exposed to heat. Moreover, the results suggest that AVP from the general circulation influences pituitary V1bR.

Variation in maternal and anxiety-like behavior associated with discrete patterns of oxytocin and vasopressin 1a receptor density in the lateral septum

PubMed Central

Curley, JP; Jensen, CL; Franks, B; Champagne, FA

2012-01-01

The relationship between anxiety and maternal behavior has been explored across species using a variety of approaches, yet there is no clear consensus on the nature or direction of this relationship. In the current study, we have assessed stable individual differences in anxiety-like behavior in a large cohort (n=57) of female F2 hybrid mice. Using open-field behavior as a continuous and categorical (high vs. low) measure we examined the relationship between the anxiety-like behavior of virgin F2 females and the subsequent maternal behavior of these females. In addition, we quantified oxytocin (OTR) and vasopressin (V1a) receptor density within the lateral septum to determine the possible correlation with anxiety-like and maternal behavior. We find that, though activity levels within the open-field do predict latency to engage in pup retrieval, anxiety-like measures on this test are otherwise not associated with subsequent maternal behavior. OTR density in the dorsal lateral septum was found to be negatively correlated with activity levels in the open-field and positively correlated with frequency of nursing behavior. V1a receptor density was significantly correlated with postpartum licking/grooming of pups. Though we do not find support for the hypothesis that individual differences in trait anxiety predict variation in maternal behavior, we do find evidence for the role of OTR and V1a receptors in predicting maternal behavior in mice and suggest possible methodological issues (such as distinguishing between trait and state anxiety) that will be a critical consideration for subsequent studies of the anxiety-maternal behavior relationship. PMID:22300676

Oxytocin, vasopressin and pair bonding: implications for autism.

PubMed

Hammock, Elizabeth A D; Young, Larry J

2006-12-29

Understanding the neurobiological substrates regulating normal social behaviours may provide valuable insights in human behaviour, including developmental disorders such as autism that are characterized by pervasive deficits in social behaviour. Here, we review the literature which suggests that the neuropeptides oxytocin and vasopressin play critical roles in modulating social behaviours, with a focus on their role in the regulation of social bonding in monogamous rodents. Oxytocin and vasopressin contribute to a wide variety of social behaviours, including social recognition, communication, parental care, territorial aggression and social bonding. The effects of these two neuropeptides are species-specific and depend on species-specific receptor distributions in the brain. Comparative studies in voles with divergent social structures have revealed some of the neural and genetic mechanisms of social-bonding behaviour. Prairie voles are socially monogamous; males and females form long-term pair bonds, establish a nest site and rear their offspring together. In contrast, montane and meadow voles do not form a bond with a mate and only the females take part in rearing the young. Species differences in the density of receptors for oxytocin and vasopressin in ventral forebrain reward circuitry differentially reinforce social-bonding behaviour in the two species. High levels of oxytocin receptor (OTR) in the nucleus accumbens and high levels of vasopressin 1a receptor (V1aR) in the ventral pallidum contribute to monogamous social structure in the prairie vole. While little is known about the genetic factors contributing to species-differences in OTR distribution, the species-specific distribution pattern of the V1aR is determined in part by a species-specific repetitive element, or 'microsatellite', in the 5' regulatory region of the gene encoding V1aR (avpr1a). This microsatellite is highly expanded in the prairie vole (as well as the monogamous pine vole) compared to a very short version in the promiscuous montane and meadow voles. These species differences in microsatellite sequence are sufficient to change gene expression in cell culture. Within the prairie vole species, intraspecific variation in the microsatellite also modulates gene expression in vitro as well as receptor distribution patterns in vivo and influences the probability of social approach and bonding behaviour. Similar genetic variation in the human AVPR1A may contribute to variations in human social behaviour, including extremes outside the normal range of behaviour and those found in autism spectrum disorders. In sum, comparative studies in pair-bonding rodents have revealed neural and genetic mechanisms contributing to social-bonding behaviour. These studies have generated testable hypotheses regarding the motivational systems and underlying molecular neurobiology involved in social engagement and social bond formation that may have important implications for the core social deficits characterizing autism spectrum disorders.

Oxytocin, vasopressin and pair bonding: implications for autism

PubMed Central

Hammock, Elizabeth A.D; Young, Larry J

2006-01-01

Understanding the neurobiological substrates regulating normal social behaviours may provide valuable insights in human behaviour, including developmental disorders such as autism that are characterized by pervasive deficits in social behaviour. Here, we review the literature which suggests that the neuropeptides oxytocin and vasopressin play critical roles in modulating social behaviours, with a focus on their role in the regulation of social bonding in monogamous rodents. Oxytocin and vasopressin contribute to a wide variety of social behaviours, including social recognition, communication, parental care, territorial aggression and social bonding. The effects of these two neuropeptides are species-specific and depend on species-specific receptor distributions in the brain. Comparative studies in voles with divergent social structures have revealed some of the neural and genetic mechanisms of social-bonding behaviour. Prairie voles are socially monogamous; males and females form long-term pair bonds, establish a nest site and rear their offspring together. In contrast, montane and meadow voles do not form a bond with a mate and only the females take part in rearing the young. Species differences in the density of receptors for oxytocin and vasopressin in ventral forebrain reward circuitry differentially reinforce social-bonding behaviour in the two species. High levels of oxytocin receptor (OTR) in the nucleus accumbens and high levels of vasopressin 1a receptor (V1aR) in the ventral pallidum contribute to monogamous social structure in the prairie vole. While little is known about the genetic factors contributing to species-differences in OTR distribution, the species-specific distribution pattern of the V1aR is determined in part by a species-specific repetitive element, or ‘microsatellite’, in the 5′ regulatory region of the gene encoding V1aR (avpr1a). This microsatellite is highly expanded in the prairie vole (as well as the monogamous pine vole) compared to a very short version in the promiscuous montane and meadow voles. These species differences in microsatellite sequence are sufficient to change gene expression in cell culture. Within the prairie vole species, intraspecific variation in the microsatellite also modulates gene expression in vitro as well as receptor distribution patterns in vivo and influences the probability of social approach and bonding behaviour. Similar genetic variation in the human AVPR1A may contribute to variations in human social behaviour, including extremes outside the normal range of behaviour and those found in autism spectrum disorders. In sum, comparative studies in pair-bonding rodents have revealed neural and genetic mechanisms contributing to social-bonding behaviour. These studies have generated testable hypotheses regarding the motivational systems and underlying molecular neurobiology involved in social engagement and social bond formation that may have important implications for the core social deficits characterizing autism spectrum disorders. PMID:17118932

Effects of OPC-51803, a novel, nonpeptide vasopressin V2-receptor agonist, on micturition frequency in Brattleboro and aged rats.

PubMed

Nakamura, Shigeki; Hirano, Takahiro; Yamamura, Yoshitaka; Itoh, Shuji; Kondo, Kazumi; Mori, Toyoki; Kambe, Toshimi

2003-12-01

We assessed the effects of OPC-51803 ((5R)-2-[1-(2-chloro-4-(1-pyrrolidinyl)benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]-N-isopropylacetamide), a nonpeptide vasopressin V(2)-receptor agonist, on micturition frequency in female homozygous Brattleboro rats (strain carries hereditary diabetes insipidus) and aged male Sprague-Dawley rats with polyuria. Female homozygous Brattleboro rats exhibited more diuresis and a larger micturition frequency over a 24-h period than did the heterozygous controls. In Brattleboro rats, an oral administration of OPC-51803 at 0.03 and 0.3 mg/kg significantly decreased urinary frequency and was accompanied by decreased urine volume. However, little effect was seen in the mean and maximal micturition volume. Aged male Sprague-Dawley rats (25-month-old) showed a significant increase in urine volume throughout a 0- to 24-h period compared with mature (6-month-old) rats. Orally administered OPC-51803 at 0.3 mg/kg decreased not only urine volume but also urinary frequency in aged rats. Furthermore, OPC-51803 prolonged the time prior to the first micturition. Therefore, OPC-51803 decreased micturition frequency in both rat species by reducing urine outflow. This suggests that the compound will be useful for treating micturition disorders that result in frequent micturition, such as that from polyuria, nocturnal polyuria, and some kinds of urinary incontinence.

Discovery of highly selective brain-penetrant vasopressin 1a antagonists for the potential treatment of autism via a chemogenomic and scaffold hopping approach.

PubMed

Ratni, Hasane; Rogers-Evans, Mark; Bissantz, Caterina; Grundschober, Christophe; Moreau, Jean-Luc; Schuler, Franz; Fischer, Holger; Alvarez Sanchez, Ruben; Schnider, Patrick

2015-03-12

From a micromolar high throughput screening hit 7, the successful complementary application of a chemogenomic approach and of a scaffold hopping exercise rapidly led to a low single digit nanomolar human vasopressin 1a (hV1a) receptor antagonist 38. Initial optimization of the mouse V1a activities delivered suitable tool compounds which demonstrated a V1a mediated central in vivo effect. This novel series was further optimized through parallel synthesis with a focus on balancing lipophilicity to achieve robust aqueous solubility while avoiding P-gp mediated efflux. These efforts led to the discovery of the highly potent and selective brain-penetrant hV1a antagonist RO5028442 (8) suitable for human clinical studies in people with autism.

Selective vasopressin-1a receptor antagonist prevents brain edema, reduces astrocytic cell swelling and GFAP, V1aR and AQP4 expression after focal traumatic brain injury.

PubMed

Marmarou, Christina R; Liang, Xiuyin; Abidi, Naqeeb H; Parveen, Shanaz; Taya, Keisuke; Henderson, Scott C; Young, Harold F; Filippidis, Aristotelis S; Baumgarten, Clive M

2014-09-18

A secondary and often lethal consequence of traumatic brain injury is cellular edema that we posit is due to astrocytic swelling caused by transmembrane water fluxes augmented by vasopressin-regulated aquaporin-4 (AQP4). We therefore tested whether vasopressin 1a receptor (V1aR) inhibition would suppress astrocyte AQP4, reduce astrocytic edema, and thereby diminish TBI-induced edematous changes. V1aR inhibition by SR49059 significantly reduced brain edema after cortical contusion injury (CCI) in rat 5h post-injury. Injured-hemisphere brain water content (n=6 animals/group) and astrocytic area (n=3/group) were significantly higher in CCI-vehicle (80.5±0.3%; 18.0±1.4 µm(2)) versus sham groups (78.3±0.1%; 9.5±0.9 µm(2)), and SR49059 blunted CCI-induced increases in brain edema (79.0±0.2%; 9.4±0.8µm(2)). CCI significantly up-regulated GFAP, V1aR and AQP4 protein levels and SR49059 suppressed injury induced up regulation (n=6/group). In CCI-vehicle, sham and CCI-SR49059 groups, GFAP was 1.58±0.04, 0.47±0.02, and 0.81±0.03, respectively; V1aR was 1.00±0.06, 0.45±0.05, and 0.46±0.09; and AQP4 was 2.03±0.34, 0.49±0.04, and 0.92±0.22. Confocal immunohistochemistry gave analogous results. In CCI-vehicle, sham and CCI-SR49059 groups, fluorescence intensity of GFAP was 349±38, 56±5, and 244±30, respectively, V1aR was 601±71, 117.8±14, and 390±76, and AQP4 was 818±117, 158±5, and 458±55 (n=3/group). The results support that edema was predominantly cellular following CCI and documented that V1aR inhibition with SR49059 suppressed injury-induced up regulation of GFAP, V1A and AQP4, blunting edematous changes. Our findings suggest V1aR inhibitors may be potential therapeutic tools to prevent cellular swelling and provide treatment for post-traumatic brain edema. Copyright © 2014 Elsevier B.V. All rights reserved.

Physiological insights into novel therapies for nephrogenic diabetes insipidus.

PubMed

Sands, Jeff M; Klein, Janet D

2016-12-01

Fundamental kidney physiology research can provide important insight into how the kidney works and suggest novel therapeutic opportunities to treat human diseases. This is especially true for nephrogenic diabetes insipidus (NDI). Over the past decade, studies elucidating the molecular physiology and signaling pathways regulating water transport have suggested novel therapeutic possibilities. In patients with congenital NDI due to mutations in the type 2 vasopressin receptor (V2R) or acquired NDI due to lithium (or other medications), there are no functional abnormalities in the aquaporin-2 (AQP2) water channel, or in another key inner medullary transport protein, the UT-A1 urea transporter. If it is possible to phosphorylate and/or increase the apical membrane accumulation of these proteins, independent of vasopressin or cAMP, one may be able to treat NDI. Sildenifil (through cGMP), erlotinib, and simvastatin each stimulate AQP2 insertion into the apical plasma membrane. Some recent human data suggest that sildenafil and simvastatin may improve urine concentrating ability. ONO-AE1-329 (ONO) stimulates the EP4 prostanoid receptor (EP4), which stimulates kinases that in turn phosphorylate AQP2 and UT-A1. Clopidogrel is a P2Y12-R antagonist that potentiates the effect of vasopressin and increases AQP2 abundance. Metformin stimulates AMPK to phosphorylate and activate AQP2 and UT-A1, and it increases urine concentrating ability in two rodent models of NDI. Since metformin, sildenafil, and simvastatin are commercially available and have excellent safety records, the potential for rapidly advancing them into clinical trials is high. Copyright © 2016 the American Physiological Society.

Physiological insights into novel therapies for nephrogenic diabetes insipidus

PubMed Central

2016-01-01

Fundamental kidney physiology research can provide important insight into how the kidney works and suggest novel therapeutic opportunities to treat human diseases. This is especially true for nephrogenic diabetes insipidus (NDI). Over the past decade, studies elucidating the molecular physiology and signaling pathways regulating water transport have suggested novel therapeutic possibilities. In patients with congenital NDI due to mutations in the type 2 vasopressin receptor (V2R) or acquired NDI due to lithium (or other medications), there are no functional abnormalities in the aquaporin-2 (AQP2) water channel, or in another key inner medullary transport protein, the UT-A1 urea transporter. If it is possible to phosphorylate and/or increase the apical membrane accumulation of these proteins, independent of vasopressin or cAMP, one may be able to treat NDI. Sildenifil (through cGMP), erlotinib, and simvastatin each stimulate AQP2 insertion into the apical plasma membrane. Some recent human data suggest that sildenafil and simvastatin may improve urine concentrating ability. ONO-AE1-329 (ONO) stimulates the EP4 prostanoid receptor (EP4), which stimulates kinases that in turn phosphorylate AQP2 and UT-A1. Clopidogrel is a P2Y12-R antagonist that potentiates the effect of vasopressin and increases AQP2 abundance. Metformin stimulates AMPK to phosphorylate and activate AQP2 and UT-A1, and it increases urine concentrating ability in two rodent models of NDI. Since metformin, sildenafil, and simvastatin are commercially available and have excellent safety records, the potential for rapidly advancing them into clinical trials is high. PMID:27534996

Diabetes Insipidus.

PubMed

Lu, H A Jenny

2017-01-01

Disruption of water and electrolyte balance is frequently encountered in clinical medicine. Regulating water metabolism is critically important. Diabetes insipidus (DI) presented with excessive water loss from the kidney is a major disorder of water metabolism. To understand the molecular and cellular mechanisms and pathophysiology of DI and rationales of clinical management of DI is important for both research and clinical practice. This chapter will first review various forms of DI focusing on central diabetes insipidus (CDI) and nephrogenic diabetes insipidus (NDI ) . This is followed by a discussion of regulatory mechanisms underlying CDI and NDI , with a focus on the regulatory axis of vasopressin, vasopressin receptor 2 (V2R ) and the water channel molecule, aquaporin 2 (AQP2 ). The clinical manifestation, diagnosis and management of various forms of DI will also be discussed with highlights of some of the latest therapeutic strategies that are developed from in vitro experiments and animal studies.

Metformin improves urine concentration in rodents with nephrogenic diabetes insipidus

PubMed Central

Efe, Orhan; Klein, Janet D.; LaRocque, Lauren M.; Ren, Huiwen; Sands, Jeff M.

2016-01-01

Urine concentration is regulated by vasopressin. Congenital nephrogenic diabetes insipidus (NDI) is caused by vasopressin type 2 receptor (V2R) mutations. We studied whether metformin could improve urine concentration in rodent models of congenital NDI by stimulating AMPK. To block the V2R in rats, tolvaptan (10 mg/kg/d) was given by oral gavage with or without metformin (800 mg/kg/d). Control rats received vehicle with or without metformin. Tamoxifen-induced V2R KO mice were given metformin (600 mg/kg) or vehicle twice daily. Urine osmolality in tolvaptan-treated rats (1,303 ± 126 mOsM) was restored to control levels by metformin (2,335 ± 273 mOsM) within 3 days and was sustained for up to 10 days. Metformin increased protein abundance of inner medullary urea transporter UT-A1 by 61% and aquaporin 2 (AQP2) by 44% in tolvaptan-treated rats, and immunohistochemistry showed increased membrane accumulation of AQP2 with acute and chronic AMPK stimulation. Outer medullary Na+-K+-2Cl– cotransporter 2 (NKCC2) abundance increased (117%) with AMPK stimulation in control rats but not in V2R-blocked rats. Metformin increased V2R KO mouse urine osmolality within 3 hours, and the increase persisted for up to 12 hours. Metformin increased AQP2 in the V2R KO mice similar to the tolvaptan-treated rats. These results indicate that AMPK activators, such as metformin, might provide a promising treatment for congenital NDI. PMID:27478876

Acute Prosocial Effects of Oxytocin and Vasopressin When Given Alone or in Combination with 3,4-Methylenedioxymethamphetamine in Rats: Involvement of the V1A Receptor

PubMed Central

Ramos, Linnet; Hicks, Callum; Kevin, Richard; Caminer, Alex; Narlawar, Rajeshwar; Kassiou, Michael; McGregor, Iain S

2013-01-01

The neuropeptides oxytocin (OT) and vasopressin (AVP) are recognized for their modulation of social processes in humans when delivered peripherally. However, there is surprisingly little evidence for acute social effects of peripherally administered OT or AVP in animal models. On the other hand, the party drug 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy') has powerful prosocial effects in rats that appear to occur through stimulation of central OT release. Here, we directly compared the social effects of peripherally administered OT and AVP with those of MDMA, and examined a possible role for the vasopressin 1A receptor (V1AR) in the observed prosocial effects. Adult male Long-Evans rats were tested in a social interaction paradigm after OT (0.1, 0.25, 0.5, and 1 mg/kg, intraperitoneal (IP)), AVP (0.001, 0.0025, 0.005, 0.01, and 0.1 mg/kg, IP), and MDMA (2.5, 5 mg/kg, IP), or combined low doses of OT and MDMA, or AVP and MDMA. The effects of pretreatment with the non-peptide OT receptor antagonist compound 25 (C25; 5 mg/kg, IP) and the V1AR antagonist SR49059 (1 mg/kg, IP) were also examined. OT (0.5 mg/kg), AVP (0.01 mg/kg), and MDMA (5 mg/kg) potently increased ‘adjacent lying', where rats meeting for the first time lie passively next to each other. C25 did not inhibit adjacent lying induced by OT, whereas SR49059 inhibited adjacent lying induced by MDMA (5 mg/kg), OT (0.5 mg/kg), and AVP (0.01 mg/kg). Interestingly, when ineffective doses of OT and MDMA, or AVP and MDMA, were combined, a robust increase in adjacent lying was observed. These results show for the first time acute prosocial effects of peripherally injected OT and AVP in laboratory rats, and suggest a commonality of action of OT, AVP, and MDMA in stimulating social behavior that involves V1ARs. PMID:23676791

MDMA ('Ecstasy'), oxytocin and vasopressin modulate social preference in rats: A role for handling and oxytocin receptors.

PubMed

Ramos, Linnet; Hicks, Callum; Caminer, Alex; Couto, Kalliu; Narlawar, Rajeshwar; Kassiou, Michael; McGregor, Iain S

In laboratory rats, peripheral administration of the neuropeptides oxytocin (OT) and vasopressin (AVP) induces similar prosocial effects (i.e. increased adjacent lying) to the party drug 3,4-methylenedioxymethamphetamine (MDMA), which are sensitive to vasopressin V 1A receptor (V 1A R) antagonism. Here, we employed a social preference paradigm to further compare the prosocial effects of OT, AVP and MDMA. We also investigated the possible involvement of the V 1A R and oxytocin receptor (OTR) in rodent social preference. The social preference paradigm measures investigation times towards an empty wire cage (presented for 4min) followed by an identical cage containing a novel rat (also presented for 4min). Social preference is defined as greater investigation time towards the inhabited cage than the empty cage. Results indicated that well-handled rats exhibited no social preference at baseline, while intraperitoneally injected MDMA (5mg/kg), OT (0.5mg/kg) and AVP (0.005mg/kg) increased social preference. However, this effect was primarily due to reduced investigation of the empty cage. In contrast, rats that received minimal prior handling displayed a social preference at baseline, while MDMA (5mg/kg), OT (0.5mg/kg) and AVP (0.005mg/kg) reduced investigation times towards both the empty and inhabited cages. Lower doses of MDMA, OT and AVP were ineffective. The OTR antagonist Compound 25 (C25, 5mg/kg), but not the V 1A R antagonist SR49059 (1mg/kg), reduced the baseline social preference seen in minimally-handled rats and prevented the social preference induced by OT and AVP (but not MDMA) in well-handled rats. Overall, these results further confirm prosocial actions of MDMA, OT and AVP, which are dependent on handling history. These findings also indicate that social preference is sensitive to OTR rather than V 1A R modulation. Copyright © 2016 Elsevier Inc. All rights reserved.

Systemic salt loading decreases body temperature and increases heat-escape/cold-seeking behaviour via the central AT1 and V1 receptors in rats.

PubMed

Konishi, Masahiro; Nagashima, Kei; Kanosue, Kazuyuki

2002-11-15

Salt loading decreases body core temperature (T(core)) at neutral ambient temperature (26 degrees C) and increases heat-escape/cold-seeking behaviour in desalivated rats. In this study, we tested the hypothesis that brain angiotensin II (AII) and arginine vasopressin (AVP) are associated with these responses. Surgically desalivated rats (n = 28) were administered an injection (S.C., 10 ml kg(-1)) of either normal saline (154 mM, NS) or hypertonic saline (2500 mM, HS) following an intracerebroventricular injection (10 microl kg(-1)) of an AII AT(1)-receptor antagonist (candesartan, 5 microg microl(-1)), an AVP V(1)-receptor antagonist ((beta-mercapto-beta, beta-cyclopenta-methylene propionyl(1), O-Me-Tyr(2), Arg(8))-vasopressin, 0.5 microg microl(-1)), or normal saline (154 mM). Each rat was placed in a behaviour box, first at 26 degrees C for 1 h to allow the measurement of baseline T(core) and movement. The ambient temperature was then elevated to 40 degrees C for the next 2 h, during which time the rat was able to trigger a 0 degrees C air reward for 30 s by moving into a specific area of the box (operant behaviour). The S.C. HS significantly decreased baseline T(core) at 26 degrees C (36.5 +/- 0.1 degrees C) and increased counts of operant behaviour at 40 degrees C (57 +/- 3) compared with results obtained following S.C. NS injection (37.4 +/- 0.1 degrees C and 42 +/- 1, respectively). These responses to s.c. HS were inhibited by the intracerebroventricular injection of AT(1) (37.3 +/- 0.1 degrees C and 43 +/- 2, respectively; P < 0.05) and V(1) antagonists (37.2 +/- 0.2 degrees C and 42 +/- 2, respectively; P < 0.05), although administration of both antagonists with S.C. NS had no effect. These results suggest that brain AII and AVP are involved in the decrease in T(core) observed at neutral ambient temperature and the increase in heat-escape/cold-seeking behaviour in response to osmotic stimulation, via the central AT(1) and V(1) receptors, respectively

A Phase 2, Double-Blind, Placebo-Controlled Randomized Trial Assessing the Efficacy of ABT-436, a Novel V1b Receptor Antagonist, for Alcohol Dependence

PubMed Central

Ryan, Megan L; Falk, Daniel E; Fertig, Joanne B; Rendenbach-Mueller, Beatrice; Katz, David A; Tracy, Katherine A; Strain, Eric C; Dunn, Kelly E; Kampman, Kyle; Mahoney, Elizabeth; Ciraulo, Domenic A; Sickles-Colaneri, Laurie; Ait-Daoud, Nassima; Johnson, Bankole A; Ransom, Janet; Scott, Charles; Koob, George F; Litten, Raye Z

2017-01-01

Alcohol use disorder has been linked to dysregulation of the brain stress systems, producing a negative emotional state leading to chronic relapsing behavior. Vasopressin receptors appear to have a regulatory role in stress, anxiety, and alcohol. This study evaluated the novel compound, ABT-436, a V1b receptor antagonist, in alcohol-dependent participants in a 12-week clinical trial. Men and women (n=150) who met criteria for DSM–IV alcohol dependence were recruited across four sites. Participants received double-blind ABT-436 or placebo, and a computerized behavioral intervention. ABT-436 was titrated to 800 mg/day during weeks 2–12. Although the primary outcome, percentage of heavy drinking days, was lower in participants receiving ABT-436 compared with placebo, this difference was not statistically significant (31.3 vs 37.6, respectively; p=0.172; d=0.20). However, participants receiving ABT-436 had significantly greater percentage of days abstinent than those receiving placebo (51.2 vs 41.6, respectively; p=0.037; d=0.31). No significant differences were found between treatment groups on any other measures of drinking, alcohol craving, or alcohol-related consequences. Smokers receiving ABT-436 smoked significantly fewer cigarettes per week than those receiving placebo (p=0.046). ABT-436 was well tolerated, with diarrhea (mild-to-moderate severity) being the most common side effect. In subgroup analyses, participants with relatively higher baseline levels of stress responded better to ABT-436 than placebo on select drinking outcomes, suggesting there may be value in testing medications targeting the vasopressin receptor in high stress, alcohol-dependent patients. PMID:27658483

Personality in Chimpanzees (Pan troglodytes): Exploring the Hierarchical Structure and Associations with the Vasopressin V1A Receptor Gene

PubMed Central

Latzman, Robert D.; Hopkins, William D.; Keebaugh, Alaine C.; Young, Larry J.

2014-01-01

One of the major contributions of recent personality psychology is the finding that traits are related to each other in an organized hierarchy. To date, however, researchers have yet to investigate this hierarchy in nonhuman primates. Such investigations are critical in confirming the cross-species nature of trait personality helping to illuminate personality as neurobiologically-based and evolutionarily-derived dimensions of primate disposition. Investigations of potential genetic polymorphisms associated with hierarchical models of personality among nonhuman primates represent a critical first step. The current study examined the hierarchical structure of chimpanzee personality as well as sex-specific associations with a polymorphism in the promoter region of the vasopressin V1a receptor gene (AVPR1A), a gene associated with dispositional traits, among 174 chimpanzees. Results confirmed a hierarchical structure of personality across species and, despite differences in early rearing experiences, suggest a sexually dimorphic role of AVPR1A polymorphisms on hierarchical personality profiles at a higher-order level. PMID:24752497

Quantitative systems pharmacology analysis of drug combination and scaling to humans: the interaction between noradrenaline and vasopressin on vasoconstriction.

PubMed

Yin, Anyue; Yamada, Akihiro; Stam, Wiro B; van Hasselt, Johan G C; van der Graaf, Piet H

2018-06-02

Development of combination therapies has received significant interest in recent years. Previously a two-receptor one-transducer (2R-1T) model was proposed to characterize drug interactions with two receptors that lead to the same phenotypic response through a common transducer pathway. We applied, for the first time, the 2R-1T model to characterize the interaction of noradrenaline and arginine-vasopressin on vasoconstriction, and performed inter-species scaling to humans using this mechanism-based model. Contractile data was obtained from in vitro rat small mesenteric arteries after exposure to single or combined challenges of noradrenaline and arginine-vasopressin with or without pre-treatment with the irreversible α-adrenoceptor antagonist, phenoxybenzamine. Data was analysed using the 2R-1T model to characterize the observed exposure-response relationships and drug-drug interaction. The model was then scaled to humans by accounting for differences in receptor density. With receptor affinities set to literature values, the 2R-1T model satisfactorily characterized the interaction between noradrenaline and arginine-vasopressin in rat small mesenteric arteries (relative standard error ≤ 20%), as well as the effect of phenoxybenzamine. Furthermore, after scaling the model to human vascular tissue, the model also adequately predicted the interaction between both agents on human renal arteries. The 2R-1T model can be of relevance to quantitatively characterize the interaction between two drugs that interact via different receptors and a common transducer pathway. Its mechanistic properties are valuable for scaling the model across species. This approach is therefore of significant value to rationally optimize novel combination treatments. This article is protected by copyright. All rights reserved.

Two Novel Mutations in the Aquaporin 2 Gene in a Girl with Congenital Nephrogenic Diabetes Insipidus

PubMed Central

Cho, Su Jin; Zheng, Shou Huan; Cho, Hee Yeon; Ha, Il Soo; Choi, Yong

2005-01-01

Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited disorder characterized by insensitivity of the kidney to the antidiuretic effect of vasopressin. There are three inheritance patterns of CNDI: the X-linked recessive form associated with vasopressin V2 receptor gene mutations, and the autosomal recessive and dominant forms associated with aquaporin-2 gene (AQP2) mutations. The evaluation for polyuria and polydipsia in a one-month-old Korean girl revealed no response to vasopressin and confirmed the diagnosis of CNDI. Because the child was female without family history of CNDI, her disease was thought to be an autosomal recessive form. We analyzed the AQP2 gene and detected a compound heterozygous missense point mutation: 70Ala (GCC) to Asp (GAC) in exon 1 inherited from her father and 187Arg (CGC) to His (CAC) in exon 3 inherited from her mother. The first mutation is located within the first NPA motif of the AQP2 molecule and the second one right after the second NPA motif. This is the first report to characterize AQP2 mutations in Korean patients with autosomal recessive CNDI, and expands the spectrum of AQP2 mutations by reporting two novel mutation, 70Ala (GCC) to Asp (GAC) and 187Arg (CGC) to His (CAC). PMID:16361827

Individual differences in gene expression of vasopressin, D2 receptor, POMC and orexin: vulnerability to relapse to heroin-seeking in rats

PubMed Central

Zhou, Yan; Leri, Francesco; Cummins, Erin; Jeanne Kreek, Mary

2014-01-01

Individual vulnerability to stress-induced relapse during abstinence from chronic heroin exposure is a key feature of opiate addiction, with limited studies on this topic. Arginine vasopressin (AVP) and its V1b receptor, components of the brain stress responsive systems, play a role in heroin-seeking behavior triggered by foot shock (FS) stress in rats. In this study, we tested whether individual differences in the FS-induced heroin-seeking were associated with alterations of AVP and V1b, as well as other stress responsive systems, including pro-opiomelanocortin (POMC), orexin, plasma ACTH and corticosterone, as well as dopamine D2 receptor (D2) and plasma prolactin. Sprague-Dawley rats were subjected to 3-hour intravenous heroin self-administration (SA) and then tested in extinction, FS-induced and heroin priming-induced reinstatements. The rats that self-administered heroin were divided to high and low reinstatement responders induced by FS (H-RI; L-RI). Over SA sessions, both the H-RI and L-RI displayed similar active lever responding, heroin infusion and total heroin intake. Compared to the L-RI, however, the H-RI showed greater active lever responses during stress-induced reinstatement, with higher AVP mRNA levels in medial/basolateral amygdala and lower D2 mRNA levels in caudate putamen. However, heroin priming resulted in similar reinstatement in both groups and produced similarly low POMC and high orexin mRNA levels in hypothalamus. Our results indicate that: 1) enhanced amygdalar AVP and reduced striatal D2 expression may be related to individual vulnerability to stress-induced reinstatement of heroin- seeking; and 2) heroin abstinence-associated alterations of hypothalamic orexin and POMC expression may be involved in drug priming-induced heroin-seeking. PMID:25446223

Age and sex differences in oxytocin and vasopressin V1a receptor binding densities in the rat brain: focus on the social decision-making network.

PubMed

Smith, Caroline J W; Poehlmann, Max L; Li, Sara; Ratnaseelan, Aarane M; Bredewold, Remco; Veenema, Alexa H

2017-03-01

Oxytocin (OT) and vasopressin (AVP) regulate various social behaviors via activation of the OT receptor (OTR) and the AVP V1a receptor (V1aR) in the brain. Social behavior often differs across development and between the sexes, yet our understanding of age and sex differences in brain OTR and V1aR binding remains incomplete. Here, we provide an extensive analysis of OTR and V1aR binding density throughout the brain in juvenile and adult male and female rats, with a focus on regions within the social decision-making network. OTR and V1aR binding density were higher in juveniles than in adults in regions associated with reward and socio-spatial memory and higher in adults than in juveniles in key regions of the social decision-making network and in cortical regions. We discuss possible implications of these shifts in OTR and V1aR binding density for the age-specific regulation of social behavior. Furthermore, sex differences in OTR and V1aR binding density were less numerous than age differences. The direction of these sex differences was region-specific for OTR but consistently higher in females than in males for V1aR. Finally, almost all sex differences in OTR and V1aR binding density were already present in juveniles and occurred in regions with denser binding in adults compared to juveniles. Possible implications of these sex differences for the sex-specific regulation of behavior, as well potential underlying mechanisms, are discussed. Overall, these findings provide an important framework for testing age- and sex-specific roles of OTR and V1aR in the regulation of social behavior.

A novel mutation affecting the arginine-137 residue of AVPR2 in dizygous twins leads to nephrogenic diabetes insipidus and attenuated urine exosome aquaporin-2.

PubMed

Hinrichs, Gitte R; Hansen, Louise H; Nielsen, Maria R; Fagerberg, Christina; Dieperink, Hans; Rittig, Søren; Jensen, Boye L

2016-04-01

Mutations in the vasopressin V2 receptor gene AVPR2 may cause X-linked nephrogenic diabetes insipidus by defective apical insertion of aquaporin-2 in the renal collecting duct principal cell. Substitution mutations with exchange of arginine at codon 137 can cause nephrogenic syndrome of inappropriate antidiuresis or congenital X-linked nephrogenic diabetes insipidus. We present a novel mutation in codon 137 within AVPR2 with substitution of glycine for arginine in male dizygotic twins. Nephrogenic diabetes insipidus was demonstrated by water deprivation test and resistance to vasopressin administration. While a similar urine exosome release rate was shown between probands and controls by western blotting for the marker ALIX, there was a selective decrease in exosome aquaporin-2 versus aquaporin-1 protein in probands compared to controls. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

A Single Dose, Randomized, Controlled Proof-Of-Mechanism Study of a Novel Vasopressin 1a Receptor Antagonist (RG7713) in High-Functioning Adults with Autism Spectrum Disorder

PubMed Central

Umbricht, Daniel; del Valle Rubido, Marta; Hollander, Eric; McCracken, James T; Shic, Frederick; Scahill, Lawrence; Noeldeke, Jana; Boak, Lauren; Khwaja, Omar; Squassante, Lisa; Grundschober, Christophe; Kletzl, Heidemarie; Fontoura, Paulo

2017-01-01

The core symptoms of autism spectrum disorder (ASD) include impaired social communication, repetitive behaviors, and restricted interests. No effective pharmacotherapy for these core deficits exists. Within the domain of social communication, the vasopressin system is implicated in social cognition and social signaling deficits of ASD, and represents a potential therapeutic target. We assessed the effects of a single 20 mg intravenous dose of the arginine vasopressin receptor 1A (V1a) antagonist, RG7713, on exploratory biomarkers (eye tracking), behavioral and clinical measures of social cognition and communication (affective speech recognition (ASR), reading the mind in the eyes, olfactory identification, scripted interaction), and safety and tolerability in a multicenter, randomized, double-blind, placebo-controlled, cross-over study of 19 high-functioning adult male subjects with DSM-IV Autistic Disorder (age 18–45 years; full scale IQ >70; ABC-Irritability subscale ⩽13). Eye-tracking showed an increase in biological motion orienting preference with RG7713 (ES=0.8, p=0.047) and a non-significant improvement in the composite score (ES=0.2, p=0.29). RG7713 reduced ability to detect lust (ES=−0.8, p=0.03) and fear (ES=−0.7, p=0.07) in ASR. However, when all eight individual emotion subscales were combined into an overall ASR performance score, the reduction was non-significant (ES=−0.1, p=0.59). Thirteen adverse events were reported in 10 subjects; all were of mild (11/13) or moderate (2/13) severity. Although interpretation should be cautious due to multiple comparisons and small sample size, these results provide preliminary evidence from experimental and behavioral biomarkers, that blockade of the V1a receptor may improve social communication in adults with high-functioning ASD. ClinicalTrials.gov identifier: NCT01474278 A Study of RO5028442 in Adult Male High-Functioning Autistic Patients. Available at: https://clinicaltrials.gov/ct2/show/NCT01474278 PMID:27711048

Involvement of arginine-vasopressin in the diuretic and hypotensive effects of Pereskia grandifolia Haw. (Cactaceae).

PubMed

Kazama, Caroline Calixto; Uchida, Denise Thiemi; Canzi, Karina Natally; de Souza, Priscila; Crestani, Sandra; Gasparotto, Arquimedes; Laverde, Antonio

2012-10-31

Pereskia grandifolia Haw. (Cactaceae), popularly known as "ora-pro-nobis" is well recognized in Brazilian traditional medicine as a diuretic agent, although no scientific data have been published to support this effect. The aim of this work is to evaluate the diuretic and hypotensive activities of the infusion (INFPG) and the ethanol extract (HEPG) of Pereskia grandifolia and possible mechanism of action. The infusions (2.5-10%) and the HEPG (3-100 mg/kg) were orally administered in a single dose or daily (for seven days) to rats. The urine excretion rate, pH, density, conductivity and content of Na(+), K(+), Cl(-) and HCO(3)(-) were measured in the urine of saline-loaded animals. In collected serum samples the concentration of electrolytes, urea, creatinine, aldosterone, vasopressin and angiotensin converting enzyme (ACE) activity were evaluated. The involvement of V(2) vasopressin receptor in the diuretic activity and the hypotensive effect of HEPG were also determined. Water excretion rate was significantly increased by HEPG, while the urinary K(+) and Cl(-) excretion was significantly reduced in acute and prolonged treatment. The oral administration of the HEPG (30mg/kg) significantly reduced serum levels of vasopressin and the mean arterial pressure (MAP) in normotensive rats. All other evaluated parameters have not been affected by any treatment. The results showed that HEPG could present compound(s) responsible for aquaretic activities with no signs of toxicity, and this effect could involve a reduction in the arginine-vasopressin release. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

(/sup 3/H)-(Thr4,Gly7)OT: a highly selective ligand for central and peripheral OT receptors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elands, J.; Barberis, C.; Jard, S.

1988-01-01

Oxytocin receptors in rat hippocampal synaptic plasma membranes were compared with mammary gland and uterine oxytocin receptors. For this purpose, a highly specific oxytocic agonist (Thr4,Gly7)oxytocin was tritiated. We demonstrated that this ligand labels oxytocin receptors selectively. Scatchard analyses revealed a high affinity for all the oxytocin receptors investigated, with equilibrium dissociation constants between 1.0 and 2.0 nM. Binding appeared to take place at a single population of receptor sites. Competition experiments confirmed the high affinity of arginine vasopressin for hippocampal oxytocin receptors but also revealed that mammary gland and uterine oxytocin receptors do not discriminate more efficiently between oxytocinmore » and arginine vasopressin. This lack in specificity is not affected by applying different concentrations of Mg ions.« less

The Impact of Oxytocin Gene Knockout on Sexual Behavior and Gene Expression Related to Neuroendocrine Systems in the Brain of Female Mice.

PubMed

Zimmermann-Peruzatto, Josi Maria; Lazzari, Virgínia Meneghini; Agnes, Grasiela; Becker, Roberta Oriques; de Moura, Ana Carolina; Guedes, Renata Padilha; Lucion, Aldo Bolten; Almeida, Silvana; Giovenardi, Márcia

2017-07-01

Social relations are built and maintained from the interaction among individuals. The oxytocin (OT), vasopressin (VP), estrogen, dopamine, and their receptors are involved in the modulation of sexual behavior in females. This study aimed to analyze the impact of OT gene knockout (OTKO) on sexual behavior and the gene expression of oxytocin (OTR), estrogen alpha (ERα), estrogen beta (ERβ), vasopressin (V 1a R), and dopamine (D 2 R) receptors in the olfactory bulb (OB), prefrontal cortex (PFC), hippocampus (HPC), and hypothalamus (HPT), as well as in the synthesis of VP in the HPT of female mice. Wild-type (WT) littermates were used for comparisons. The C DNAs were synthesized by polymerase chain reaction and the gene expression was calculated with the 2 -ΔΔCt formula. Our results showed that the absence of OT caused an increase in the frequency and duration of non-receptive postures and a decrease in receptive postures in the OTKO. OTKO females showed a significant decrease in the gene expression of OTR in the HPC, V 1a R in the HPT, and ERα and ERβ in the PFC. There was no significant difference in the gene expression of D 2 R of OTKO. However, OTKO showed an increased gene expression of V 1a R in the HPC. There is no significant difference in VP mRNA synthesis in the HPT between OTKO and WT. Our findings demonstrate that the absence of OT leads to significant changes in the expression of the studied genes (OTR, ERα, ERβ, V 1a R), and these changes may contribute to the decreased sexual behavior observed in OTKO females.

Elevated corticosterone in the dorsal hindbrain increases plasma norepinephrine and neuropeptide Y, and recruits a vasopressin response to stress

PubMed Central

Daubert, Daisy L.; Looney, Benjamin M.; Clifton, Rebekah R.; Cho, Jake N.

2014-01-01

Repeated stress and chronically elevated glucocorticoids cause exaggerated cardiovascular responses to novel stress, elevations in baseline blood pressure, and increased risk for cardiovascular disease. We hypothesized that elevated corticosterone (Cort) within the dorsal hindbrain (DHB) would: 1) enhance arterial pressure and neuroendocrine responses to novel and repeated restraint stress, 2) increase c-Fos expression in regions of the brain involved in sympathetic stimulation during stress, and 3) recruit a vasopressin-mediated blood pressure response to acute stress. Small pellets made of 10% Cort were implanted on the surface of the DHB in male Sprague-Dawley rats. Blood pressure was measured by radiotelemetry. Cort concentration was increased in the DHB in Cort-treated compared with Sham-treated rats (60 ± 15 vs. 14 ± 2 ng Cort/g of tissue, P < 0.05). DHB Cort significantly increased the integrated arterial pressure response to 60 min of restraint stress on days 6, 13, and 14 following pellet implantation (e.g., 731 ± 170 vs. 1,204 ± 68 mmHg/60 min in Sham- vs. Cort-treated rats, day 6, P < 0.05). Cort also increased baseline blood pressure by day 15 (99 ± 2 vs. 108 ± 3 mmHg for Sham- vs. Cort-treated rats, P < 0.05) and elevated baseline plasma norepinephrine and neuropeptide Y concentrations. Cort significantly enhanced stress-induced c-Fos expression in vasopressin-expressing neurons in the paraventricular nucleus of the hypothalamus, and blockade of peripheral vasopressin V1 receptors attenuated the effect of DHB Cort to enhance the blood pressure response to restraint. These data indicate that glucocorticoids act within the DHB to produce some of the adverse cardiovascular consequences of chronic stress, in part, by a peripheral vasopressin-dependent mechanism. PMID:24829502

Potent aquaretic agent. A novel nonpeptide selective vasopressin 2 antagonist (OPC-31260) in men.

PubMed Central

Ohnishi, A; Orita, Y; Okahara, R; Fujihara, H; Inoue, T; Yamamura, Y; Yabuuchi, Y; Tanaka, T

1993-01-01

Solute-free water diuretics (aquaretics) by antagonizing hydrosmotic vasopressin receptors (V2) may be useful in treating water-retaining diseases. The effects of intravenous administration of a newly developed nonpeptide, selective V2 antagonist, OPC-31260, at doses ranging from 0.017 to 1.0 mg/kg to groups of healthy, normally hydrated men were compared with those of 0.33 mg/kg furosemide and placebo. OPC-31260 increased the hypotonic urine volume dose dependently for the first 4 h, while furosemide induced sodium diuresis for 2 h. The absolute increase in the cumulative response in the urine to the highest doses of OPC-31260 was not significantly different from that to furosemide. The higher doses of OPC-31260 rapidly lowered urine osmolality for 2 h, particularly between minutes 15 and 45 (e.g., 1.0-mg/kg dose: 63 +/- 2 mOsm/kg in urine collected between minutes 30 and 45). In a marked hypotonic diuresis, mean free water clearance of the 4-h urine increased dose proportionally into the positive range, reaching 1.80 +/- 0.21 ml/min at 1.0 mg/kg. Whereas furosemide induced marked Na and K diuresis, OPC-31260 increased urinary Na excretion only slightly. At 4 h, 0.75 and 1.0 mg/kg of OPC-31260 almost doubled the plasma arginine vasopressin; and the higher doses increased plasma osmolality and plasma Na slightly, but did not alter plasma K, blood pressure, or heart rate. OPC-31260 thus safely induced a potent aquaretic effect in men. Images PMID:8254021

Selective and non-selective OT receptor agonists induce different locomotor behaviors in male rats via central OT receptors and peripheral V1a receptors.

PubMed

Wolfe, Monica; Wisniewska, Halina; Tariga, Hiroe; Ibanez, Gerardo; Collins, James C; Wisniewski, Kazimierz; Qi, Steve; Srinivasan, Karthik; Hargrove, Diane; Lindstrom, Beatriz Fioravanti

2018-05-21

Oxytocin (OT) continues to inspire much research due to its diverse physiological effects. While the best-understood actions of OT are uterine contraction and milk ejection, OT is also implicated in maternal and bonding behaviors, and potentially in CNS disorders such as autism, schizophrenia, and pain. The dissection of the mechanism of action of OT is complicated by the fact that this peptide activates not only its cognate receptor but also vasopressin type 1a (V1a) receptors. In this study, we evaluated OT and a selective OT receptor (OTR) agonist, FE 204409, in an automated assay that measures rat locomotor activity. The results showed: 1) Subcutaneous (sc) administration of OT decreased locomotor behavior (distance traveled, stereotypy, and rearing). This effect was reversed by a V1a receptor (V1aR) antagonist ([Pmp1,Tyr(ME)2]AVP, sc), suggesting that OT acts through peripheral V1aR to inhibit locomotor activity. 2) A selective OTR agonist (FE 204409, sc) increased stereotypy. This effect was reversed by an OTR antagonist dosed icv, suggesting a central OTR site of action. Our findings identify distinct behavioral effects for OT and the selective agonist FE 204409, adding to the growing body of evidence that the V1aR mediates many effects attributed to OT and that peptides administered systemically at supra-physiological doses may activate receptors in the brain. Our studies further emphasize the importance of utilizing selective agonists and antagonists to assess therapeutic indications. Copyright © 2018 Elsevier Ltd. All rights reserved.

Prairie Voles as a Model for Understanding the Genetic and Epigenetic Regulation of Attachment Behaviors.

PubMed

Sadino, Julie M; Donaldson, Zoe R

2018-04-06

Over a lifetime, humans build relationships with family, friends, and partners that are critically important for our mental and physical health. Unlike commonly used laboratory mice and rats, Microtine rodents provide a unique model to study the neurobiology underlying pair bonding and the selective attachments that form between adults. Comparisons between monogamous prairie voles and the closely related but nonmonogamous meadow and montane voles have revealed that brain-region-specific neuropeptide receptor patterning modulates social behavior between and within species. In particular, diversity in vasopressin 1a receptor (V1aR) distribution has been linked to individual and species differences in monogamy-related behaviors such as partner preference, mate guarding, and space use. Given the importance of differential receptor expression for regulating social behavior, a critical question has emerged: What are the genetic and epigenetic mechanisms that underlie brain-region-specific receptor patterns? This review will summarize what is known about how the vasopressin (AVP)-V1aR axis regulates social behaviors via signaling in discrete brain regions. From this work, we propose that brain-region-specific regulatory mechanisms facilitate robust evolvability of V1aR expression to generate diverse sociobehavioral traits. Translationally, we provide a perspective on how these studies have contributed to our understanding of human social behaviors and how brain-region-specific regulatory mechanisms might be harnessed for targeted therapies to treat social deficits in psychiatric disorders such as depression, complicated grief, and autism spectrum disorder.

Molecular cloning and characterization of V2-type receptor in two ray-finned fish, gray bichir, Polypterus senegalus and medaka, Oryzias latipes.

PubMed

Konno, Norifumi; Kurosawa, Mayumi; Kaiya, Hiroyuki; Miyazato, Mikiya; Matsuda, Kouhei; Uchiyama, Minoru

2010-07-01

In tetrapods, vasopressin (VP) and vasotocin (VT) are involved in various aspects of physiology and behavior including osmoregulation, cardiovascular function, reproduction, stress response and social behavior. Pharmacological and molecular studies have identified three types of VP/VT receptors, V1a-type (V1aR), V1b-type (V1bR) and V2-type (V2R). On the other hand, only V1aR has so far been identified in teleosts. In the present study, we successfully cloned V2Rs from two ray-finned fish, gray bichir and medaka. Phylogenetic analysis showed that the cloned receptors belong to the V2R group of lobe-finned fish and tetrapods. The amino acid sequences of bichir V2R and medaka V2R were high identity (60-65.5% and 53.2-80.9%, respectively) with other known V2R members, respectively. Reverse transcriptase PCR revealed that ray-finned fish V2R transcripts have been detected in various tissues including brain, gill, heart, liver, kidney and reproductive organs, suggesting that ray-finned fish V2R might mediate multiple functions of VT. In functional analysis, the cells transfected with the cloned receptors responded with the accumulation of intracellular cAMP in a concentration-dependent manner following VT stimulation, but not respond with [Ca(2+)]i. Furthermore, pretreatment with mammalian V2R antagonist (OPC-31260) to the cells transfected with medaka V2R significantly inhibited an increase of the VT-induced intracellular cAMP. These results suggest that ray-finned fish possess a functional V2R linked to adenylate cyclase and the cAMP signaling pathway as well as V2Rs of lobe-finned fish and tetrapods. Thus, the present study suggests that functional V2R evolved prior to the divergence of the ray- and lobe-finned fish lineages. Copyright 2010 Elsevier Inc. All rights reserved.

Adiponectin selectively inhibits oxytocin neurons of the paraventricular nucleus of the hypothalamus

PubMed Central

Hoyda, Ted D; Fry, Mark; Ahima, Rexford S; Ferguson, Alastair V

2007-01-01

Adiponectin is an adipocyte derived hormone which acts in the brain to modulate energy homeostasis and autonomic function. The paraventricular nucleus of the hypothalamus (PVN) which plays a key role in controlling pituitary hormone secretion has been suggested to be a central target for adiponectin actions. A number of hormones produced by PVN neurons have been implicated in the regulation of energy homeostasis including oxytocin, corticotropin releasing hormone and thyrotropin releasing hormone. In the present study we investigated the role of adiponectin in controlling the excitability of magnocellular (MNC – oxytocin or vasopressin secreting) neurons within the PVN. Using RT-PCR techniques we have shown expression of both adiponectin receptors in the PVN. Patch clamp recordings from MNC neurons in hypothalamic slices have also identified mixed (27% hyperpolarization, 42% depolarization) effects of adiponectin in modulating the excitability of the majority of MNC neurons tested. These effects are maintained when cells are placed in synaptic isolation using tetrodotoxin. Additionally we combined electrophysiological recordings with single cell RT-PCR to examine the actions of adiponectin on MNC neurons which expressed oxytocin only, vasopressin only, or both oxytocin and vasopressin mRNA and assess the profile of receptor expression in these subgroups. Adiponectin was found to hyperpolarize 100% of oxytocin neurons tested (n = 6), while vasopressin cells, while all affected (n = 6), showed mixed responses. Further analysis indicates oxytocin neurons express both receptors (6/7) while vasopressin neurons express either both receptors (3/8) or one receptor (5/8). In contrast 6/6 oxytocin/vasopressin neurons were unaffected by adiponectin. Co-expressing oxytocin and vasopressin neurons express neither receptor (4/6). The results presented in this study suggest that adiponectin plays specific roles in controlling the excitability oxytocin secreting neurons, actions which correlate with the current literature showing increased oxytocin secretion in the obese population. PMID:17947308

Vasopressin V1a receptor polymorphism and interval walking training effects in middle-aged and older people.

PubMed

Masuki, Shizue; Mori, Masayuki; Tabara, Yasuharu; Miki, Tetsuro; Sakurai, Akihiro; Morikawa, Mayuko; Miyagawa, Ken; Higuchi, Keiichi; Nose, Hiroshi

2010-03-01

We assessed whether single nucleotide polymorphism rs1042615 of the vasopressin V1a receptor altered the indices of lifestyle-related diseases in middle-aged and older people (mean+/-SD: 64+/-7 years), and, if so, whether it also altered the effects of interval walking training (IWT). CC, CT, and TT carriers of rs1042615 (42, 118, and 64 men, respectively; 113, 263, and 154 women, respectively) performed IWT. We included 5 sets of 3-minute fast walking at > or =70% peak aerobic capacity for walking and 3-minute slow walking at 40% peak aerobic capacity per day for > or =4 days per week for 5 months. Before IWT, the body mass index and diastolic blood pressure (DBP) for men were 25.1+/-0.3 kg/m(2) (mean+/-SE) and 84+/-1 mm Hg in TT, higher than the 23.6+/-0.4 kg/m(2) and 78+/-1 mm Hg in CC, respectively (P<0.01), differences that disappeared after IWT despite similar training achievement between groups (P>0.6). After IWT, body mass index and DBP decreased in TT (-0.9+/-0.1 kg/m(2) and -5+/-1 mm Hg, respectively), more than in CC (-0.5+/-0.1 kg/m(2) and 1+/-1 mm Hg, respectively; P<0.05), with a greater decrease in low-density lipoprotein cholesterol in TT than CC carriers (P<0.01). The decreases in DBP and low-density lipoprotein cholesterol were still greater in TT carriers even after adjustment for their pretraining values. On the other hand, for women, these parameters before IWT and their changes after IWT were similar among CC, CT, and TT carriers. Thus, polymorphism rs1042615 of the V1a receptor altered body mass index and DBP in middle-aged and older men and the training-induced responses of DBP and low-density lipoprotein cholesterol, whereas women did not show any of these responses.

Brain-Targeted (Pro)Renin Receptor Knockdown attenuates Angiotensin II-Dependent Hypertension

PubMed Central

Li, Wencheng; Peng, Hua; Cao, Theresa; Sato, Ryosuke; McDaniels, Sarah. J.; Kobori, Hiroyuki; Navar, L. Gabriel; Feng, Yumei

2012-01-01

The (pro)renin receptor is a newly discovered member of the brain renin-angiotensin system. To investigate the role of brain (pro)renin receptor in hypertension, adeno-associated virus-mediated (pro)renin receptor shRNA was used to knockdown (pro)renin receptor expression in the brain of non-transgenic normotensive and human renin-angiotensinogen double transgenic hypertensive mice. Blood pressure was monitored using implanted telemetric probes in conscious animals. Real-time PCR and immunostaining were performed to determine (pro)renin receptor, angiotensin II type 1 receptor and vasopressin mRNA levels. Plasma vasopressin levels were determined by Enzyme-Linked Immuno Sorbent Assay. Double transgenic mice exhibited higher blood pressure, elevated cardiac and vascular sympathetic tone, and impaired spontaneous baroreflex sensitivity. Intracerebroventricular delivery of (pro)renin receptor shRNA significantly reduced blood pressure, cardiac and vasomotor sympathetic tone, and improved baroreflex sensitivity compared to the control virus treatment in double transgenic mice. (Pro)renin receptor knockdown significantly reduced angiotensin II type 1 receptor and vasopressin levels in double transgenic mice. These data indicate that (pro)renin receptor knockdown in the brain attenuates angiotensin II-dependent hypertension and is associated with a decrease insympathetic tone and an improvement of the baroreflex sensitivity. In addition, brain-targeted (pro)renin receptor knockdown is associated with down-regulation of angiotensin II type 1 receptor and vasopressin levels. We conclude that central (pro)renin receptor contributes to the pathogenesis of hypertension in human renin-angiotensinogen transgenic mice. PMID:22526255

Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus

PubMed Central

Barak, Larry S.; Oakley, Robert H.; Laporte, Stéphane A.; Caron, Marc G.

2001-01-01

Agonist-dependent desensitization and internalization of G protein-coupled receptors (GPCR) are mediated by the binding of arrestins to phosphorylated receptors. The affinity of arrestins for the phosphorylated GPCR regulates the ability of the internalized receptor to be dephosphorylated and recycled back to the plasma membrane. In this study, we show that the naturally occurring loss of function vasopressin receptor mutation R137H, which is associated with familial nephrogenic diabetes insipidus, induces constitutive arrestin-mediated desensitization. In contrast to the wild-type vasopressin receptor, the nonsignaling R137H receptor is phosphorylated and sequestered in arrestin-associated intracellular vesicles even in the absence of agonist. Eliminating molecular determinants on the receptor that promote high affinity arrestin–receptor interaction reestablishes plasma membrane localization and the ability of the mutated receptors to signal. These findings suggest that unregulated desensitization can contribute to the etiology of a GPCR-based disease, implying that pharmacological targeting of GPCR desensitization may be therapeutically beneficial. PMID:11134505

Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus.

PubMed

Barak, L S; Oakley, R H; Laporte, S A; Caron, M G

2001-01-02

Agonist-dependent desensitization and internalization of G protein-coupled receptors (GPCR) are mediated by the binding of arrestins to phosphorylated receptors. The affinity of arrestins for the phosphorylated GPCR regulates the ability of the internalized receptor to be dephosphorylated and recycled back to the plasma membrane. In this study, we show that the naturally occurring loss of function vasopressin receptor mutation R137H, which is associated with familial nephrogenic diabetes insipidus, induces constitutive arrestin-mediated desensitization. In contrast to the wild-type vasopressin receptor, the nonsignaling R137H receptor is phosphorylated and sequestered in arrestin-associated intracellular vesicles even in the absence of agonist. Eliminating molecular determinants on the receptor that promote high affinity arrestin-receptor interaction reestablishes plasma membrane localization and the ability of the mutated receptors to signal. These findings suggest that unregulated desensitization can contribute to the etiology of a GPCR-based disease, implying that pharmacological targeting of GPCR desensitization may be therapeutically beneficial.

Terlipressin: vasopressin analog and novel drug for septic shock.

PubMed

Pesaturo, Adam B; Jennings, Heath R; Voils, Stacy A

2006-12-01

To review and assess available literature on chemistry, pharmacology, pharmacodynamics, pharmacokinetics, clinical studies, adverse events, drug interactions, and dosing and administration of terlipressin in septic shock. A literature search of MEDLINE (1966-September 2006), International Pharmaceutical Abstracts (1970-September 2006), and Cochrane database (third quarter 2006) was conducted, using key terms of terlipressin, lypressin, triglycyl-lysine vasopressin, hemodynamic support, septic shock, vasopressor, and V1 receptor agonist. Bibliographies of relevant articles were reviewed for additional references. Available English-language literature, including abstracts, animal studies, preclinical studies, clinical trials, and review articles, were examined. Because of potentially favorable pharmacokinetics versus vasopressin and limited availability of vasopressin in some countries, the effects of terlipressin, a vasopressin analog, have been studied recently for the treatment of septic shock. When administered as a 1-2 mg intravenous dose in patients with septic shock, terlipressin increases mean arterial pressure, urine output, systemic vascular resistance index, pulmonary vascular resistance index, and left and right ventricular stroke work index while decreasing heart rate, cardiac output, lactate, and oxygen delivery and consumption index. It is unclear whether lower doses of terlipressin would produce a similar vasopressor response with fewer cardiopulmonary effects and whether the effects of the drug on oxygen transport indices are detrimental. Terlipressin is a promising investigational medication for treatment of septic shock. Small trials have shown terlipressin to have favorable effects on hemodynamics in patients with septic shock refractory to conventional vasopressor treatment. It should be used with extreme caution in patients with underlying cardiac or pulmonary dysfunction. Further studies are needed to verify safety, efficacy, and dosing of terlipressin in patients with septic shock, and its use cannot be recommended in lieu of vasopressin at this time.

Cardiovascular effects of vasopressin following V(1) receptor blockade compared to effects of nitroglycerin.

PubMed

Cooke, C R; Wall, B M; Huch, K M; Mangold, T

2001-09-01

Studies to more clearly determine the mechanisms associated with arginine vasopressin (AVP)-induced vasodilation were performed in normal subjects and in quadriplegic subjects with impaired efferent sympathetic responses. Studies to compare the effects of AVP with the hemodynamic effects of nitroglycerin, an agent that primarily affects venous capacitance vessels, were also performed in normal subjects. Incremental infusions of AVP following V(1)-receptor blockade resulted in equivalent reductions in systemic vascular resistance (SVRI) in normal and in quadriplegic subjects. However, there were major differences in the effect on mean arterial pressure (MAP), which was reduced in quadriplegic subjects but did not change in normal subjects. This difference in MAP can be attributed to a difference in the magnitude of increase in cardiac output (CI), which was twofold greater in normal than in quadriplegic subjects. These observations are consistent with AVP-induced vasodilation of arterial resistance vessels with reflex sympathetic enhancement of CI and are clearly different from the hemodynamic effects of nitroglycerin, i.e., reductions in MAP, CI, and indexes of cardiac preload, with only minor changes in SVRI.

The cellular distribution of fluorescently labeled arrestins provides a robust, sensitive, and universal assay for screening G protein-coupled receptors.

PubMed

Oakley, Robert H; Hudson, Christine C; Cruickshank, Rachael D; Meyers, Diane M; Payne, Richard E; Rhem, Shay M; Loomis, Carson R

2002-11-01

G protein-coupled receptors (GPCRs) have proven to be a rich source of therapeutic targets; therefore, finding compounds that regulate these receptors is a critical goal in drug discovery. The Transfluor technology utilizes the redistribution of fluorescently labeled arrestins from the cytoplasm to agonist-occupied receptors at the plasma membrane to monitor quantitatively the activation or inactivation of GPCRs. Here, we show that the Transfluor technology can be quantitated on the INCell Analyzer system (INCAS) using the vasopressin V(2) receptor (V(2)R), which binds arrestin with high affinity, and the beta(2)-adrenergic receptor (beta(2)AR), which binds arrestin with low affinity. U2OS cells stably expressing an arrestin-green fluorescent protein conjugate and either the V(2)R or the beta(2)AR were plated in 96-well plastic plates and analyzed by the INCAS at a screening rate of 5 min per plate. Agonist dose-response and antagonist dose-inhibition curves revealed signal-to-background ratios of approximately 25:1 and 8:1 for the V(2)R and beta(2)AR, respectively. EC(50) values agreed closely with K(d) values reported in the literature for the different receptor agonists. In addition, small amounts of arrestin translocation induced by sub-EC(50) doses of agonist were distinguished from the background noise of untreated cells. Furthermore, differences in the magnitude of arrestin translocation distinguished partial agonists from full agonists, and Z' values for these ligands were >0.5. These data show that the Transfluor technology, combined with an automated image analysis system, provides a direct, robust, and universal assay for high throughput screening of known and orphan GPCRs.

Cholinergic regulation of the vasopressin neuroendocrine system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Michels, K.M.

1987-01-01

To clarify the physical and functional relationship between the cholinergic system, and the neurodocrine cells of the supraoptic nucleus, a combination of experiments on receptor binding, localization and function were carried out. The putative nicotinic receptor probe (/sup 125/I)alpha bungarotoxin ((/sup 125/I)alpha BTX) bound with high affinity and specificity to the vasopressin and oxytocin magnocellular neurons of the supraoptic nucleus, nucleus circularis, and paraventricular nucleus. Binding of (/sup 125/I)alpha BTX within the neural lobe was very low. In contrast, the muscarinic cholinergic receptor probe (/sup 3/H)quinuclidinylbenzilate ((/sup 3/H)QNB) did not bind to magnocellular vasopressin and oxytocin cell groups. The medianmore » eminence, which contains the neurosecretory axons, and the neural lobe of the pituitary contain low levels of (/sup 3/H)QNB binding. The physiological significance of these cholinergic receptors in regulation of vasopressin release was tested using an in vitro preparation of the supraoptic - neural lobe system.« less

Neuropeptide diversity and the regulation of social behavior in New World primates

PubMed Central

French, Jeffrey A.; Taylor, Jack H.; Mustoe, Aaryn C.; Cavanaugh, Jon

2016-01-01

Oxytocin (OT) and vasopressin (AVP) are important hypothalamic neuropeptides that regulate peripheral physiology, and have emerged as important modulators of brain function, particularly in the social realm. OT structure and the genes that ultimately determine structure are highly conserved among diverse eutherian mammals, but recent discoveries have identified surprising variability in OT and peptide structure in New World monkeys (NWM), with five new OT variants identified to date. This review explores these new findings in light of comparative OT/AVP ligand evolution, documents coevolutionary changes in the oxytocin and vasopressin receptors (OTR and V1aR), and highlights the distribution of neuropeptidergic neurons and receptors in the primate brain. Finally, the behavioral consequences of OT and AVP in regulating NWM sociality are summarized, demonstrating important neuromodulatory effects of these compounds and OT ligand-specific influences in certain social domains. PMID:27020799

Vasopressin regulates renal calcium excretion in humans

PubMed Central

Hanouna, Guillaume; Haymann, Jean-Philippe; Baud, Laurent; Letavernier, Emmanuel

2015-01-01

Antidiuretic hormone or arginine vasopressin (AVP) increases water reabsorption in the collecting ducts of the kidney. Three decades ago, experimental models have shown that AVP may increase calcium reabsorption in rat kidney. The objective of this study was to assess whether AVP modulates renal calcium excretion in humans. We analyzed calcium, potassium, and sodium fractional excretion in eight patients affected by insipidus diabetes (nephrogenic or central) under acute vasopressin receptor agonist action and in 10 patients undergoing oral water load test affected or not by inappropriate antidiuretic hormone secretion (SIADH). Synthetic V2 receptor agonist (dDAVP) reduced significantly calcium fractional excretion from 1.71% to 0.58% (P < 0.05) in patients with central diabetes insipidus. In patients with nephrogenic diabetes insipidus (resistant to AVP), calcium fractional excretion did not change significantly after injection (0.48–0.68%, P = NS). In normal subjects undergoing oral water load test, calcium fractional excretion increased significantly from 1.02% to 2.54% (P < 0.05). Patients affected by SIADH had a high calcium fractional excretion at baseline that remained stable during test from 3.30% to 3.33% (P = NS), possibly resulting from a reduced calcium absorption in renal proximal tubule. In both groups, there was a significant correlation between urine output and calcium renal excretion. In humans, dDAVP decreases calcium fractional excretion in the short term. Conversely, water intake, which lowers AVP concentration, increases calcium fractional excretion. The correlation between urine output and calcium excretion suggests that AVP-related antidiuresis increases calcium reabsorption in collecting ducts. PMID:26620256

The pathophysiology of monosymptomatic nocturnal enuresis with special emphasis on the circadian rhythm of renal physiology.

PubMed

Dossche, L; Walle, J Vande; Van Herzeele, C

2016-06-01

Nocturnal polyuria in monosymptomatic nocturnal enuresis (MNE) has so far mainly been attributed to a disturbed circadian rhythm of renal water handling. Low vasopressin levels overnight correlate with absent maximal concentrating activity, resulting in an increased nocturnal diuresis with low urinary osmolality. Therefore, treatment with desmopressin is a rational choice. Unfortunately, 20 to 60 % of children with monosymptomatic enuresis are desmopressin-resistant. There is increasing evidence that other disturbed circadian rhythms might play a role in nocturnal polyuria. This review focuses on renal aspects in the pathophysiology of nocturnal polyuria in MNE, with special emphasis on circadian rhythms. Articles related to renal circadian rhythms and enuresis were searched through the PubMed library with the goal of providing a concise review. Nocturnal polyuria can only partially be explained by blunted circadian rhythm of vasopressin secretion. Other alterations in the intrinsic renal circadian clock system also seem to be involved, especially in desmopressin-resistant enuresis. • Disturbance in the circadian rhythm of arginine vasopressin secretion is related to nocturnal polyuria in children with enuresis. • Desmopressin is recommended as a treatment for monosymptomatic nocturnal enuresis, working as a vasopressin analogue acting on V2 receptors in the collecting ducts of the kidney. What is New: • Other renal circadian rhythms might play a role in nocturnal polyuria, especially in desmopressin-resistant case.

Vasotocin- and mesotocin-induced increases in short-circuit current across tree frog skin.

PubMed

Takada, Makoto; Fujimaki-Aoba, Kayo; Hokari, Shigeru

2011-02-01

In adult amphibian skin, Na(+) crosses from outside to inside. This Na(+) transport can be measured as the amiloride-blockable short-circuit current (SCC) across the skin. We investigated the effects of arginine vasotocin (AVT) and mesotocin (MT), and those of antagonists of the vasopressin and oxytocin receptors, on the SCC across Hyla japonica skin. (1) Both AVT (100 pmol/L or more) and MT (1 nmol/L or more) increased the SCC. (2) The AVT- and MT-induced increases in SCC recovered with time (downregulation). (3) These AVT/MT-induced effects were blocked by application of OPC-31260 (vasopressin V(2)-receptor antagonist). (4) The OPC-31260 concentration needed to block the AVT-induced response was lower upon post-application (after application of agonist) than upon pre-application (before application of agonist), suggesting the number of receptors may have decreased after AVT application. (5) Upon repeated application of AVT (100 pmol/L), the induced SCC increase did not differ significantly between the 1st and 2nd applications. (6) The time to reach the half-maximum value of the AVT-induced or MT-induced increase in SCC was not significantly different between washout and post-application of OPC-31260, suggesting that post-application of OPC-31260 cleared AVT and MT from their receptors. The effects of AVT, MT, and their antagonists in H. japonica, which is adapted to a terrestrial habitat, are compared with our previously published data on Rana catesbeiana (=Lithobates catesbeianus), which is adapted to a semiaquatic habitat.

Synthesis and evaluation of C-11, F-18 and I-125 small molecule radioligands for detecting oxytocin receptors

PubMed Central

Smith, Aaron L.; Freeman, Sara M.; Stehouwer, Jeffery S.; Inoue, Kiyoshi; Voll, Ronald J.; Young, Larry J.; Goodman, Mark M.

2013-01-01

Compounds 1–4 were synthesized and investigated for selectivity and potency for the oxytocin receptor (OTR) to determine their viability as radioactive ligands. Binding assays determined 1–4 to have high binding affinity for both the human and rodent OTR and also have high selectivity for the human OTR over human vasopressin V1a receptors (V1aR). Inadequate selectivity for OTR over V1aR was found for rodent receptors in all four compounds. The radioactive (C-11, F-18, and I-125) derivatives of 1–4 were synthesized and investigated for use as autoradiography and positron emission tomography (PET) ligands. Receptor autoradiography performed with [125I]1 and [125I]2 on rodent brain slices provided the first small molecule radioligand images of the OTR and V1aR. Biodistribution studies determined [125I]1 and [125I]2 were adequate for in vivo peripheral investigations, but not for central investigations due to low uptake within the brain. A biodistribution study with [18F]3 suggested brain uptake occurred slowly over time. PET imaging studies with [18F]3 and [11C]4 using a rat model provided insufficient uptake in the brain over a 90 and 45 min scan times respectively to merit further investigations in non-human primates. PMID:22425346

V2R mutations and nephrogenic diabetes insipidus.

PubMed

Bichet, Daniel G

2009-01-01

Nephrogenic diabetes insipidus (NDI), which can be inherited or acquired, is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of the antidiuretic hormone, arginine vasopressin (AVP). Polyuria, with hyposthenuria, and polydipsia are the cardinal clinical manifestations of the disease. Nephrogenic failure to concentrate urine maximally may be due to a defect in vasopressin-induced water permeability of the distal tubules and collecting ducts, to insufficient buildup of the corticopapillary interstitial osmotic gradient, or to a combination of these two factors. Thus, the broadest definition of the term NDI embraces any antidiuretic hormone-resistant urinary-concentrating defect, including medullary disease with low interstitial osmolality, renal failure, and osmotic diuresis. About 90% of patients with congenital NDI are males with X-linked recessive NDI (OMIM 304800)(1) and have mutations in the AVP receptor 2 (AVPR2) gene that codes for the vasopressin V(2) receptor; the gene is located in chromosome region Xq28. In about 10% of the families studied, congenital NDI has an autosomal recessive or autosomal dominant mode of inheritance (OMIM 222000 and 125800)(1). Mutations have been identified in the aquaporin-2 gene (AQP2, OMIM 107777)(1), which is located in chromosome region 12q13 and codes for the vasopressin-sensitive water channel. NDI is clinically distinguishable from neurohypophyseal diabetes insipidus (OMIM 125700(1); also referred to as central or neurogenic diabetes insipidus) by a lack of response to exogenous AVP and by plasma levels of AVP that rise normally with increase in plasma osmolality. Hereditary neurohypophyseal diabetes insipidus is secondary to mutations in the gene encoding AVP (OMIM 192340)(1). Neurohypophyseal diabetes insipidus is also a component of autosomal recessive Wolfram syndrome 1 or DIDMOAD syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) (OMIM 222300)(1), an autosomal recessive disorder. Other inherited disorders with complex polyuro-polydipsic syndrome with loss of water, sodium, chloride, calcium, magnesium, and potassium include Bartter syndrome (OMIM 601678)(1) and cystinosis (OMIM 219800)(1), while long-term lithium administration is the main cause of acquired NDI. Here, we use the gene symbols approved by the HUGO Gene Nomenclature Committee (http://www.gene.ucl.ac.uk/nomenclature) and provide OMIM entry numbers [OMIM (Online Mendelian Inheritance in Man)(1); McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), 2000; World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/]. Copyright © 2009 Elsevier Inc. All rights reserved.

Osmoregulation in Polycystic Kidney Disease: Relationship with Cystogenesis and Hypertension.

PubMed

Underwood, Conor F; Phillips, Jacqueline K; Hildreth, Cara M

2018-01-01

Polycystic kidney disease (PKD) is a group of monogenetic conditions characterised by the progressive accumulation of multiple renal cysts and hypertension. One of the earliest features of PKD is a reduction in urinary concentrating capacity that impairs extracellular fluid conservation. Urinary concentrating impairment predisposes PKD patients to periods of hypohydration when fluid loss is not adequately compensated by fluid intake. The hypohydrated state provides a blood hyperosmotic stimulus for vasopressin release to minimise further water loss. However, over-activation of renal V2 receptors contributes to cyst expansion. Although suppressing vasopressin release with high water intake has been shown to impair disease progression in rodent models, whether this approach is efficacious in patients remains uncertain. The neural osmoregulatory pathway that controls vasopressin secretion also exerts a stimulatory action on vasomotor sympathetic activity and blood pressure during dehydration. Recurrent dehydration leads to a worsening of hypertension in rodents and cross-sectional data suggests that reduced urinary concentrating ability may contribute to hypertension development in the clinical PKD population. Experimental studies are required to evaluate this hypothesis and to determine the underlying mechanism. © 2018 The Author(s) Published by S. Karger AG, Basel.

Vasopressin and oxytocin receptor systems in the brain: sex differences and sex-specific regulation of social behavior

PubMed Central

Dumais, Kelly M.; Veenema, Alexa H.

2015-01-01

The neuropeptides vasopressin (VP) and oxytocin (OT) and their receptors in the brain are involved in the regulation of various social behaviors and have emerged as drug targets for the treatment of social dysfunction in several sex-biased neuropsychiatric disorders. Sex differences in the VP and OT systems may therefore be implicated in sex-specific regulation of healthy as well as impaired social behaviors. We begin this review by highlighting the sex differences, or lack of sex differences, in VP and OT synthesis in the brain. We then discuss the evidence showing the presence or absence of sex differences in VP and OT receptors in rodents and humans, as well as showing new data of sexually dimorphic V1a receptor binding in the rat brain. Importantly, we find that there is lack of comprehensive analysis of sex differences in these systems in common laboratory species, and we find that, when sex differences are present, they are highly brain region- and species- specific. Interestingly, VP system parameters (VP and V1aR) are typically higher in males, while sex differences in the OT system are not always in the same direction, often showing higher OT expression in females, but higher OT receptor expression in males. Furthermore, VP and OT receptor systems show distinct and largely non-overlapping expression in the rodent brain, which may cause these receptors to have either complementary or opposing functional roles in the sex-specific regulation of social behavior. Though still in need of further research, we close by discussing how manipulations of the VP and OT systems have given important insights into the involvement of these neuropeptide systems in the sex-specific regulation of social behavior in rodents and humans. PMID:25951955

Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior.

PubMed

Dumais, Kelly M; Veenema, Alexa H

2016-01-01

The neuropeptides vasopressin (VP) and oxytocin (OT) and their receptors in the brain are involved in the regulation of various social behaviors and have emerged as drug targets for the treatment of social dysfunction in several sex-biased neuropsychiatric disorders. Sex differences in the VP and OT systems may therefore be implicated in sex-specific regulation of healthy as well as impaired social behaviors. We begin this review by highlighting the sex differences, or lack of sex differences, in VP and OT synthesis in the brain. We then discuss the evidence showing the presence or absence of sex differences in VP and OT receptors in rodents and humans, as well as showing new data of sexually dimorphic V1a receptor binding in the rat brain. Importantly, we find that there is lack of comprehensive analysis of sex differences in these systems in common laboratory species, and we find that, when sex differences are present, they are highly brain region- and species-specific. Interestingly, VP system parameters (VP and V1aR) are typically higher in males, while sex differences in the OT system are not always in the same direction, often showing higher OT expression in females, but higher OT receptor expression in males. Furthermore, VP and OT receptor systems show distinct and largely non-overlapping expression in the rodent brain, which may cause these receptors to have either complementary or opposing functional roles in the sex-specific regulation of social behavior. Though still in need of further research, we close by discussing how manipulations of the VP and OT systems have given important insights into the involvement of these neuropeptide systems in the sex-specific regulation of social behavior in rodents and humans. Copyright © 2015 Elsevier Inc. All rights reserved.

[Congenital nephrogenic diabetes insipidus: about a case report].

PubMed

Esselmani, Hicham; Yassine, Asmaa; Bouabdellah, Mounya; Benchekroun, Laila; Handor, Najat; Elalami, Sanae; Chabraoui, Layachi

2013-01-01

Congenital nephrogenic diabetes insipidus is a rare, hereditary in nature, characterized by an inability of the kidney to concentrate urine, secondary to the manifold resistance to the action of vasopressin. X-linked forms of transmission (90%) are expressed in boys, from the neonatal period in general, by polyuria and polydipsia. Symptomatology in transmissive girls is variable but can sometimes be quite marked. These forms are secondary to mutations in the gene encoding the vasopressin V2 receptor, located at position Xq28, responsible for a loss of function of this receptor. Some of these mutations may cause a partial phenotype, less severe. Forms of autosomal, recessive or dominant are more rare (10%). Treatment is symptomatic, sometimes difficult in infants. It aims to avoid episodes of dehydration. It is based on a conventional diet hypo-osmotic and administration of hydrochlorothiazide and indomethacin. We report here the case of a child with congenital nephrogenic diabetes insipidus hospitalized at Children's Hospital of Rabat and throughout this case we review the pathophysiology and clinical and biological characteristics of the disease and including importance of contribution of clinical biochemistry laboratory in the diagnosis and monitoring of this disease.

Regional c-Fos expression induced by peripheral oxytocin administration is prevented by the vasopressin 1A receptor antagonist SR49059.

PubMed

Hicks, Callum; Ramos, Linnet; Dampney, Bruno; Baracz, Sarah J; McGregor, Iain S; Hunt, Glenn E

2016-10-01

Peripherally administered oxytocin induces a wide range of behavioural and physiological effects that are thought to be mediated by the oxytocin receptor (OTR). However, oxytocin also has considerable affinity for the vasopressin 1A receptor (V 1A R), such that various oxytocinergic effects may in fact be mediated by the V 1A R rather than the OTR. Here we used c-Fos immunohistochemistry to determine the extent to which the regional pattern of neuronal activation produced by peripheral oxytocin involves the V 1A R. Male Wistar rats were administered oxytocin (1mg/kg, IP) alone, or following pre-treatment with the V 1A R antagonist SR49059 (1mg/kg, IP), and were assessed for locomotor activity changes and for c-Fos expression across a number of brain regions. Oxytocin reduced the distance travelled by rats during a 70min test session, and this inhibitory behavioural effect was prevented by SR49059. Consistent with previous reports, oxytocin increased c-Fos expression in a number of brain regions. In several of these regions-the supraoptic and paraventricular (PVN) nuclei of the hypothalamus, locus coeruleus and nucleus of the solitary tract-the c-Fos response was prevented by SR49059 pre-treatment. Notably, SR49059 inhibited the c-Fos activation in oxytocin-synthesising magnocellular neurons in the PVN. However, c-Fos expression in the central amygdala to oxytocin was unaffected by SR49059. The current findings add to an increasing body of research suggesting that many of the functional effects of oxytocin may be V 1A R mediated. Copyright © 2016 Elsevier Inc. All rights reserved.

The contributions of oxytocin and vasopressin pathway genes to human behavior.

PubMed

Ebstein, Richard P; Knafo, Ariel; Mankuta, David; Chew, Soo Hong; Lai, Poh San

2012-03-01

Arginine vasopressin (AVP) and oxytocin (OXT) are social hormones and mediate affiliative behaviors in mammals and as recently demonstrated, also in humans. There is intense interest in how these simple nonapeptides mediate normal and abnormal behavior, especially regarding disorders of the social brain such as autism that are characterized by deficits in social communication and social skills. The current review examines in detail the behavioral genetics of the first level of human AVP-OXT pathway genes including arginine vasopressin 1a receptor (AVPR1a), oxytocin receptor (OXTR), AVP (AVP-neurophysin II [NPII]) and OXT (OXT neurophysin I [NPI]), oxytocinase/vasopressinase (LNPEP), ADP-ribosyl cyclase (CD38) and arginine vasopressin 1b receptor (AVPR1b). Wherever possible we discuss evidence from a variety of research tracks including molecular genetics, imaging genomics, pharmacology and endocrinology that support the conclusions drawn from association studies of social phenotypes and detail how common polymorphisms in AVP-OXT pathway genes contribute to the behavioral hard wiring that enables individual Homo sapiens to interact successfully with conspecifics. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. Copyright © 2011 Elsevier Inc. All rights reserved.

Pathophysiology, diagnosis and management of nephrogenic diabetes insipidus.

PubMed

Bockenhauer, Detlef; Bichet, Daniel G

2015-10-01

Healthy kidneys maintain fluid and electrolyte homoeostasis by adjusting urine volume and composition according to physiological needs. The final urine composition is determined in the last tubular segment: the collecting duct. Water permeability in the collecting duct is regulated by arginine vasopressin (AVP). Secretion of AVP from the neurohypophysis is regulated by a complex signalling network that involves osmosensors, barosensors and volume sensors. AVP facilitates aquaporin (AQP)-mediated water reabsorption via activation of the vasopressin V2 receptor (AVPR2) in the collecting duct, thus enabling concentration of urine. In nephrogenic diabetes insipidus (NDI), inability of the kidneys to respond to AVP results in functional AQP deficiency. Consequently, affected patients have constant diuresis, resulting in large volumes of dilute urine. Primary forms of NDI result from mutations in the genes that encode the key proteins AVPR2 and AQP2, whereas secondary forms are associated with biochemical abnormalities, obstructive uropathy or the use of certain medications, particularly lithium. Treatment of the disease is informed by identification of the underlying cause. Here we review the clinical aspects and diagnosis of NDI, the various aetiologies, current treatment options and potential future developments.

Dehydration-induced modulation of κ-opioid inhibition of vasopressin neurone activity

PubMed Central

Scott, Victoria; Bishop, Valerie R; Leng, Gareth; Brown, Colin H

2009-01-01

Dehydration increases vasopressin (antidiuretic hormone) secretion from the posterior pituitary gland to reduce water loss in the urine. Vasopressin secretion is determined by action potential firing in vasopressin neurones, which can exhibit continuous, phasic (alternating periods of activity and silence), or irregular activity. Autocrine κ-opioid inhibition contributes to the generation of activity patterning of vasopressin neurones under basal conditions and so we used in vivo extracellular single unit recording to test the hypothesis that changes in autocrine κ-opioid inhibition drive changes in activity patterning of vasopressin neurones during dehydration. Dehydration increased the firing rate of rat vasopressin neurones displaying continuous activity (from 7.1 ± 0.5 to 9.0 ± 0.6 spikes s−1) and phasic activity (from 4.2 ± 0.7 to 7.8 ± 0.9 spikes s−1), but not those displaying irregular activity. The dehydration-induced increase in phasic activity was via an increase in intraburst firing rate. The selective κ-opioid receptor antagonist nor-binaltorphimine increased the firing rate of phasic neurones in non-dehydrated rats (from 3.4 ± 0.8 to 5.3 ± 0.6 spikes s−1) and dehydrated rats (from 6.4 ± 0.5 to 9.1 ± 1.2 spikes s−1), indicating that κ-opioid feedback inhibition of phasic bursts is maintained during dehydration. In a separate series of experiments, prodynorphin mRNA expression was increased in vasopressin neurones of hyperosmotic rats, compared to hypo-osmotic rats. Hence, it appears that dynorphin expression in vasopressin neurones undergoes dynamic changes in proportion to the required secretion of vasopressin so that, even under stimulated conditions, autocrine feedback inhibition of vasopressin neurones prevents over-excitation. PMID:19822541

Interactions of sex and early life social experiences at two developmental stages shape nonapeptide receptor profiles.

PubMed

Hiura, Lisa C; Ophir, Alexander G

2018-05-31

Early life social experiences are critical to behavioral and cognitive development, and can have a tremendous influence on developing social phenotypes. Most work has focused on outcomes of experiences at a single stage of development (e.g., perinatal, or post-weaning). Few studies have assessed the impact of social experience at multiple developmental stages and across sex. Oxytocin and vasopressin are profoundly important for modulating social behavior and these nonapeptide systems are highly sensitive to developmental social experience, particularly in brain areas important for social behavior. We investigated whether oxytocin receptor (OTR) and vasopressin receptor (V1aR) distributions of prairie voles (Microtus ochrogaster) change as a function of parental composition within the natal nest or social composition after weaning. We raised pups either in the presence or absence of their fathers. At weaning, offspring were housed either individually or with a same-sex sibling. We also examined whether changes in receptor distributions are sexually dimorphic because the impact of the developmental environment on the nonapeptide system could be sex-dependent. We found that differences in nonapeptide receptor expression were region-, sex-, and rearing condition-specific, indicating a high level of complexity in the ways that early life experiences shape the social brain. We found many more differences in V1aR density compared to OTR density, indicating that nonapeptide receptors demonstrate differential levels of neural plasticity and sensitivity to environmental and biological variables. Our data highlight that critical factors including biological sex and multiple experiences across the developmental continuum interact in complex ways to shape the social brain. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Effects of angiotensin, vasopressin and atrial natriuretic peptide on intraocular pressure in anesthetized rats

NASA Technical Reports Server (NTRS)

Palm, D. E.; Shue, S. G.; Keil, L. C.; Balaban, C. D.; Severs, W. B.

1995-01-01

The effects of atrial natriuretic peptide (ANP), vasopressin (AVP) and angiotensin (ANG) on blood and intraocular pressures of pentobarbital anesthetized rats were evaluated following intravenous, intracerebroventricular or anterior chamber routes of administration. Central injections did not affect intraocular pressure. Equipressor intravenous infusions of ANG raised, whereas AVP decreased, intraocular pressure. Direct infusions of a balanced salt solution (0.175 microliter/min) raised intraocular pressure between 30 and 60 min. Adding ANG or ANP slightly reduced this solvent effect but AVP was markedly inhibitory. An AVP-V1 receptor antagonist reversed the blunting of the solvent-induced rise by the peptide, indicating receptor specificity. Acetazolamide pretreatment lowered intraocular pressure, but the solvent-induced rise in intraocular pressure and inhibition by AVP still occurred without altering the temporal pattern. Thus, these effects appear unrelated to aqueous humor synthesis rate. The data support the possibility of intraocular pressure regulation by peptides acting from the blood and aqueous humor.

Diabetes insipidus: celebrating a century of vasopressin therapy.

PubMed

Qureshi, Sana; Galiveeti, Sneha; Bichet, Daniel G; Roth, Jesse

2014-12-01

Diabetes mellitus, widely known to the ancients for polyuria and glycosuria, budded off diabetes insipidus (DI) about 200 years ago, based on the glucose-free polyuria that characterized a subset of patients. In the late 19th century, clinicians identified the posterior pituitary as the site of pathology, and pharmacologists found multiple bioactivities there. Early in the 20th century, the amelioration of the polyuria with extracts of the posterior pituitary inaugurated a new era in therapy and advanced the hypothesis that DI was due to a hormone deficiency. Decades later, a subset of patients with polyuria unresponsive to therapy were recognized, leading to the distinction between central DI and nephrogenic DI, an early example of a hormone-resistant condition. Recognition that the posterior pituitary had 2 hormones was followed by du Vigneaud's Nobel Prize winning isolation, sequencing, and chemical synthesis of oxytocin and vasopressin. The pure hormones accelerated the development of bioassays and immunoassays that confirmed the hormone deficiency in vasopressin-sensitive DI and abundant levels of hormone in patients with the nephrogenic disorder. With both forms of the disease, acquired and inborn defects were recognized. Emerging concepts of receptors and of genetic analysis led to the recognition of patients with mutations in the genes for 1) arginine vasopressin (AVP), 2) the AVP receptor 2 (AVPR2), and 3) the aquaporin 2 water channel (AQP2). We recount here the multiple skeins of clinical and laboratory research that intersected frequently over the centuries since the first recognition of DI.

Oxytocin, vasopressin, and autism: is there a connection?

PubMed

Insel, T R; O'Brien, D J; Leckman, J F

1999-01-15

Autism is a poorly understood developmental disorder characterized by social impairment, communication deficits, and compulsive behavior. The authors review evidence from animal studies demonstrating that the nonapeptides, oxytocin and vasopressin, have unique effects on the normal expression of species-typical social behavior, communication, and rituals. Based on this evidence, they hypothesize that an abnormality in oxytocin or vasopressin neurotransmission may account for several features of autism. As autism appears to be a genetic disorder, mutations in the various peptide, peptide receptor, or lineage-specific developmental genes could lead to altered oxytocin or vasopressin neurotransmission. Many of these genes have been cloned and sequenced, and several polymorphisms have been identified. Recent gene targeting studies that alter expression of either the peptides or their receptors in the rodent brain partially support the autism hypothesis. While previous experience suggests caution in hypothesizing a cause or suggesting a treatment for autism, the available preclinical evidence with oxytocin and vasopressin recommends the need for clinical studies using gene scanning, pharmacological and neurobiological approaches.

Investigation of pyrazolo-sulfonamides as putative small molecule oxytocin receptor agonists.

PubMed

Katte, Timothy A; Reekie, Tristan A; Werry, Eryn L; Jorgensen, William T; Boyd, Rochelle; Wong, Erick C N; Gulliver, Damien W; Connor, Mark; Kassiou, Michael

2017-08-18

The neuropeptide oxytocin has been implicated in multiple central nervous system functions in mammalian species. Increased levels have been reported to improve trust, alleviate symptoms related to autism and social phobias, and reduce social anxiety. Hoffman-La Roche published a patent claiming to have found potent small molecule oxytocin receptor agonists, smaller than the first non-peptide oxytocin agonist reported, WAY 267,464. We selected two of the more potent compounds from the patent and, in addition, created WAY 267,464 hybrid structures and determined their oxytocin and vasopressin receptor activity. Human embryonic kidney and Chinese hamster ovary cells were used for the expression of oxytocin or vasopressin 1a receptors and activity assessed via IP1 accumulation assays and calcium FLIPR assays. The results concluded that the reported compounds in the patent and the hybrid structures have no activity at the oxytocin or vasopressin 1a receptors. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Sex-specific modulation of juvenile social play behavior by vasopressin and oxytocin depends on social context

PubMed Central

Bredewold, Remco; Smith, Caroline J. W.; Dumais, Kelly M.; Veenema, Alexa H.

2014-01-01

We recently demonstrated that vasopressin (AVP) in the lateral septum modulates social play behavior differently in male and female juvenile rats. However, the extent to which different social contexts (i.e., exposure to an unfamiliar play partner in different environments) affect the regulation of social play remains largely unknown. Given that AVP and the closely related neuropeptide oxytocin (OXT) modulate social behavior as well as anxiety-like behavior, we hypothesized that these neuropeptides may regulate social play behavior differently in novel (novel cage) as opposed to familiar (home cage) social environments. Administration of the specific AVP V1a receptor (V1aR) antagonist (CH2)5Tyr(Me2)AVP into the lateral septum enhanced home cage social play behavior in males but reduced it in females, confirming our previous findings. These effects were context-specific because V1aR blockade did not alter novel cage social play behavior in either sex. Furthermore, social play in females was reduced by AVP in the novel cage and by OXT in the home cage. Additionally, females administered the specific OXT receptor antagonist desGly-NH2,d(CH2)5−[Tyr(Me)2,Thr4]OVT showed less social play in the novel as compared to the home cage. AVP enhanced anxiety-related behavior in males (tested on the elevated plus-maze), but failed to do so in females, suggesting that exogenous AVP alters social play and anxiety-related behavior via distinct and sex-specific mechanisms. Moreover, none of the other drug treatments that altered social play had an effect on anxiety, suggesting that these drug-induced behavioral alterations are relatively specific to social behavior. Overall, we showed that AVP and OXT systems in the lateral septum modulate social play in juvenile rats in neuropeptide-, sex- and social context-specific ways. These findings underscore the importance of considering not only sex, but also social context, in how AVP and OXT modulate social behavior. PMID:24982623

AVP and Glu systems interact to regulate levels of anxiety in BALB/cJ mice.

PubMed

An, Xiao-Lei; Tai, Fa-Dao

2014-07-01

Whilethe roles of glutamic acid (Glu), arginine vasopressin (AVP) and their respective receptors in anxiety have been thoroughly investigated, the effects of interactions among Glu, N-methyl-D-aspartic acid (NMDA) receptor, AVP and a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor on anxiety are still unclear. In the present study, the agonist and antagonist of the NMDA receptor and AMPA receptor, as well as the antagonist of AVP V1 receptor (V1aR) were introduced into BALB/cJ mice by intracerebroventricular microinjection, and the anxiety-like behaviors of the mice were evaluated by open field and elevated plus-maze tests. Compared with C57BL/6 mice, BALB/cJ mice displayed higher levels of anxiety-like behavior. Significant anxiolytic effects were found in the NMDA receptor antagonist (MK-801) and the AMPA receptor or V1aR antagonist (SSRI49415), as well as combinations of AVP/MK-801 and SSRI49415/DNQX. These results indicated that anxiety-like behaviors expressed in BALB/CJ mice may be due to a coordination disorder among glutamate, NMDA receptor, AMPA receptor, AVP and V1aR, resulting in the up-regulation of the NMDA receptor and V1aR and down-regulation of the AMPA receptor. However, because the AMPA receptor can execute its anxiolytic function by suppressing AVP and V1aR, we cannot exclude the possibility of the NMDA receptor being activated by AVP acting on V1aR.

Vasopressin and nitroglycerin decrease portal and hepatic venous pressure and hepato-splanchnic blood flow.

PubMed

Wisén, E; Svennerholm, K; Bown, L S; Houltz, E; Rizell, M; Lundin, S; Ricksten, S-E

2018-03-26

Various methods are used to reduce venous blood pressure in the hepato-splanchnic circulation, and hence minimise blood loss during liver surgery. Previous studies show that combination of vasopressin and nitroglycerin reduces portal pressure and flow in patients with portal hypertension, and in this study we investigated this combination in patients with normal portal pressure. In all, 13 patients were studied. Measurements were made twice to confirm baseline (C1 and BL), during vasopressin infusion 4.8 U/h (V), and during vasopressin infusion combined with nitroglycerin infusion (V + N). Portal venous pressure (PVP), hepatic venous pressure (HVP), central haemodynamics and arterial and venous blood gases were obtained at each measuring point, and portal (splanchnic) and hepato-splanchnic blood flow changes were calculated. Vasopressin alone did not affect PVP, whereas HVP increased slightly. In combination with nitroglycerin, PVP decreased from 10.1 ± 1.6 to 8.9 ± 1.3 mmHg (P < 0.0001), and HVP decreased from 7.9 ± 1.9 to 6.2 ± 1.3 mmHg (P = 0.001). Vasopressin reduced portal blood flow by 47 ± 19% and hepatic venous flow by 11 ± 18%, respectively. Addition of nitroglycerin further reduced portal- and hepatic flow by 55 ± 13% and 30 ± 13%, respectively. Vasopressin alone had minor effects on central haemodynamics, whereas addition of nitroglycerin reduced cardiac index (3.2 ± 0.7 to 2.7 ± 0.5; P < 0.0001). The arterial-portal vein lactate gradient was unaffected. The combination of vasopressin and nitroglycerin decreases portal pressure and hepato-splanchnic blood flow, and could be a potential treatment to reduce bleeding in liver resection surgery. © 2018 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Therapeutic and diagnostic potential of a vasopressin-2 antagonist for impaired water handling in cirrhosis.

PubMed

Inoue, T; Ohnishi, A; Matsuo, A; Kawai, B; Kunihiro, N; Tada, Y; Koizumi, F; Chau, T; Okada, K; Yamamura, Y; Tanaka, T

1998-05-01

Progressive cirrhosis is associated with increasing difficulty to handle free water. We examined the therapeutic potential of an orally active nonpeptide vasopressin-2 receptor antagonist (OPC-31260) in the management of edema and ascites in patients with cirrhosis. By means of its chemical blockade of the vasopressin-2 receptor in the kidney, we also assessed the ability of renal water handling in the early stage of cirrhosis. A single 30 mg dose of OPC-31260 was administered orally to eight biopsy-proven patients with cirrhosis who had ascites or peripheral edema. The aquaretic responses were compared with those in six healthy subjects. In the patients with cirrhosis, OPC-31260 significantly (p < 0.01) increased the urinary excretion rate at 0 to 2 hours, and significantly (p < 0.01) lowered urine osmolality at 2 to 4 hours after administration. Free water clearance increased from -0.48 +/- 0.14 to +0.19 +/- 0.21 ml/min (p < 0.05) at 0 to 4 hours after administration. However, these aquaretic responses in the patients with cirrhosis were only approximately half the responses observed in the healthy subjects. A significant (p < 0.05) inverse relationship was observed between indocyanine green retention at 15 minutes after administration and the maximal free water clearance after administration to the patients with cirrhosis. Urinary sodium excretion did not change significantly in the patients, whereas it increased twofold in the healthy subjects. Urinary vasopressin excretion tended to increase in the patients, whereas it increased twofold to threefold (p < 0.01 to 0.05) from the baseline in the healthy subjects. Urinary prostaglandin E2 excretion was not increased, and serum sodium and plasma vasopressin levels were elevated only slightly in both groups. Even though a hyporesponsiveness was observed in the group of patients with cirrhosis compared with the healthy group, the novel vasopressin-2 antagonist induced hypotonic diuresis in patients with cirrhosis, suggesting a therapeutic potential in managing water excess. This drug response may be a new index to assess impairment of water handling in patients with cirrhosis.

Variation in neural V1aR predicts sexual fidelity and space use among male prairie voles in semi-natural settings

PubMed Central

Ophir, Alexander G.; Wolff, Jerry O.; Phelps, Steven M.

2008-01-01

Although prairie voles (Microtus ochrogaster) are socially monogamous, males vary in both sexual and spatial fidelity. Most males form pairbonds, cohabit with one female, and defend territories. Wandering males, in contrast, have expansive home ranges that overlap many males and females. In the laboratory, pairing is regulated by arginine vasopressin and its predominant CNS receptor, vasopressin 1a receptor (V1aR). We investigated individual differences in forebrain V1aR expression of male prairie voles in mixed-sex seminatural enclosures. Individual differences in V1aR were compared with space use measured by radio telemetry and paternity determined with microsatellite markers. Animals engaging in extra-pair fertilizations (EPFs) as either wanderers or paired residents overlapped significantly more in same- and opposite-sex home ranges. Surprisingly, neither social fidelity measured by space use nor sexual fidelity measured by paternity was associated with V1aR expression in the ventral pallidum (VPall) or lateral septum, areas causally related to pairbond formation. In contrast, V1aR expression in the posterior cingulate/retrosplenial cortex (PCing) and laterodorsal thalamus (LDThal), areas implicated in spatial memory, strongly covaried with space use and paternity. Animals engaging in EPFs either as wanderers or paired residents exhibited low levels of LDThal and PCing V1aR expression. Individual differences in brain and behavior parallel differences between prairie voles and promiscuous congeners. The concordance among space use, paternity, and V1aR in spatial circuits suggests a common link between the mechanisms of spatial behaviors and success at EPF. The combined data demonstrate how organismal biology can inform our understanding of individual and species differences in behavioral mechanisms. PMID:18212120

Prenatal Testosterone Exposure Decreases Aldosterone Production but Maintains Normal Plasma Volume and Increases Blood Pressure in Adult Female Rats.

PubMed

More, Amar S; Mishra, Jay S; Hankins, Gary D; Kumar, Sathish

2016-08-01

Plasma testosterone levels are elevated in pregnant women with preeclampsia and polycystic ovaries; their offspring are at increased risk for hypertension during adult life. We tested the hypothesis that prenatal testosterone exposure induces dysregulation of the renin-angiotensin-aldosterone system, which is known to play an important role in water and electrolyte balance and blood pressure regulation. Female rats (6 mo old) prenatally exposed to testosterone were examined for adrenal expression of steroidogenic genes, telemetric blood pressure, blood volume and Na(+) and K(+) levels, plasma aldosterone, angiotensin II and vasopressin levels, and vascular responses to angiotensin II and arg(8)-vasopressin. The levels of Cyp11b2 (aldosterone synthase), but not the other adrenal steroidogenic genes, were decreased in testosterone females. Accordingly, plasma aldosterone levels were lower in testosterone females. Plasma volume and serum and urine Na(+) and K(+) levels were not significantly different between control and testosterone females; however, prenatal testosterone exposure significantly increased plasma vasopressin and angiotensin II levels and arterial pressure in adult females. In testosterone females, mesenteric artery contractile responses to angiotensin II were significantly greater, while contractile responses to vasopressin were unaffected. Angiotensin II type-1 receptor expression was increased, while angiotensin II type-2 receptor was decreased in testosterone arteries. These results suggest that prenatal testosterone exposure downregulates adrenal Cyp11b2 expression, leading to decreased plasma aldosterone levels. Elevated angiotensin II and vasopressin levels along with enhanced vascular responsiveness to angiotensin II may serve as an underlying mechanism to maintain plasma volume and Na(+) and K(+) levels and mediate hypertension in adult testosterone females. © 2016 by the Society for the Study of Reproduction, Inc.

Modulation of mouse Leydig cell steroidogenesis through a specific arginine-vasopressin receptor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tahri-Joutei, A.; Pointis, G.

1988-01-01

Characterization of specific vasopressin binding sites was investigated in purified mouse Leydig cells using tritiated arginine-vasopressin. Binding of radioligand was saturable, time- and temperature-dependent and reversible. (/sup 3/H)-AVP was found to bind to a single class of sites with high affinity and low capacity. Binding displacements with specific selection analogs of AVP indicated the presence of V/sub 1/ subtype receptors on Leydig cells. The ability of AVP to displace (/sup 3/H)-AVP binding was greater than LVP and oxytocin. The unrelated peptides, somatostatin and substance P, were less potent, while neurotensin and LHRH did not displace (/sup 3/H)-AVP binding. The time-coursemore » effects of AVP-pretreatment on basal and hCG-stimulated testosterone and cAMP accumulations were studied in primary culture of Leydig cells. Basal testosterone accumulation was significantly increased by a 24 h AVP-pretreatment of Leydig cells. This effect was potentiated by the phosphodiesterase inhibitor (MIX) and was concomitantly accompanied by a slight but significant increase in cAMP accumulation. AVP-pretreatment of the cells for 72 h had no effect on basal testosterone accumulation, but exerted a marked inhibitory effect on the hCG-stimulated testosterone accumulation. This reduction of testosterone accumulation occurred even in the presence of MIX and was not accompanied by any significant change of cAMP levels.« less

Inhibition of oxytocin and vasopressin neuron activity in rat hypothalamic paraventricular nucleus by relaxin-3-RXFP3 signalling.

PubMed

Kania, Alan; Gugula, Anna; Grabowiecka, Agnieszka; de Ávila, Camila; Blasiak, Tomasz; Rajfur, Zenon; Lewandowski, Marian H; Hess, Grzegorz; Timofeeva, Elena; Gundlach, Andrew L; Blasiak, Anna

2017-06-01

Relaxin-3 is a stress-responsive neuropeptide that acts at its cognate receptor, RXFP3, to alter behaviours including feeding. In this study, we have demonstrated a direct, RXFP3-dependent, inhibitory action of relaxin-3 on oxytocin and vasopressin paraventricular nucleus (PVN) neuron electrical activity, a putative cellular mechanism of orexigenic actions of relaxin-3. We observed a Gα i/o -protein-dependent inhibitory influence of selective RXFP3 activation on PVN neuronal activity in vitro and demonstrated a direct action of RXFP3 activation on oxytocin and vasopressin PVN neurons, confirmed by their abundant expression of RXFP3 mRNA. Moreover, we demonstrated that RXFP3 activation induces a cadmium-sensitive outward current, which indicates the involvement of a characteristic magnocellular neuron outward potassium current. Furthermore, we identified an abundance of relaxin-3-immunoreactive axons/fibres originating from the nucleus incertus in close proximity to the PVN, but associated with sparse relaxin-3-containing fibres/terminals within the PVN. The paraventricular nucleus of the hypothalamus (PVN) plays an essential role in the control of food intake and energy expenditure by integrating multiple neural and humoral inputs. Recent studies have demonstrated that intracerebroventricular and intra-PVN injections of the neuropeptide relaxin-3 or selective relaxin-3 receptor (RXFP3) agonists produce robust feeding in satiated rats, but the cellular and molecular mechanisms of action associated with these orexigenic effects have not been identified. In the present studies, using rat brain slices, we demonstrated that relaxin-3, acting through its cognate G-protein-coupled receptor, RXFP3, hyperpolarized a majority of putative magnocellular PVN neurons (88%, 22/25), including cells producing the anorexigenic neuropeptides, oxytocin and vasopressin. Importantly, the action of relaxin-3 persisted in the presence of tetrodotoxin and glutamate/GABA receptor antagonists, indicating its direct action on PVN neurons. Similar inhibitory effects on PVN oxytocin and vasopressin neurons were produced by the RXFP3 agonist, RXFP3-A2 (82%, 80/98 cells). In situ hybridization histochemistry revealed a strong colocalization of RXFP3 mRNA with oxytocin and vasopressin immunoreactivity in rat PVN neurons. A smaller percentage of putative parvocellular PVN neurons was sensitive to RXFP3-A2 (40%, 16/40 cells). These data, along with a demonstration of abundant peri-PVN and sparse intra-PVN relaxin-3-immunoreactive nerve fibres, originating from the nucleus incertus, the major source of relaxin-3 neurons, identify a strong inhibitory influence of relaxin-3-RXFP3 signalling on the electrical activity of PVN oxytocin and vasopressin neurons, consistent with the orexigenic effect of RXFP3 activation observed in vivo. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Effect of arginine vasopressin in the nucleus raphe magnus on antinociception in the rat.

PubMed

Yang, Jun; Chen, Jian-Min; Liu, Wen-Yan; Song, Cao-You; Wang, Cheng-Hai; Lin, Bao-Cheng

2006-09-01

Previous work has shown that arginine vasopressin (AVP) regulates antinociception through brain nuclei rather than the spinal cord and peripheral organs. The present study investigated the nociceptive effect of AVP in the nucleus raphe magnus (NRM) of the rat. Microinjection of AVP into the NRM increased pain threshold in a dose-dependent manner, while local administration of AVP-receptor antagonist-d(CH2)5Tyr(Et)DAVP decreased the pain threshold. Pain stimulation elevated AVP concentration in the NRM perfuse liquid. NRM pretreatment with AVP-receptor antagonist completely reversed AVP's effect on pain threshold in the NRM. The data suggest that AVP in the NRM is involved in antinociception.

Polyuria due to vasopressin V2 receptor antagonism is not associated with increased ureter diameter in ADPKD patients.

PubMed

Casteleijn, Niek F; Messchendorp, A Lianne; Bae, Kyong T; Higashihara, Eiji; Kappert, Peter; Torres, Vicente; Meijer, Esther; Leliveld, Anna M

2017-06-01

Tolvaptan, a vasopressin V2 receptor antagonist, has been shown to reduce the rates of growth in total kidney volume (TKV) and renal function loss in ADPKD patients, but also leads to polyuria because of its aquaretic effect. Prolonged polyuria can result in ureter dilatation with consequently renal function loss. Therefore, we aimed to investigate the effect of tolvaptan-induced polyuria on ureter diameter in ADPKD patients. 70 ADPKD patients were included (51 were randomized to tolvaptan and 19 to placebo). At baseline and after 3 years of treatment renal function was measured (mGFR) and MRI was performed to measure TKV and ureter diameter at the levels of renal pelvis and fifth lumbar vertebral body (L5). In these patients [65.7 % male, age 41 ± 9 years, mGFR 74 ± 27 mL/min/1.73 m 2 and TKV 1.92 (1.27-2.67) L], no differences were found between tolvaptan and placebo-treated patients in 24-h urine volume at baseline (2.5 vs. 2.5 L, p = 0.8), nor in ureter diameter at renal pelvis and L5 (4.0 vs. 4.2 mm, p = 0.4 and 3.0 vs. 3.1 mm, p = 0.3). After 3 years of treatment 24-h urine volume was higher in tolvaptan-treated patients when compared to placebo (4.7 vs. 2.3 L, p < 0.001), but no differences were found in ureter diameter between both groups (renal pelvis: 4.2 vs. 4.4 mm, p = 0.4 and L5: 3.1 vs. 3.3 mm, p = 0.4). Tolvaptan-induced polyuria did not lead to an increase in ureter diameter, suggesting that tolvaptan is a safe therapy from a urological point of view.

Polyuria due to vasopressin V2 receptor antagonism is not associated with increased ureter diameter in ADPKD patients

PubMed Central

Casteleijn, Niek F.; Messchendorp, A. Lianne; Bae, Kyong T.; Higashihara, Eiji; Kappert, Peter; Torres, Vicente; Meijer, Esther; Leliveld, Anna M.

2017-01-01

Background Tolvaptan, a vasopressin V2 receptor antagonist, has been shown to reduce the rates of growth in total kidney volume (TKV) and renal function loss in ADPKD patients, but also leads to polyuria because of its aquaretic effect. Prolonged polyuria can result in ureter dilatation with consequently renal function loss. Therefore, we aimed to investigate the effect of tolvaptan-induced polyuria on ureter diameter in ADPKD patients. Methods 70 ADPKD patients were included (51 were randomized to tolvaptan and 19 to placebo). At baseline and after 3 years of treatment renal function was measured (mGFR) and MRI was performed to measure TKV and ureter diameter at the levels of renal pelvis and fifth lumbar vertebral body (L5). Results In these patients [65.7 % male, age 41 ± 9 years, mGFR 74 ± 27 mL/min/1.73 m2 and TKV 1.92 (1.27–2.67) L], no differences were found between tolvaptan and placebo-treated patients in 24-h urine volume at baseline (2.5 vs. 2.5 L, p = 0.8), nor in ureter diameter at renal pelvis and L5 (4.0 vs. 4.2 mm, p = 0.4 and 3.0 vs. 3.1 mm, p = 0.3). After 3 years of treatment 24-h urine volume was higher in tolvaptan-treated patients when compared to placebo (4.7 vs. 2.3 L, p < 0.001), but no differences were found in ureter diameter between both groups (renal pelvis: 4.2 vs. 4.4 mm, p = 0.4 and L5: 3.1 vs. 3.3 mm, p = 0.4). Conclusions Tolvaptan-induced polyuria did not lead to an increase in ureter diameter, suggesting that tolvaptan is a safe therapy from a urological point of view. PMID:27339446

Novel de novo AVPR2 Variant in a Patient with Congenital Nephrogenic Diabetes Insipidus

PubMed Central

Joshi, Shivani; Brandstrom, Per; Gregersen, Niels; Rittig, Søren; Christensen, Jane Hvarregaard

2017-01-01

Early diagnosis and treatment of congenital nephrogenic diabetes insipidus (CNDI) are essential due to the risk of intellectual disability caused by repeated episodes of dehydration and rapid rehydration. Timely genetic testing for disease-causing variants in the arginine vasopressin receptor 2 (AVPR2) gene is possible in at-risk newborns with a known family history of X-linked CNDI. In this study, a Swedish male with no family history was diagnosed with CNDI at 6 months of age during an episode of gastroenteritis. We analyzed the coding regions of AVPR2 by PCR and direct DNA sequencing and identified an 80-bp duplication in exon 2 (GenBank NM_000054.4; c.800_879dup) in the proband. This variant leads to a frameshift and introduces a stop codon four codons downstream (p.Ala294Profs*4). The variant gene product either succumbs to nonsense-mediated decay or is translated to a truncated nonfunctional vasopressin V2 receptor. This variant was absent in four unaffected family members, including his parents, as well as in 100 alleles from healthy controls, and is thus considered a novel de novo disease-causing variant. Identification of the disease-causing variant facilitated precise diagnosis of CNDI in the proband. Furthermore, it allows future genetic counseling in the family. This case study highlights the importance of genetic testing in sporadic infant cases with CNDI that can occur due to de novo variants in AVPR2 or several generations of female transmission of the disease-causing variant. PMID:29177155

Effects of an oral vasopressin receptor antagonist (OPC-31260) in a dog with syndrome of inappropriate secretion of antidiuretic hormone.

PubMed

Fleeman, L M; Irwin, P J; Phillips, P A; West, J

2000-12-01

The syndrome of inappropriate secretion of antidiuretic hormone is a rare disorder in dogs characterised by hypo-osmolality and persistent arginine vasopressin production in the absence of hypovolaemia and/or hypotension. The study describes the efficacy and safety of the nonpeptide selective arginine vasopressin V2 receptor antagonist OPC-31260 in a dog with the naturally occurring syndrome. The detailed case history of a dog with spontaneous syndrome of inappropriate secretion of antidiuretic hormone that received long-term therapy with oral OPC-31260 is presented. Effects of the first dose of OPC-31260 and of a dose administered after a continuous dosing period of 12 days are reported. Packed cell volume, plasma sodium, total protein, arginine vasopressin, renin activity, atrial natriuretic peptide, urine specific gravity, urine output, heart rate and body weight were monitored for 2 h before, and for 4 h after, the first dose of OPC-31260. The same parameters plus plasma osmolality and urine osmolality were monitored when an identical dose was administered after 12 days of therapy. Oral administration of OPC-31260 at 3 mg/kg body weight resulted in marked aquaresis with increased urine output and decline in urine specific gravity within 1 h. Corresponding increases in concentrations of plasma sodium, plasma osmolality and plasma renin activity were recorded over a 4 h period. Arginine vasopressin concentration remained inappropriately elevated throughout the study. Results were similar when the trial procedure was repeated after a stabilisation period of 12 days. Long-term therapy with OPC-31260 at a dose of 3 mg/kg body weight orally every 12 h resulted in good control of clinical signs with no deleterious effects detected during a 3-year follow-up period. Despite sustained clinical benefits observed in this case, plasma sodium did not normalise with continued administration of the drug. Treatment of a dog with naturally occurring syndrome of inappropriate secretion of antidiuretic hormone with OPC-31260 at 3 mg/kg body weight orally every 12 h resulted in marked aquaresis and significant palliation of clinical signs with no discernible side-effects detected over a 3-year period. Thus, OPC-31260 appears to offer a feasible medical alternative to water restriction for treatment of dogs with syndrome of inappropriate secretion of antidiuretic hormone. Higher doses of OPC-31260 may be required to achieve and maintain normal plasma sodium in dogs with this syndrome.

Transient Diabetes Insipidus After Discontinuation of Vasopressin in Neurological Intensive Care Unit Patients: Case Series and Literature Review.

PubMed

Bohl, Michael A; Forseth, James; Nakaji, Peter

2017-01-01

Arginine vasopressin (AVP) is a common second-line or third-line vasopressor used in critically ill neurosurgical patients. Neurosurgical indications include hyperdynamic therapy for vasospasm, maintenance of cerebral perfusion pressure in patients with intracranial hypertension, and prevention of hypotension in patients with sepsis. A series of 6 neurosurgical patients receiving AVP infusions developed severe but transient diabetes insipidus (tDI) after cessation of AVP. To our knowledge, no previous reports of this phenomenon in neurosurgical patients have been published. We reviewed the clinical histories, intensive care unit treatment, medication administration records, and laboratory values of these patients, and we found recurrent elevated serum sodium and urine output and decreased urine specific gravity after discontinuation of AVP. Resolution of tDI occurred upon resumption of AVP or administration of desmopressin. Elevated serum sodium levels were often severe, resulting in worsened clinical outcomes. When AVP was resumed, tDI typically recurred if AVP was again tapered and discontinued. Routine administration of desmopressin was useful in controlling sodium levels until the tDI resolved. Recognition of this phenomenon has caused us to change our clinical management of neurosurgical patients receiving AVP. We hypothesize that tDI is caused by downregulation of the V2 receptor mass in the renal distal convoluted tubule and collecting duct cells. When AVP is discontinued, patients develop nephrogenic tDI secondary to decreased V2 receptor binding, which explains why desmopressin is effective in correcting tDI. Future research includes a large prospective study to determine risk factors for tDI, its incidence, and its pathophysiology. Copyright © 2016 Elsevier Inc. All rights reserved.

Osmotic Stress Induces Transcriptional Changes in Vasopressin and Vasopressin 1b Receptor Gene Expression

DTIC Science & Technology

2000-08-29

adaptation . Invertebrate organisms as ancient and varied as coelenterates [hydra: (Grimmelikhuijzen et aI., 1982)], gastropods [the land-living mollusks...mammalian salt and water homeostasis. To further define central nervous system adaptation to osmotic challenges, transcription ofAVP and vasopressin Ib...long-term adaptation to an III osmotic challenge. Compared to rats maintained on tap water, salt-drinking rats had increased levels ofAVP and Vt.,R

Endothelin ETA Receptor Blockade, by Activating ETB Receptors, Increases Vascular Permeability and Induces Exaggerated Fluid Retention.

PubMed

Vercauteren, Magali; Trensz, Frederic; Pasquali, Anne; Cattaneo, Christophe; Strasser, Daniel S; Hess, Patrick; Iglarz, Marc; Clozel, Martine

2017-05-01

Endothelin (ET) receptor antagonists have been associated with fluid retention. It has been suggested that, of the two endothelin receptor subtypes, ET B receptors should not be blocked, because of their involvement in natriuresis and diuresis. Surprisingly, clinical data suggest that ET A -selective antagonists pose a greater risk of fluid overload than dual antagonists. The purpose of this study was to evaluate the contribution of each endothelin receptor to fluid retention and vascular permeability in rats. Sitaxentan and ambrisentan as ET A -selective antagonists and bosentan and macitentan as dual antagonists were used as representatives of each class, respectively. ET A -selective antagonism caused a dose-dependent hematocrit/hemoglobin decrease that was prevented by ET B -selective receptor antagonism. ET A -selective antagonism led to a significant blood pressure reduction, plasma volume expansion, and a greater increase in vascular permeability than dual antagonism. Isolated vessel experiments showed that ET A -selective antagonism increased vascular permeability via ET B receptor overstimulation. Acutely, ET A -selective but not dual antagonism activated sympathetic activity and increased plasma arginine vasopressin and aldosterone concentrations. The hematocrit/hemoglobin decrease induced by ET A -selective antagonism was reduced in Brattleboro rats and in Wistar rats treated with an arginine vasopressin receptor antagonist. Finally, the decrease in hematocrit/hemoglobin was larger in the venous than in the arterial side, suggesting fluid redistribution. In conclusion, by activating ET B receptors, endothelin receptor antagonists (particularly ET A -selective antagonists) favor edema formation by causing: 1) fluid retention resulting from arginine vasopressin and aldosterone activation secondary to vasodilation, and 2) increased vascular permeability. Plasma volume redistribution may explain the clinical observation of a hematocrit/hemoglobin decrease even in the absence of signs of fluid retention. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Apparent loss-of-function mutant GPCRs revealed as constitutively desensitized receptors.

PubMed

Wilbanks, Alyson M; Laporte, Stéphane A; Bohn, Laura M; Barak, Larry S; Caron, Marc G

2002-10-08

The DRY motif is a triplet amino acid sequence (aspartic acid, arginine, and tyrosine) that is highly conserved in G protein-coupled receptors (GPCRs). Recently, we have shown that a molecular determinant for nephrogenic diabetes insipidus, the vasopressin receptor with a substitution at the DRY motif arginine (V2R R137H), is a constitutively desensitized receptor that is unable to couple to G proteins due to its constitutive association with beta-arrestin [Barak, L. S. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 93-98]. Additionally, the mutant receptors are localized in endocytic vesicles, identical to wild-type receptors stimulated with agonist. In this study, we asked whether the constitutively desensitized phenotype observed in the V2R R137H represents a general paradigm that may be extended to other GPCRs. We show that arginine substitutions in the DRY motifs of the alpha(1B) adrenergic receptor (alpha(1B)-AR) and angiotensin II type 1A receptor (AT(1A)R) result in receptors that are uncoupled from G proteins, associated with beta-arrestins, and found localized in endocytic vesicles rather than at the plasma membrane in the absence of agonists. The localization of the alpha(1B)-ARs and AT(1A)Rs with arginine substitutions can be restored to the plasma membrane by either using selective antagonists or preventing the endocytosis of the beta-arrestin-receptor complexes. These results indicate that the arginine residue of the DRY motif is essential for preserving the localization of the inactive receptor complex. Furthermore, constitutive desensitization may underlie some loss-of-function receptor phenotypes and represent an unappreciated mechanism of hormonal resistance.

Vasopressin and the Regulation of Thirst.

PubMed

Bichet, Daniel G

2018-01-01

Recent experiments using optogenetic tools allow the identification and functional analysis of thirst neurons and vasopressin producing neurons. Two major advances provide a detailed anatomy of taste for water and arginine-vasopressin (AVP) release: (1) thirst and AVP release are regulated not only by the classical homeostatic, intero-sensory plasma osmolality negative feedback, but also by novel, extero-sensory, anticipatory signals. These anticipatory signals for thirst and vasopressin release converge on the same homeostatic neurons of circumventricular organs that monitor the composition of the blood; (2) acid-sensing taste receptor cells (which express polycystic kidney disease 2-like 1 protein) on the tongue that were previously suggested as the sour taste sensors also mediate taste responses to water. The tongue has a taste for water. The median preoptic nucleus (MnPO) of the hypothalamus could integrate multiple thirst-generating stimuli including cardiopulmonary signals, osmolality, angiotensin II, oropharyngeal and gastric signals, the latter possibly representing anticipatory signals. Dehydration is aversive and MnPO neuron activity is proportional to the intensity of this aversive state. © 2018 The Author(s) Published by S. Karger AG, Basel.

Selective localization of oxytocin receptors and vasopressin 1a receptors in the human brainstem

PubMed Central

Freeman, Sara M.; Smith, Aaron L.; Goodman, Mark M.; Bales, Karen L.

2017-01-01

Intranasal oxytocin affects a suite of human social behaviors, including trust, eye contact, and emotion recognition. However, it is unclear where oxytocin receptors (OXTR) and the structurally related vasopressin 1a receptors (AVPR1a) are expressed in the human brain. We have previously described a reliable, pharmacologically informed receptor autoradiography protocol for visualizing these receptors in postmortem primate brain tissue. We used this technique in human brainstem tissue to identify the neural targets of oxytocin and vasopressin. To determine binding selectivity of the OXTR radioligand and AVPR1a radioligand, sections were incubated in four conditions: radioligand alone, radioligand with the selective AVPR1a competitor SR49059, and radioligand with a low or high concentration of the selective OXTR competitor ALS-II-69. We found selective OXTR binding in the spinal trigeminal nucleus, a conserved region of OXTR expression in all primate species investigated to date. We found selective AVPR1a binding in the nucleus prepositus, an area implicated in eye gaze stabilization. The tissue's postmortem interval was not correlated with either the specific or nonspecific binding of either radioligand, indicating that it will not likely be a factor in similar postmortem studies. This study provides critical data for future studies of OXTR and AVPR1a in human brain tissue. PMID:26911439

Effects of acupuncture on vasopressin-induced emesis in conscious dogs.

PubMed

Tatewaki, Makoto; Strickland, Carmen; Fukuda, Hiroyuki; Tsuchida, Daisuke; Hoshino, Etsuo; Pappas, Theodore N; Takahashi, Toku

2005-02-01

Although acupuncture has a significant clinical benefit, the mechanism of acupuncture remains unclear. Vasopressin, a posterior pituitary hormone, is involved in nausea and vomiting in humans and dogs. To investigate the antiemetic effects of acupuncture on vasopressin-induced emesis, gastroduodenal motor activity and the frequency of retching and vomiting were simultaneously recorded in conscious dogs. In seven dogs, four force transducers were implanted on the serosal surfaces of the gastric body, antrum, pylorus, and duodenum. Gastroduodenal motility was continuously monitored throughout the experiment. Vasopressin was intravenously infused at a dose of 0.1 U x kg(-1) x min(-1) for 20 min. Electroacupuncture (EA, 1-30 Hz) at pericardium-6 (PC6), bladder-21 (BL21), or stomach-36 (ST36) was performed before, during, and after the vasopressin infusion. To investigate whether the opioid pathway is involved in EA-induced antiemetic effects, naloxone (a central and peripheral opioid receptor antagonist) or naloxone methiodide (a peripheral opioid receptor antagonist) was administered before, during, and after EA and vasopressin infusion. Intravenous infusion of vasopressin induced retching and vomiting in all dogs tested. Retrograde peristaltic contractions occurred before the onset of retching and vomiting. EA (10 Hz) at PC6 significantly reduced the number of episodes of retching and vomiting. EA at PC6 also suppressed retrograde peristaltic contractions. In contrast, EA at BL21 or ST36 had no antiemetic effects. The antiemetic effect of EA was abolished by pretreatment with naloxone but not naloxone methiodide. It is suggested that the antiemetic effect of acupuncture is mediated via the central opioid pathway.

Familial forms of diabetes insipidus: clinical and molecular characteristics.

PubMed

Babey, Muriel; Kopp, Peter; Robertson, Gary L

2011-07-05

Over the past two decades, the genetic and molecular basis of familial forms of diabetes insipidus has been elucidated. Diabetes insipidus is a clinical syndrome characterized by the excretion of abnormally large volumes of diluted urine (polyuria) and increased fluid intake (polydipsia). The most common type of diabetes insipidus is caused by lack of the antidiuretic hormone arginine vasopressin (vasopressin), which is produced in the hypothalamus and secreted by the neurohypophysis. This type of diabetes insipidus is referred to here as neurohypophyseal diabetes insipidus. The syndrome can also result from resistance to the antidiuretic effects of vasopressin on the kidney, either at the level of the vasopressin 2 receptor or the aquaporin 2 water channel (which mediates the re-absorption of water from urine), and is referred to as renal or nephrogenic diabetes insipidus. Differentiation between these two types of diabetes insipidus and primary polydipsia can be difficult owing to the existence of partial as well as complete forms of vasopressin deficiency or resistance. Seven different familial forms of diabetes insipidus are known to exist. The clinical presentation, genetic basis and cellular mechanisms responsible for them vary considerably. This information has led to improved methods of differential diagnosis and could provide the basis of new forms of therapy.

Vasopressin Receptor Signaling and Cycling of Water Channels in Renal Epithelia.

DTIC Science & Technology

1994-08-31

functional similarities to the renal cortical collecting tubule (Bentley, 1958; DiBona , 1981 and others). Recently, we demonstrated that the apical...changes in the toad urinary bladder epithelial surface. J. Cell Biol., 61, 544-547. 27 DiBona , D. R. 1981. Vasopressin action of the conformational state

Effect of the addition of vasopressin or vasopressin plus nitroglycerin to epinephrine on arterial blood pressure during cardiopulmonary resuscitation in humans.

PubMed

Ducros, Laurent; Vicaut, Eric; Soleil, Christian; Le Guen, Morgan; Gueye, Papa; Poussant, Thomas; Mebazaa, Alexandre; Payen, Didier; Plaisance, Patrick

2011-11-01

Infusion of a vasopressor during cardiopulmonary resuscitation (CPR) in humans increases end decompression (diastolic) arterial blood pressure, and consequently increases vital organ perfusion pressure and survival. Several vasoactive drugs have been tested alone or in combination, but their hemodynamic effects have not been investigated clinically in humans. We tested the hypothesis that epinephrine (1 mg) co-administered with vasopressin (40 IU) ± nitroglycerin (300 μg) results in higher diastolic blood pressure than epinephrine alone. A prospective, randomized, double-blinded controlled trial in the prehospital setting. The study included 48 patients with witnessed cardiac arrest. Patients received either epinephrine alone (E alone) or epinephrine plus vasopressin (E+V) or epinephrine plus vasopressin plus nitroglycerin (E+V+N). A femoral arterial catheter was inserted for arterial pressure measurement. The primary end point was diastolic blood pressure during CPR, 15 min after the first drug administration (T = 15 min). After exclusions, a total of 44 patients were enrolled. Diastolic blood pressures (mm Hg) at T = 15 min were not statistically different between groups (median [interquartile range]: 20 [10], 15 [6], and 15 [13] for E alone, E+V, and E+V+N, respectively. The rate of return of spontaneous circulation was 63% (n = 10) in the epinephrine group, 43% (n = 6) in the epinephrine plus vasopressin group, and 36% (n = 5) in the triple therapy group (NS). Addition of vasopressin or vasopressin plus nitroglycerin to epinephrine did not increase perfusion blood pressure compared to epinephrine alone in humans in cardiac arrest, suggesting the absence of benefit in using these drug combination(s). Copyright © 2011 Elsevier Inc. All rights reserved.

Supraoptic oxytocin and vasopressin neurons function as glucose and metabolic sensors

PubMed Central

Song, Zhilin; Levin, Barry E.; Stevens, Wanida

2014-01-01

Neurons in the supraoptic nuclei (SON) produce oxytocin and vasopressin and express insulin receptors (InsR) and glucokinase. Since oxytocin is an anorexigenic agent and glucokinase and InsR are hallmarks of cells that function as glucose and/or metabolic sensors, we evaluated the effect of glucose, insulin, and their downstream effector ATP-sensitive potassium (KATP) channels on calcium signaling in SON neurons and on oxytocin and vasopressin release from explants of the rat hypothalamo-neurohypophyseal system. We also evaluated the effect of blocking glucokinase and phosphatidylinositol 3 kinase (PI3K; mediates insulin-induced mobilization of glucose transporter, GLUT4) on responses to glucose and insulin. Glucose and insulin increased intracellular calcium ([Ca2+]i). The responses were glucokinase and PI3K dependent, respectively. Insulin and glucose alone increased vasopressin release (P < 0.002). Oxytocin release was increased by glucose in the presence of insulin. The oxytocin (OT) and vasopressin (VP) responses to insulin+glucose were blocked by the glucokinase inhibitor alloxan (4 mM; P ≤ 0.002) and the PI3K inhibitor wortmannin (50 nM; OT: P = 0.03; VP: P ≤ 0.002). Inactivating KATP channels with 200 nM glibenclamide increased oxytocin and vasopressin release (OT: P < 0.003; VP: P < 0.05). These results suggest that insulin activation of PI3K increases glucokinase-mediated ATP production inducing closure of KATP channels, opening of voltage-sensitive calcium channels, and stimulation of oxytocin and vasopressin release. The findings are consistent with SON oxytocin and vasopressin neurons functioning as glucose and “metabolic” sensors to participate in appetite regulation. PMID:24477542

Supraoptic oxytocin and vasopressin neurons function as glucose and metabolic sensors.

PubMed

Song, Zhilin; Levin, Barry E; Stevens, Wanida; Sladek, Celia D

2014-04-01

Neurons in the supraoptic nuclei (SON) produce oxytocin and vasopressin and express insulin receptors (InsR) and glucokinase. Since oxytocin is an anorexigenic agent and glucokinase and InsR are hallmarks of cells that function as glucose and/or metabolic sensors, we evaluated the effect of glucose, insulin, and their downstream effector ATP-sensitive potassium (KATP) channels on calcium signaling in SON neurons and on oxytocin and vasopressin release from explants of the rat hypothalamo-neurohypophyseal system. We also evaluated the effect of blocking glucokinase and phosphatidylinositol 3 kinase (PI3K; mediates insulin-induced mobilization of glucose transporter, GLUT4) on responses to glucose and insulin. Glucose and insulin increased intracellular calcium ([Ca(2+)]i). The responses were glucokinase and PI3K dependent, respectively. Insulin and glucose alone increased vasopressin release (P < 0.002). Oxytocin release was increased by glucose in the presence of insulin. The oxytocin (OT) and vasopressin (VP) responses to insulin+glucose were blocked by the glucokinase inhibitor alloxan (4 mM; P ≤ 0.002) and the PI3K inhibitor wortmannin (50 nM; OT: P = 0.03; VP: P ≤ 0.002). Inactivating K ATP channels with 200 nM glibenclamide increased oxytocin and vasopressin release (OT: P < 0.003; VP: P < 0.05). These results suggest that insulin activation of PI3K increases glucokinase-mediated ATP production inducing closure of K ATP channels, opening of voltage-sensitive calcium channels, and stimulation of oxytocin and vasopressin release. The findings are consistent with SON oxytocin and vasopressin neurons functioning as glucose and "metabolic" sensors to participate in appetite regulation.

Pharmacologic characterization of the oxytocin receptor in human uterine smooth muscle cells

PubMed Central

Tahara, Atsuo; Tsukada, Junko; Tomura, Yuichi; Wada, Koh-ichi; Kusayama, Toshiyuki; Ishii, Noe; Yatsu, Takeyuki; Uchida, Wataru; Tanaka, Akihiro

2000-01-01

[3H]-oxytocin was used to characterize the oxytocin receptor found in human uterine smooth muscle cells (USMC). Specific binding of [3H]-oxytocin to USMC plasma membranes was dependent upon time, temperature and membrane protein concentration. Scatchard plot analysis of equilibrium binding data revealed the existence of a single class of high-affinity binding sites with an apparent equilibrium dissociation constant (Kd) of 0.76 nM and a maximum receptor density (Bmax) of 153 fmol mg−1 protein. The Hill coefficient (nH) did not differ significantly from unity, suggesting binding to homogenous, non-interacting receptor populations. Competitive inhibition of [3H]-oxytocin binding showed that oxytocin and vasopressin (AVP) receptor agonists and antagonists displaced [3H]-oxytocin in a concentration-dependent manner. The order of potencies for peptide agonists and antagonists was: oxytocin>[Asu1,6]-oxytocin>AVP= atosiban>d(CH2)5Tyr(Me)AVP>[Thr4,Gly7]-oxytocin>dDAVP, and for nonpeptide antagonists was: L-371257>YM087>SR 49059>OPC-21268>SR 121463A>OPC-31260. Oxytocin significantly induced concentration-dependent increase in intracellular Ca2+ concentration ([Ca2+]i) and hyperplasia in USMC. The oxytocin receptor antagonists, atosiban and L-371257, potently and concentration-dependently inhibited oxytocin-induced [Ca2+]i increase and hyperplasia. In contrast, the V1A receptor selective antagonist, SR 49059, and the V2 receptor selective antagonist, SR 121463A, did not potently inhibit oxytocin-induced [Ca2+]i increase and hyperplasia. The potency order of antagonists in inhibiting oxytocin-induced [Ca2+]i increase and hyperplasia was similar to that observed in radioligand binding assays. In conclusion, these data provide evidence that the high-affinity [3H]-oxytocin binding site found in human USMC is a functional oxytocin receptor coupled to [Ca2+]i increase and cell growth. Thus human USMC may prove to be a valuable tool in further investigation of the physiologic and pathophysiologic roles of oxytocin in the uterus. PMID:10694212

Oxytocin binding sites in bovine mammary tissue

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhao, Xin.

1989-01-01

Oxytocin binding sites were identified and characterized in bovine mammary tissue. ({sup 3}H)-oxytocin binding reached equilibrium by 50 min at 20{degree}C and by 8 hr at 4{degree}C. The half-time of displacement at 20{degree}C was approximately 1 hr. Thyrotropin releasing hormone, adrenocorticotropin, angiotensin I, angiotensin II, pentagastrin, bradykinin, xenopsin and L-valyl-histidyl-L-leucyl-L-threonyl-L-prolyl-L-valyl-L-glutamyl-L-lysine were not competitive. In the presence of 10 nM LiCl, addition of oxytocin to dispersed bovine mammary cells, in which phosphatidylinositol was pre-labelled, caused a time and dose-dependent increase in radioactive inositiol monophosphate incorporation. The possibility that there are distinct vasopressin receptors in bovine mammary tissue was investigated. ({sup 3}H)-vasopressinmore » binding reached equilibrium by 40 min at 20{degree}. The half-time of displacement at 20{degree}C was approximately 1 hr. The ability of the peptides to inhibit ({sup 3}H)-vasopressin binding was: (Thr{sup 4},Gly{sup 7})-oxytocin > Arg{sup 8}-vasopressin > (lys{sup 8})-vasopressin > (Deamino{sup 1},D-arg{sup 8})-vasopressin > oxytocin > d (CH{sub 2}){sub 5}Tyr(Me)AVP.« less

Epibatidine, an alkaloid from the poison frog Epipedobates tricolor, is a powerful ganglionic depolarizing agent.

PubMed

Fisher, M; Huangfu, D; Shen, T Y; Guyenet, P G

1994-08-01

Epibatidine, a newly discovered alkaloid from the skin of Dendrobatidae frogs, has structural similarities to nicotine. We examined the effects of epibatidine on cardiorespiratory function and ganglionic synaptic transmission. Superior cervical or splanchnic sympathetic nerve discharge (sSND) and phrenic nerve discharge (PND) were recorded along with arterial pressure (AP) in urethane-anesthetized, paralyzed and artificially ventilated rats. Epibatidine administered i.v. at low doses (0.5-2 micrograms/kg) produced a transient increase in AP and sSND, followed by a decrease and return to baseline; this low dose of epibatidine also produced a dose-dependent increase in PND. At high doses (cumulative dose of 8-16 micrograms/kg), epibatidine produced bradycardia, a profound depression in sSND and a transient elimination of PND. After i.v. administration of the ganglionic blocker chlorisondamine (5 mg/kg), AP was still increased by 1 microgram/kg epibatidine (+39 +/- 11 mm Hg). This pressor effect was not altered by pretreatment with the alpha-1 adrenergic antagonist phentolamine (+40 +/- 10 mm Hg); however, it was blocked by additional pretreatment with the vasopressin antagonist [beta-mercapto-beta,beta-cyclopentamethylenepropiony1, O-ET-Tyr2,Val4,Arg8]vasopressin (50 micrograms/kg i.v.; +2 +/- 0.4 mm Hg). Low doses of epibatidine (0.5-2 micrograms/kg) produced firing of postganglionic neurons in a decentralized ganglion preparation and potentiated synaptic transmission; at high doses (cumulative dose of 8-16 micrograms/kg), the alkaloid blocked ganglionic synaptic transmission. These results suggest that epibatidine is a potent agonist of ganglionic nicotinic receptors and that the alkaloid elicits cardiorespiratory effects similar to those of nicotine.

Neuroscience of opiates for addiction medicine: From stress-responsive systems to behavior.

PubMed

Zhou, Yan; Leri, Francesco

2016-01-01

Opiate addiction, similarly to addiction to other psychoactive drugs, is chronic relapsing brain disease caused by drug-induced short-term and long-term neuroadaptations at the molecular, cellular, and behavioral levels. Preclinical research in laboratory animals has found important interactions between opiate exposure and stress-responsive systems. In this review, we will discuss the dysregulation of several stress-responsive systems in opiate addiction: vasopressin and its receptor system, endogenous opioid systems (including proopiomelanocortin/mu opioid receptor and dynorphin/kappa opioid receptor), orexin and its receptor system, and the hypothalamic-pituitary-adrenal axis. A more complete understanding of how opiates alter these stress systems, through further laboratory-based studies, is required to identify novel and effective pharmacological targets for the long-term treatment of heroin addiction. © 2016 Elsevier B.V. All rights reserved.

Oxytocin receptor and vasopressin receptor 1a genes are respectively associated with emotional and cognitive empathy.

PubMed

Uzefovsky, F; Shalev, I; Israel, S; Edelman, S; Raz, Y; Mankuta, D; Knafo-Noam, A; Ebstein, R P

2015-01-01

Empathy is the ability to recognize and share in the emotions of others. It can be considered a multifaceted concept with cognitive and emotional aspects. Little is known regarding the underlying neurochemistry of empathy and in the current study we used a neurogenetic approach to explore possible brain neurotransmitter pathways contributing to cognitive and emotional empathy. Both the oxytocin receptor (OXTR) and the arginine vasopressin receptor 1a (AVPR1a) genes contribute to social cognition in both animals and humans and hence are prominent candidates for contributing to empathy. The following research examined the associations between polymorphisms in these two genes and individual differences in emotional and cognitive empathy in a sample of 367 young adults. Intriguingly, we found that emotional empathy was associated solely with OXTR, whereas cognitive empathy was associated solely with AVPR1a. Moreover, no interaction was observed between the two genes and measures of empathy. The current findings contribute to our understanding of the distinct neurogenetic pathways involved in cognitive and emotional empathy and underscore the pervasive role of both oxytocin and vasopressin in modulating human emotions. Copyright © 2014 Elsevier Inc. All rights reserved.

Differential Regulation of Endosomal GPCR/β-Arrestin Complexes and Trafficking by MAPK*

PubMed Central

Khoury, Etienne; Nikolajev, Ljiljana; Simaan, May; Namkung, Yoon; Laporte, Stéphane A.

2014-01-01

β-Arrestins are signaling adaptors that bind to agonist-occupied G protein-coupled receptors (GPCRs) and target them for endocytosis; however, the mechanisms regulating receptor/β-arrestin complexes and trafficking in endosomes, remain ill defined. Here we show, in live cells, differential dynamic regulation of endosomal bradykinin B2 receptor (B2R) complexes with either β-arrestin-1 or -2. We find a novel role for MAPK in the B2R/β-arrestin-2 complex formation, receptor trafficking and signaling mediated by an ERK1/2 regulatory motif in the hinge domain of the rat β-arrestin-2 (PET178P), but not rat β-arrestin-1 (PER177P). While the ERK1/2 regulatory motif is conserved between rat and mouse β-arrestin-2, it is surprisingly not conserved in human β-arrestin-2 (PEK178P). However, mutation of lysine 178 to threonine is sufficient to confer MAPK sensitivity to the human β-arrestin-2. Furthermore, substitution for a phosphomimetic residue in both the rat and the human β-arrestin-2 (T/K178D) significantly stabilizes B2R/β-arrestin complexes in endosomes, delays receptor recycling to the plasma membrane and maintains intracellular MAPK signaling. Similarly, the endosomal trafficking of β2-adrenergic, angiotensin II type 1 and vasopressin V2 receptors was altered by the β-arrestin-2 T178D mutant. Our findings unveil a novel subtype specific mode of MAPK-dependent regulation of β-arrestins in intracellular trafficking and signaling of GPCRs, and suggest differential endosomal receptor/β-arrestin-2 signaling roles among species. PMID:25016018

Role of Vasopressin in Rat Models of Salt-Dependent Hypertension.

PubMed

Prager-Khoutorsky, Masha; Choe, Katrina Y; Levi, David I; Bourque, Charles W

2017-05-01

Dietary salt intake increases both plasma sodium and osmolality and therefore increases vasopressin (VP) release from the neurohypophysis. Although this effect could increase blood pressure by inducing fluid reabsorption and vasoconstriction, acute activation of arterial baroreceptors inhibits VP neurons via GABA A receptors to oppose high blood pressure. Here we review recent findings demonstrating that this protective mechanism fails during chronic high salt intake in rats. Two recent studies showed that chronic high sodium intake causes an increase in intracellular chloride concentration in VP neurons. This effect causes GABA A receptors to become excitatory and leads to the emergence of VP-dependent hypertension. One study showed that the increase in intracellular chloride was provoked by a decrease in the expression of the chloride exporter KCC2 mediated by local secretion of brain-derived neurotrophic factor and activation of TrkB receptors. Prolonged high dietary salt intake can cause pathological plasticity in a central homeostatic circuit that controls VP secretion and thereby contribute to peripheral vasoconstriction and hypertension.

Ethanol causes desensitization of receptor-mediated phospholipase C activation in isolated hepatocytes.

PubMed

Higashi, K; Hoek, J B

1991-02-05

The effect of ethanol on receptor-mediated phospholipase C-linked signal transduction processes was investigated in isolated rat hepatocytes. Pretreatment of the cells with ethanol (6-300 mM) markedly inhibited a subsequent stimulation of phospholipase C by vasopressin, angiotensin II, or epidermal growth factor. By contrast, the effects of the alpha 1-adrenergic agonist phenylephrine and of glucagon were not affected by ethanol pretreatment. Ethanol inhibited the agonist-induced decrease in polyphosphoinositides, the formation of inositol phosphates, and the increase in cytosolic free Ca2+ levels, as detected with the intracellular Ca2+ indicator indo-1. The effects of ethanol were concentration dependent and were pronounced at low concentrations of agonists but were not significant at saturating levels. Pretreatment of the cells with the protein kinase C inhibitor H7 partly prevented the inhibition by ethanol of vasopressin-induced phospholipase C activation. By contrast, pretreatment of the cells with (Rp)-adenosine cyclic 3':5'-phosphorothioate [Rp)-cAMP-S), a competitive inhibitor of protein kinase A, potentiated the inhibitory effect of ethanol on the Ca2+ mobilization by vasopressin. (Rp)-cAMP-S similarly potentiated the inhibition of phospholipase C by the protein kinase C-activating phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). The kinase A inhibitor also made the Ca2+ mobilization by phenylephrine sensitive to ethanol, indicating that the formation of cAMP in the cells played a role in suppressing the sensitivity to ethanol. Pretreatment of the cells with ethanol enhanced the inhibitory effects of TPA on the vasopressin-induced phospholipase C activation at all concentrations of the hormone; however, these synergistic effects were prevented when TPA was added prior to ethanol, a condition that prevents the activation of phospholipase C by ethanol. The data indicate that ethanol causes desensitization of the receptor-mediated phospholipase C secondary to the ethanol-induced activation of phospholipase C and activation of protein kinase C. Ethanol treatment also affects the sensitivity of the phospholipase C system to control by protein kinases A and C. The data indicate that ethanol can affect the control of intracellular signal transduction processes in liver cells under physiologically relevant conditions.

Comparative Perspectives on Oxytocin and Vasopressin Receptor Research in Rodents and Primates: Translational Implications

PubMed Central

Freeman, Sara M.; Young, Larry J.

2016-01-01

In the last several decades, sophisticated experimental techniques have been used to determine the neurobiology of the oxytocin and vasopressin systems in rodents. Using a suite of methodologies, including electrophysiology, site-specific selective pharmacology, receptor autoradiography, in vivo microdialysis, and genetic and optogenetic manipulations, we have gained unprecedented knowledge about how these neuropeptides engage neural circuits to regulate behaviour, particularly social behaviour. Based on this foundation of information from rodent studies, we have started generating new hypotheses and frameworks about how the oxytocin and vasopressin systems could be acting in humans to influence social cognition. However, despite the recent inundation of publications using intranasal oxytocin in humans, we still know very little about the neurophysiology of the oxytocin system in primates more broadly. Furthermore, the design and analysis of these human studies have remained largely uninformed of the potential neurobiological mechanisms underlying their findings. Although the methods available for studying the oxytocin and vasopressin systems in humans are incredibly limited as a result of practical and ethical considerations, there is great potential to fill the gaps in our knowledge by developing better nonhuman primate models of social functioning. Behavioural pharmacology and receptor autoradiography have been used to study the oxytocin and vasopressin systems in nonhuman primates, and there is now great potential to broaden our understanding of the neurobiology of these systems. In this review, we discuss comparative findings in receptor distributions in rodents and primates, with perspectives on the functionality of conserved regions of expression in these distinct mammalian clades. We also identify specific ways that established technologies can be used to answer basic research questions in primates. Finally, we highlight areas of future research in nonhuman primates that are experimentally poised to yield critical insights into the anatomy, physiology and behavioural effects of the oxytocin system, given its remarkable translational potential. PMID:26940141

Maternal neglect with reduced depressive-like behavior and blunted c-fos activation in Brattleboro mothers, the role of central vasopressin.

PubMed

Fodor, Anna; Klausz, Barbara; Pintér, Ottó; Daviu, Nuria; Rabasa, Cristina; Rotllant, David; Balazsfi, Diana; Kovacs, Krisztina B; Nadal, Roser; Zelena, Dóra

2012-09-01

Early mother-infant relationships exert important long-term effects in offspring and are disturbed by factors such as postpartum depression. We aimed to clarify if lack of vasopressin influences maternal behavior paralleled by the development of a depressive-like phenotype. We compared vasopressin-deficient Brattleboro mothers with heterozygous and homozygous normal ones. The following parameters were measured: maternal behavior (undisturbed and separation-induced); anxiety by the elevated plus maze; sucrose and saccharin preference and forced swim behavior. Underlying brain areas were examined by c-fos immunocytochemistry among rest and after swim-stress. In another group of rats, vasopressin 2 receptor agonist was used peripherally to exclude secondary changes due to diabetes insipidus. Results showed that vasopressin-deficient rats spend less time licking-grooming their pups through a centrally driven mechanism. There was no difference between genotypes during the pup retrieval test. Vasopressin-deficient mothers tended to explore more the open arms of the plus maze, showed more preference for sucrose and saccharin and struggled more in the forced swim test, suggesting that they act as less depressive. Under basal conditions, vasopressin-deficient mothers had more c-fos expression in the medial preoptic area, shell of nucleus accumbens, paraventricular nucleus of the hypothalamus and amygdala, but not in other structures. In these areas the swim-stress-induced activation was smaller. In conclusion, vasopressin-deficiency resulted in maternal neglect due to a central effect and was protective against depressive-like behavior probably as a consequence of reduced activation of some stress-related brain structures. The conflicting behavioral data underscores the need for more sex specific studies. Copyright © 2012 Elsevier Inc. All rights reserved.

Novel evolutionary lineages of the invertebrate oxytocin/vasopressin superfamily peptides and their receptors in the common octopus (Octopus vulgaris)

PubMed Central

Kanda, Atsuhiro; Satake, Honoo; Kawada, Tsuyoshi; Minakata, Hiroyuki

2004-01-01

The common octopus, Octopus vulgaris, is the first invertebrate species that was shown to possess two oxytocin/vasopressin (OT/VP) superfamily peptides, octopressin (OP) and cephalotocin (CT). Previously, we cloned a GPCR (G-protein-coupled receptor) specific to CT [CTR1 (CT receptor 1)]. In the present study, we have identified an additional CTR, CTR2, and a novel OP receptor, OPR. Both CTR2 and OPR include domains and motifs typical of GPCRs, and the intron– exon structures are in accord with those of OT/VP receptor genes. CTR2 and OPR expressed in Xenopus oocytes induced calcium-mediated inward chloride current in a CT- and OP-specific manner respectively. Several regions and residues, which are requisite for binding of the vertebrate OT/VP receptor family with their ligands, are highly conserved in CTRs, but not in OPR. These different sequences between CTRs and OPR, as well as the amino acid residues of OP and CT at positions 2–5, were presumed to play crucial roles in the binding selectivity to their receptors, whereas the difference in the polarity of OT/VP family peptide residues at position 8 confers OT and VP with the binding specificity in vertebrates. CTR2 mRNA was present in various peripheral tissues, and OPR mRNA was detected in both the nervous system and peripheral tissues. Our findings suggest that the CT and OP genes, similar to the OT/VP family, evolved through duplication, but the ligand–receptor selectivity were established through different evolutionary lineages from those of their vertebrate counterparts. PMID:15504101

Oxytocin and vasopressin neural networks: implications for social behavioral diversity and translational neuroscience

PubMed Central

Johnson, Zachary V.; Young, Larry J.

2017-01-01

Oxytocin- and vasopressin-related systems are present in invertebrate and vertebrate bilaterian animals, including humans, and exhibit conserved neuroanatomical and functional properties. In vertebrates, these systems innervate conserved neural networks that regulate social learning and behavior, including conspecific recognition, social attachment, and parental behavior. Individual and species-level variation in central organization of oxytocin and vasopressin systems has been linked to individual and species variation in social learning and behavior. In humans, genetic polymorphisms in the genes encoding oxytocin and vasopressin peptides and/or their respective target receptors have been associated with individual variation in social recognition, social attachment phenotypes, parental behavior, and psychiatric phenotypes such as autism. Here we describe both conserved and variable features of central oxytocin and vasopressin systems in the context of social behavioral diversity, with a particular focus on neural networks that modulate social learning, behavior, and salience of sociosensory stimuli during species-typical social contexts. PMID:28434591

Signaling Modification by GPCR Heteromer and Its Implication on X-Linked Nephrogenic Diabetes Insipidus

PubMed Central

Harikumar, Kaleeckal G.; Miller, Laurence J.; Chow, Billy K. C.

2016-01-01

The involvement of secretin (SCT) and secretin receptor (SCTR) in regulating body water homeostasis is well established. Identified as one of the vasopressin (Vp)-independent mechanisms in fluid balance, SCT regulates aquaporin 2 (AQP2) in the kidney distal collecting duct cells through activating intracellular cAMP production. This ability to bypass Vp-mediated water reabsorption in kidney implicates SCT’s potential to treat nephrogenic diabetes insipidus (NDI). Research on NDI in the past has largely been focused on the searching for mutations in vasopressin receptor 2 (AVPR2), while the functional relationship between SCTR, AVPR2 and NDI remains unclear. Here, we demonstrate the interaction between SCTR and AVPR2 to modulate cellular signaling in vitro. Interestingly, we show in this report that upon heteromer formation with SCTR, R137H, a NDI-causing AVPR2 mutant that is defective in trafficking to cell surface, can functionally be rescued. Our data may provide an explanation for this clinically mild case of NDI, and insights into the pathological development of NDI in the future. PMID:27649563

The Nonpeptide Oxytocin Receptor Agonist WAY 267,464: Receptor-Binding Profile, Prosocial Effects and Distribution of c-Fos Expression in Adolescent Rats

PubMed Central

Hicks, C.; Jorgensen, W.; Brown, C.; Fardell, J.; Koehbach, J.; Gruber, C. W.; Kassiou, M.; Hunt, G. E.; McGregor, I. S.

2012-01-01

Previous research suggests that the nonpeptide oxytocin receptor (OTR) agonist WAY 267,464 may only partly mimic the effects of oxytocin in rodents. The present study further explored these differences and related them to OTR and vasopressin 1a receptor (V1aR) pharmacology and regional patterns of c-Fos expression. Binding data for WAY 267,464 and oxytocin were obtained by displacement binding assays on cellular membranes, while functional receptor data were generated by luciferase reporter assays. For behavioural testing, adolescent rats were tested in a social preference paradigm, the elevated plus-maze (EPM) and for locomotor activity changes following WAY 267,464 (10 and 100 mg/kg, i.p.) or oxytocin (0.1 and 1 mg/kg, i.p.). The higher doses were also examined for their effects on regional c-Fos expression. Results showed that WAY 267,464 had higher affinity (Ki) at the V1aR than the OTR (113 versus 978 nm). However, it had no functional response at the V1aR and only a weak functional effect (EC50) at the OTR (881 nm). This suggests WAY 267,464 is an OTR agonist with weak affinity and a possible V1aR antagonist. Oxytocin showed high binding at the OTR (1.0 nm) and V1aR (503 nm), with a functional EC50 of 9.0 and 59.7 nm, respectively, indicating it is a potent OTR agonist and full V1aR agonist. WAY 267,464 (100 mg/kg), but not oxytocin, significantly increased the proportion of time spent with a live rat, over a dummy rat, in the social preference test. Neither compound affected EPM behaviour, whereas the higher doses of WAY 267,464 and oxytocin suppressed locomotor activity. WAY 267,464 and oxytocin produced similar c-Fos expression in the paraventricular hypothalamic nucleus, central amygdala, lateral parabrachial nucleus and nucleus of the solitary tract, suggesting a commonality of action at the OTR with the differential doses employed. However, WAY 267,464 caused greater c-Fos expression in the medial amygdala and the supraoptic nucleus than oxytocin, and lesser effects in the locus coeruleus. Overall, our results confirm the differential effects of WAY 267,464 and oxytocin and suggest that this may reflect contrasting actions of WAY 267,464 and oxytocin at the V1aR. Antagonism of the V1aR by WAY 267,464 could underlie some of the prosocial effects of this drug either through a direct action or through disinhibition of oxytocin circuitry that is subject to vasopressin inhibitory influences. PMID:22420322

Arginine vasopressin and oxytocin modulate human social behavior.

PubMed

Ebstein, Richard P; Israel, Salomon; Lerer, Elad; Uzefovsky, Florina; Shalev, Idan; Gritsenko, Inga; Riebold, Mathias; Salomon, Shahaf; Yirmiya, Nurit

2009-06-01

Increasing evidence suggests that two nonapeptides, arginine vasopressin and oxytocin, shape human social behavior in both nonclinical and clinical subjects. Evidence is discussed that in autism spectrum disorders genetic polymorphisms in the vasopressin-oxytocin pathway, notably the arginine vasopressin receptor 1a (AVPR1a), the oxytocin receptor (OXTR), neurophysin I and II, and CD38 (recently shown to be critical for social behavior by mediating oxytocin secretion) contribute to deficits in socialization skills in this group of patients. We also present first evidence that CD38 expression in lymphoblastoid cells derived from subjects diagnosed with autism is correlated with social skill phenotype inventoried by the Vineland Adaptive Behavioral Scales. Additionally, we discuss molecular genetic evidence that in nonclinical subjects both AVPR1a and OXTR genes contribute to prosocial or altruistic behavior inventoried by two experimental paradigms, the dictator game and social values orientation. The role of the AVPR1a is also analyzed in prepulse inhibition. Prepulse inhibition of the startle response to auditory stimuli is a largely autonomic response that resonates with social cognition in both animal models and humans. First results are presented showing that intranasal administration of arginine vasopressin increases salivary cortisol levels in the Trier Social Stress test. To summarize, accumulating studies employing a broad array of cutting-edge tools in psychology, neuroeconomics, molecular genetics, pharmacology, electrophysiology, and brain imaging are beginning to elaborate the intriguing role of oxytocin and arginine vasopressin in human social behavior. We expect that future studies will continue this advance and deepen our understanding of these complex events.

Cellular plasticity in the supraoptic and paraventricular nuclei after prolonged dehydration in the desert rodent Meriones shawi: Vasopressin and GFAP immunohistochemical study.

PubMed

Gamrani, Halima; Elgot, Abdeljalil; El Hiba, Omar; Fèvre-Montange, Michelle

2011-02-23

Supraoptic (SON) and paraventricular (PVN) nuclei are part of the hypothalamic-neurohypophysial system, they constitute the main source for vasopressin and they represent also obvious examples of activity-dependent neuroglial plasticity. Certain physiological conditions such as dehydration are accompanied by a structural remodeling of the neurons, their synaptic inputs and their surrounding glia. In the present work, an adult Meriones shawi (a rodent adapted to desert life) is used as an animal model. Using GFAP and vasopressin expressions as indicators successively of astrocytes and neuronal activations, the effect of a prolonged episode of water deprivation on the SON and PVN, hypothalamus nuclei were examined. We studied the immunoreactivity of GFAP and vasopressin in various hydration states (total deprivation of drinking water for 1 and 2months compared to hydrated animals). Prolonged dehydration produces an important decrease of GFAP immunoreactivity in both SON and PVN after 1 and 2months of water restriction. This decrease is accompanied by increased vasopressin immunoreactivity following the same periods of water deprivation. These findings may explain a real communication between vasopressin neurons and their surrounding astrocytes, thus the retraction of astrocytes and their processes is accompanied by an enhancement of vasopressin neuron density and their projecting fibers in response to this osmotic stress situation. Furthermore, these data could open further investigations concerning the possible involvement of the communication between astrocytes and vasopressin neurons in both PVN and SON in the regulation of Meriones hydrous balance and resistance to dehydration. Copyright © 2010. Published by Elsevier B.V.

Mutations in the AVPR2, AVP-NPII, and AQP2 genes in Turkish patients with diabetes insipidus.

PubMed

Duzenli, Duygu; Saglar, Emel; Deniz, Ferhat; Azal, Omer; Erdem, Beril; Mergen, Hatice

2012-12-01

The aim of this study was to identify mutations in three different genes, the arginine-vasopressin-neurophysin II (AVP-NPII) gene, the arginine-vasopressin receptor 2 (AVPR2) gene, and the vasopressin-sensitive water channel aquaporin-2 (AQP2) gene in Turkish patients affected by central diabetes insipidus or nephrogenic diabetes insipidus. This study included 15 patients from unrelated families. Prospective clinical data were collected for all patients including the patients underwent a water deprivation-desmopressin test. The coding regions of the AVPR2, AQP2, and AVP-NPII genes were amplified by polymerase chain reaction and submitted to direct sequence analysis. Of the 15 patients with diabetes insipidus referred to Gulhane Military Medical Academy, Department of Endocrinology and Metabolism, eight patients have AVPR2 mutations, five patients have AQP2 mutations and two patients have AVP-NPII mutations. Of the patients, which have AVPR2 mutations, one is compound heterozygous for AVPR2 gene. Seven of these mutations are novel. Comparison of the clinical outcomes of these mutations may facilitate in understanding the functions of AVP-NPII, AQP2, and AVPR2 genes in future studies.

Combination of secretin and fluvastatin ameliorates the polyuria associated with X-linked nephrogenic diabetes insipidus in mice.

PubMed

Procino, Giuseppe; Milano, Serena; Carmosino, Monica; Barbieri, Claudia; Nicoletti, Maria C; Li, Jian H; Wess, Jürgen; Svelto, Maria

2014-07-01

X-linked nephrogenic diabetes insipidus (X-NDI) is a disease caused by inactivating mutations of the vasopressin (AVP) type 2 receptor (V2R) gene. Loss of V2R function prevents plasma membrane expression of the AQP2 water channel in the kidney collecting duct cells and impairs the kidney concentration ability. In an attempt to develop strategies to bypass V2R signaling in X-NDI, we evaluated the effects of secretin and fluvastatin, either alone or in combination, on kidney function in a mouse model of X-NDI. The secretin receptor was found to be functionally expressed in the kidney collecting duct cells. Based on this, X-NDI mice were infused with secretin for 14 days but urinary parameters were not altered by the infusion. Interestingly, secretin significantly increased AQP2 levels in the collecting duct but the protein primarily accumulated in the cytosol. Since we previously reported that fluvastatin treatment increased AQP2 plasma membrane expression in wild-type mice, secretin-infused X-NDI mice received a single injection of fluvastatin. Interestingly, urine production by X-NDI mice treated with secretin plus fluvastatin was reduced by nearly 90% and the urine osmolality was doubled. Immunostaining showed that secretin increased intracellular stores of AQP2 and the addition of fluvastatin promoted AQP2 trafficking to the plasma membrane. Taken together, these findings open new perspectives for the pharmacological treatment of X-NDI.

Combination of secretin and fluvastatin ameliorates the polyuria associated with X-linked nephrogenic diabetes insipidus in mice

PubMed Central

Procino, Giuseppe; Milano, Serena; Carmosino, Monica; Barbieri, Claudia; Nicoletti, Maria C; H. Li, Jian; Wess, Jürgen; Svelto, Maria

2014-01-01

X-linked nephrogenic diabetes insipidus (X-NDI) is a disease caused by inactivating mutations of the vasopressin (AVP) type 2 receptor (V2R) gene. Loss of V2R function prevents plasma membrane expression of the AQP2 water channel in the kidney collecting duct cells and impairs the kidney concentration ability. In an attempt to develop strategies to bypass V2R signaling in X-NDI, we evaluated the effects of secretin and fluvastatin, either alone or in combination, on kidney function in a mouse model of X-NDI. The secretin receptor was found to be functionally expressed in the kidney collecting duct cells. Based on this, X-NDI mice were infused with secretin for 14 days but urinary parameters were not altered by the infusion. Interestingly, secretin significantly increased AQP2 levels in the collecting duct but the protein primarily accumulated in the cytosol. Since we previously reported that fluvastatin treatment increased AQP2 plasma membrane expression in wild-type mice, secretin-infused X-NDI mice received a single injection of fluvastatin. Interestingly, urine production by X-NDI mice treated with secretin plus fluvastatin was reduced by nearly 90% and the urine osmolality was doubled. Immunostaining showed that secretin increased intracellular stores of AQP2 and the addition of fluvastatin promoted AQP2 trafficking to the plasma membrane. Taken together, these findings open new perspectives for the pharmacological treatment of X-NDI. PMID:24522493

Peptides as modifiers of Na+-induced pinocytosis in starved Amoeba proteus.

PubMed

Josefsson, J O; Johansson, P

1985-01-01

Low concentrations of six peptide hormones; glucagon, vasoactive intestinal peptide, substance P, angiotensin II, lysine-vasopressin, arginine-vasopressin, and the chemotactic peptide fMet-Leu-Phe, activated the capacity for pinocytosis in starved Amoeba proteus. Competitive inhibitors of the chemotactic peptide in leucocytes inhibited activation by fMet-Leu-Phe, suggesting that its action in the amoeba is mediated by specific receptors. The opioid peptides, beta-endorphin, dynorphin (1-13) and leu-enkephalin abolished through a naloxone-sensitive mechanism activation by hormones and several other activating agents. Also, low concentrations of beef and pork insulin inhibited activation by peptide hormones. An insulin analogue of low potency in mammalian cells was inactive in the amoeba. These results support the hypothesis that besides opioid receptors, there may be insulin receptors and possibly receptors for several other peptide hormones in Amoeba proteus.

Regulation of the macrophage oxytocin receptor in response to inflammation

PubMed Central

Szeto, Angela; Sun-Suslow, Ni; Mendez, Armando J.; Hernandez, Rosa I.; Wagner, Klaus V.

2017-01-01

It has been demonstrated that the neuropeptide oxytocin (OT) attenuates oxidative stress and inflammation in macrophages. In the current study, we examined the role of inflammation on the expression of the oxytocin receptor (OXTR). We hypothesized that OXTR expression is increased during the inflammation through a nuclear factor-κB (NF-κB)-mediated pathway, thus responding as an acute-phase protein. Inflammation was induced by treating macrophages (human primary, THP-1, and murine) with lipopolysaccharide (LPS) and monitored by expression of IL-6. Expression of OXTR and vasopressin receptors was assessed by qPCR, and OXTR expression was confirmed by immunoblotting. Inflammation upregulated OXTR transcription 10- to 250-fold relative to control in THP-1 and human primary macrophages and increased OXTR protein expression. In contrast, vasopressin receptor-2 mRNA expression was reduced following LPS treatment. Blocking NF-κB activation prevented the increase in OXTR transcription. OT treatment of control cells and LPS-treated cells increased ERK1/2 phosphorylation, demonstrating activation of the OXTR/Gαq/11 signaling pathway. OT activation of OXTR reduced secretion of IL-6 in LPS-activated macrophages. Collectively, these findings suggest that OXTR is an acute-phase protein and that its increased expression is regulated by NF-κB and functions to attenuate cellular inflammatory responses in macrophages. PMID:28049625

Oxytocin differently regulates pressor responses to stress in WKY and SHR rats: the role of central oxytocin and V1a receptors.

PubMed

Wsol, A; Szczepanska-Sadowska, E; Kowalewski, S; Puchalska, L; Cudnoch-Jedrzejewska, A

2014-01-01

The role of central oxytocin in the regulation of cardiovascular parameters under resting conditions and during acute stress was investigated in male normotensive Wistar-Kyoto (WKY; n = 40) and spontaneously hypertensive rats (SHR; n = 28). In Experiment 1, mean arterial blood pressure (MABP) and heart rate (HR) were recorded in WKY and SHR rats at rest and after an air-jet stressor during intracerebroventricular (ICV) infusions of vehicle, oxytocin or oxytocin receptor (OTR) antagonist. In Experiment 2, the effects of vehicle, oxytocin and OTR antagonist were determined in WKY rats after prior administration of a V1a vasopressin receptor (V1aR) antagonist. Resting MABP and HR were not affected by any of the ICV infusions either in WKY or in SHR rats. In control experiments (vehicle), the pressor response to stress was significantly higher in SHR. Oxytocin enhanced the pressor response to stress in the WKY rats but reduced it in SHR. During V1aR blockade, oxytocin infusion entirely abolished the pressor response to stress in WKY rats. Combined blockade of V1aR and OTR elicited a significantly greater MABP response to stress than infusion of V1a antagonist and vehicle. This study reveals significant differences in the regulation of blood pressure in WKY and SHR rats during alarming stress. Specifically, the augmentation of the pressor response to stress by exogenous oxytocin in WKY rats is caused by its interaction with V1aR, and endogenous oxytocin regulates the magnitude of the pressor response to stress in WKY rats by simultaneous interaction with OTR and V1aR.

Drug-induced and genetic alterations in stress-responsive systems: Implications for specific addictive diseases.

PubMed

Zhou, Yan; Proudnikov, Dmitri; Yuferov, Vadim; Kreek, Mary Jeanne

2010-02-16

From the earliest work in our laboratory, we hypothesized, and with studies conducted in both clinical research and animal models, we have shown that drugs of abuse, administered or self-administered, on a chronic basis, profoundly alter stress-responsive systems. Alterations of expression of specific genes involved in stress responsivity, with increases or decreases in mRNA levels, receptor, and neuropeptide levels, and resultant changes in hormone levels, have been documented to occur after chronic intermittent exposure to heroin, morphine, other opiates, cocaine, other stimulants, and alcohol in animal models and in human molecular genetics. The best studied of the stress-responsive systems in humans and mammalian species in general is undoubtedly the HPA axis. In addition, there are stress-responsive systems in other parts in the brain itself, and some of these include components of the HPA axis, such as CRF and CRF receptors, along with POMC gene and gene products. Several other stress-responsive systems are known to influence the HPA axis, such as the vasopressin-vasopressin receptor system. Orexin-hypocretin, acting at its receptors, may effect changes which suggest that it should be properly categorized as a stress-responsive system. However, less is known about the interactions and connectivity of some of these different neuropeptide and receptor systems, and in particular, about the possible connectivity of fast-acting (e.g., glutamate and GABA) and slow-acting (including dopamine, serotonin, and norepinephrine) neurotransmitters with each of these stress-responsive components and the resultant impact, especially in the setting of chronic exposure to drugs of abuse. Several of these stress-responsive systems and components, primarily based on our laboratory-based and human molecular genetics research of addictive diseases, will be briefly discussed in this review. Copyright 2009 Elsevier B.V. All rights reserved.

Pharmacologic characterization of the oxytocin receptor in human uterine smooth muscle cells.

PubMed

Tahara, A; Tsukada, J; Tomura, Y; Wada, K i; Kusayama, T; Ishii, N; Yatsu, T; Uchida, W; Tanaka, A

2000-01-01

[(3)H]-oxytocin was used to characterize the oxytocin receptor found in human uterine smooth muscle cells (USMC). Specific binding of [(3)H]-oxytocin to USMC plasma membranes was dependent upon time, temperature and membrane protein concentration. Scatchard plot analysis of equilibrium binding data revealed the existence of a single class of high-affinity binding sites with an apparent equilibrium dissociation constant (K(d)) of 0.76 nM and a maximum receptor density (B(max)) of 153 fmol mg(-1) protein. The Hill coefficient (n(H)) did not differ significantly from unity, suggesting binding to homogenous, non-interacting receptor populations. Competitive inhibition of [(3)H]-oxytocin binding showed that oxytocin and vasopressin (AVP) receptor agonists and antagonists displaced [(3)H]-oxytocin in a concentration-dependent manner. The order of potencies for peptide agonists and antagonists was: oxytocin>[Asu(1,6)]-oxytocin>AVP= atosiban>d(CH(2))(5)Tyr(Me)AVP>[Thr(4),Gly(7)]-oxytocin>dDAVP, and for nonpeptide antagonists was: L-371257>YM087>SR 49059>OPC-21268>SR 121463A>OPC-31260. Oxytocin significantly induced concentration-dependent increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) and hyperplasia in USMC. The oxytocin receptor antagonists, atosiban and L-371257, potently and concentration-dependently inhibited oxytocin-induced [Ca(2+)](i) increase and hyperplasia. In contrast, the V(1A) receptor selective antagonist, SR 49059, and the V(2) receptor selective antagonist, SR 121463A, did not potently inhibit oxytocin-induced [Ca(2+)](i) increase and hyperplasia. The potency order of antagonists in inhibiting oxytocin-induced [Ca(2+)](i) increase and hyperplasia was similar to that observed in radioligand binding assays. In conclusion, these data provide evidence that the high-affinity [(3)H]-oxytocin binding site found in human USMC is a functional oxytocin receptor coupled to [Ca(2+)](i) increase and cell growth. Thus human USMC may prove to be a valuable tool in further investigation of the physiologic and pathophysiologic roles of oxytocin in the uterus. British Journal of Pharmacology (2000) 129, 131 - 139

Oxytocin, vasopressin, and the neurogenetics of sociality.

PubMed

Donaldson, Zoe R; Young, Larry J

2008-11-07

There is growing evidence that the neuropeptides oxytocin and vasopressin modulate complex social behavior and social cognition. These ancient neuropeptides display a marked conservation in gene structure and expression, yet diversity in the genetic regulation of their receptors seems to underlie natural variation in social behavior, both between and within species. Human studies are beginning to explore the roles of these neuropeptides in social cognition and behavior and suggest that variation in the genes encoding their receptors may contribute to variation in human social behavior by altering brain function. Understanding the neurobiology and neurogenetics of social cognition and behavior has important implications, both clinically and for society.

Molecular biology of hereditary diabetes insipidus.

PubMed

Fujiwara, T Mary; Bichet, Daniel G

2005-10-01

The identification, characterization, and mutational analysis of three different genes-the arginine vasopressin gene (AVP), the arginine vasopressin receptor 2 gene (AVPR2), and the vasopressin-sensitive water channel gene (aquaporin 2 [AQP2])-provide the basis for understanding of three different hereditary forms of "pure" diabetes insipidus: Neurohypophyseal diabetes insipidus, X-linked nephrogenic diabetes insipidus (NDI), and non-X-linked NDI, respectively. It is clinically useful to distinguish two types of hereditary NDI: A "pure" type characterized by loss of water only and a complex type characterized by loss of water and ions. Patients who have congenital NDI and bear mutations in the AVPR2 or AQP2 genes have a "pure" NDI phenotype with loss of water but normal conservation of sodium, potassium, chloride, and calcium. Patients who bear inactivating mutations in genes (SLC12A1, KCNJ1, CLCNKB, CLCNKA and CLCNKB in combination, or BSND) that encode the membrane proteins of the thick ascending limb of the loop of Henle have a complex polyuro-polydipsic syndrome with loss of water, sodium, chloride, calcium, magnesium, and potassium. These advances provide diagnostic and clinical tools for physicians who care for these patients.

A Novel Mutation of the Arginine Vasopressin Receptor 2 Gene in a Patient with Congenital Nephrogenic Diabetes Insipidus

PubMed Central

Tajima, Asako; Miyata, Ichiro; Katayama, Akira; Toyoda, Shigeru; Eto, Yoshikatsu

2005-01-01

We have identified a novel mutation of the arginine vasopressin receptor 2 (AVPR2) gene in a case of congenital X-linked nephrogenic diabetes insipidus (NDI). The patient was a 2-mo-old Japanese boy with persistent fever and failure to thrive. He was diagnosed as having congenital NDI by clinical and laboratory findings. Molecular analysis demonstrated that he was hemizygous for a G to C transversion in exon 2 of the AVPR2 gene which resulted in a glycine to arginine substitution (G107R) at the 107th codon of the first extracellular loop. His mother was heterozygous for the same mutation. We speculated that the G107R mutation would interfere with the binding capacity of the AVPR2, since G107R is located near F105 and R106, both of which are crucial for ligand binding. In cases of X-linked NDI, mutations in the AVPR2 gene are distributed widely. Thus, DNA analysis throughout the gene is of clinical value for the identification of female carriers, and it also gives precise information for genetic counseling. PMID:24790307

Epidemiology, pathophysiology and putative genetic basis of carbamazepine- and oxcarbazepine-induced hyponatremia.

PubMed

Berghuis, B; de Haan, G-J; van den Broek, M P H; Sander, J W; Lindhout, D; Koeleman, B P C

2016-09-01

The use of carbamazepine (CBZ) and oxcarbazepine (OXC) as first-line antiepileptic drugs in the treatment of focal epilepsy is limited by hyponatremia, a known adverse effect. Hyponatremia occurs in up to half of people taking CBZ or OXC and, although often assumed to be asymptomatic, it can lead to symptoms ranging from unsteadiness and mild confusion to seizures and coma. Hyponatremia is probably due to the antidiuretic properties of CBZ and OXC that are, at least partly, explained by stimulation of the vasopressin 2 receptor/aquaporin 2 pathway. No known genetic risk variants for CBZ- and OXC-induced hyponatremia exist, but likely candidate genes are part of the vasopressin water reabsorption pathway. © 2016 EAN.

Expression of a dominant negative PKA mutation in the kidney elicits a diabetes insipidus phenotype

PubMed Central

Gilbert, Merle L.; Yang, Linghai; Su, Thomas

2015-01-01

PKA plays a critical role in water excretion through regulation of the production and action of the antidiuretic hormone arginine vasopressin (AVP). The AVP prohormone is produced in the hypothalamus, where its transcription is regulated by cAMP. Once released into the circulation, AVP stimulates antidiuresis through activation of vasopressin 2 receptors in renal principal cells. Vasopressin 2 receptor activation increases cAMP and activates PKA, which, in turn, phosphorylates aquaporin (AQP)2, triggering apical membrane accumulation, increased collecting duct permeability, and water reabsorption. We used single-minded homolog 1 (Sim1)-Cre recombinase-mediated expression of a dominant negative PKA regulatory subunit (RIαB) to disrupt kinase activity in vivo and assess the role of PKA in fluid homeostasis. RIαB expression gave rise to marked polydipsia and polyuria; however, neither hypothalamic Avp mRNA expression nor urinary AVP levels were attenuated, indicating a primary physiological effect on the kidney. RIαB mice displayed a marked deficit in urinary concentrating ability and greatly reduced levels of AQP2 and phospho-AQP2. Dehydration induced Aqp2 mRNA in the kidney of both control and RIαB-expressing mice, but AQP2 protein levels were still reduced in RIαB-expressing mutants, and mice were unable to fully concentrate their urine and conserve water. We conclude that partial PKA inhibition in the kidney leads to posttranslational effects that reduce AQP2 protein levels and interfere with apical membrane localization. These findings demonstrate a distinct physiological role for PKA signaling in both short- and long-term regulation of AQP2 and characterize a novel mouse model of diabetes insipidus. PMID:25587115

Distribution of the Vasotocin Subtype Four Receptor (VT4R) in the Anterior Pituitary Gland of the Chicken, Gallus gallus, and its Possible Role in the Avian Stress Response.

PubMed

Selvam, R; Jurkevich, A; Kang, S W; Mikhailova, M V; Cornett, L E; Kuenzel, W J

2013-01-01

The neurohormone arginine vasotocin (AVT) in non mammalian vertebrates is homologous to arginine vasopressin (AVP) in mammals. Its actions are mediated via G protein-coupled receptors that belong to the vasotocin/mesotocin family. Because of the known regulatory effects of nonapeptide hormones on anterior pituitary functions, receptor subtypes in that family have been proposed to be located in anterior pituitary cells. Recently, an avian vasotocin receptor subtype designated VT4R has been cloned, which shares 69% sequence homology with a human vasopressin receptor, the V1aR. In the present study, a polyclonal antibody to the VT4R was developed and validated to confirm its specificity to the VT4R. The antibody was used to test the hypothesis that the VT4R is present in the avian anterior pituitary and is specifically associated with certain cell types, where its expression is modulated by acute stress. Western blotting of membrane protein extracts from pituitary tissue, the use of HeLa cells transfected with the VT4R and peptide competition assays all confirmed the specificity of the antibody to the VT4R. Dual-labelling immunofluorescence microscopy was utilised to identify pituitary cell types that contained immunoreactive VT4R. The receptor was found to be widely distributed throughout the cephalic lobe but not in the caudal lobe of the anterior pituitary. Immunoreactive VT4R was associated with corticotrophs. Approximately 89% of immunolabelled corticotrophs were shown to contain the VT4R. The immunoreactive VT4R was not found in gonadotrophs, somatotrophs or lactotrophs. To determine a possible functional role of the VT4R and previously characterised VT2R, gene expression levels in the anterior pituitary were determined after acute immobilisation stress by quantitative reverse transcriptase-polymerase chain reaction. The results showed a significant increase in plasma corticosterone levels (three- to four-fold), a significant reduction of VT4R mRNA and an increase of VT2R mRNA (P < 0.05) in acutely immobilised chicks compared to controls. The data suggest a role of the VT4R in the avian stress response. © 2012 British Society for Neuroendocrinology.

A large deletion of the AVPR2 gene causing severe nephrogenic diabetes insipidus in a Turkish family.

PubMed

Saglar, Emel; Deniz, Ferhat; Erdem, Beril; Karaduman, Tugce; Yönem, Arif; Cagiltay, Eylem; Mergen, Hatice

2014-05-01

X-linked nephrogenic diabetes insipidus (NDI) is a rare hereditary disease caused by mutations in arginine vasopressin type 2 receptor (AVPR2) and characterized by the production of large amounts of urine and an inability to concentrate urine in response to the antidiuretic hormone vasopressin. We have identified a novel 388 bp deletion starting in intron 1 and ending in exon 2 in the AVPR2 gene in a patient with NDI and in his family. We have revealed that this mutation is a de novo mutation for the mother of the proband patient. Prospective clinical data were collected for all family members. The water deprivation test confirmed the diagnosis of diabetes insipidus. The patient has severe symptoms like deep polyuria nocturia, polydipsia, and fatigue. He was given arginine vasopressin treatment while he was a child. However, he could not get well due to his nephrogenic type of illness. Both of his nephews have the same complains in addition to failure to grow. We have sequenced all exons and intron-exon boundaries of the AVPR2 gene of all family members. The analyses of bioinformatics and comparative genomics of the deletion were done via considering the DNA level damage. AVPR2 gene mutation results in the absence of the three transmembrane domains, two extracellular domains, and one cytoplasmic domain. Three-dimensional protein structure prediction was shown. We concluded that X-linked NDI and severity of illness in this family is caused by a novel 388 bp deletion in the AVPR2 gene that is predicted to truncate the receptor protein, and also this deletion may lead to dysfunctioning in protein activity and inefficient or inadequate binding abilities.

Potent and selective oxytocin receptor agonists without disulfide bridges.

PubMed

Adachi, Yusuke; Sakimura, Katsuya; Shimizu, Yuji; Nakayama, Masaharu; Terao, Yasuko; Yano, Takahiko; Asami, Taiji

2017-06-01

Oxytocin (OT) is a neuropeptide involved in a wide variety of physiological actions, both peripherally and centrally. Many human studies have revealed the potential of OT to treat autism spectrum disorders and schizophrenia. OT interacts with the OT receptor (OTR) as well as vasopressin 1a and 1b receptors (V 1a R, V 1b R) as an agonist, and agonistic activity for V 1a R and V 1b R may have a negative impact on the therapeutic effects of OTR agonism in the CNS. An OTR-selective agonistic peptide, FE 202767, in which the structural differences from OT are a sulfide bond instead of a disulfide bond, and N-alkylglycine replacement for Pro at position 7, was reported. However, the effects of amino acid substitutions in OT have not been comprehensively investigated to compare OTR, V 1a R, and V 1b R activities. This led us to obtain a new OTR-selective analog by comprehensive amino acid substitutions of OT and replacement of the disulfide bond. A systematic amino acid scanning (Ala, Leu, Phe, Ser, Glu, or Arg) of desamino OT (dOT) at positions 2, 3, 4, 5, 7, and 8 revealed the tolerability for the substitution at positions 7 and 8. Further detailed study showed that trans-4-hydroxyproline (trans-Hyp) at position 7 and γ-methylleucine [Leu(Me)] at position 8 were markedly effective for improving receptor selectivity without decreasing the potency at the OTR. Subsequently, a combination of these amino acid substitutions with the replacement of the disulfide bond of dOT analogs with a sulfide bond (carba analog) or an amide bond (lactam analog) yielded several promising analogs, including carba-1-[trans-Hyp 7 ,Leu(Me) 8 ]dOT (14) with a higher potency (7.2pM) at OTR than that of OT and marked selectivity (>10,000-fold) over V 1a R and V 1b R. Hence, we investigated comprehensive modification of OT and obtained new OT analogs that exhibited high potency at OTR with marked selectivity. These OTR-selective agonists could be useful to investigate OTR-mediated effects on psychiatric disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

Oxytocin and vasopressin: linking pituitary neuropeptides and their receptors to social neurocircuits

PubMed Central

Baribeau, Danielle A.; Anagnostou, Evdokia

2015-01-01

Oxytocin and vasopressin are pituitary neuropeptides that have been shown to affect social processes in mammals. There is growing interest in these molecules and their receptors as potential precipitants of, and/or treatments for, social deficits in neurodevelopmental disorders, including autism spectrum disorder. Numerous behavioral-genetic studies suggest that there is an association between these peptides and individual social abilities; however, an explanatory model that links hormonal activity at the receptor level to complex human behavior remains elusive. The following review summarizes the known associations between the oxytocin and vasopressin neuropeptide systems and social neurocircuits in the brain. Following a micro- to macro- level trajectory, current literature on the synthesis and secretion of these peptides, and the structure, function and distribution of their respective receptors is first surveyed. Next, current models regarding the mechanism of action of these peptides on microcircuitry and other neurotransmitter systems are discussed. Functional neuroimaging evidence on the acute effects of exogenous administration of these peptides on brain activity is then reviewed. Overall, a model in which the local neuromodulatory effects of pituitary neuropeptides on brainstem and basal forebrain regions strengthen signaling within social neurocircuits proves appealing. However, these findings are derived from animal models; more research is needed to clarify the relevance of these mechanisms to human behavior and treatment of social deficits in neuropsychiatric disorders. PMID:26441508

Oxytocin and vasopressin: linking pituitary neuropeptides and their receptors to social neurocircuits.

PubMed

Baribeau, Danielle A; Anagnostou, Evdokia

2015-01-01

Oxytocin and vasopressin are pituitary neuropeptides that have been shown to affect social processes in mammals. There is growing interest in these molecules and their receptors as potential precipitants of, and/or treatments for, social deficits in neurodevelopmental disorders, including autism spectrum disorder. Numerous behavioral-genetic studies suggest that there is an association between these peptides and individual social abilities; however, an explanatory model that links hormonal activity at the receptor level to complex human behavior remains elusive. The following review summarizes the known associations between the oxytocin and vasopressin neuropeptide systems and social neurocircuits in the brain. Following a micro- to macro- level trajectory, current literature on the synthesis and secretion of these peptides, and the structure, function and distribution of their respective receptors is first surveyed. Next, current models regarding the mechanism of action of these peptides on microcircuitry and other neurotransmitter systems are discussed. Functional neuroimaging evidence on the acute effects of exogenous administration of these peptides on brain activity is then reviewed. Overall, a model in which the local neuromodulatory effects of pituitary neuropeptides on brainstem and basal forebrain regions strengthen signaling within social neurocircuits proves appealing. However, these findings are derived from animal models; more research is needed to clarify the relevance of these mechanisms to human behavior and treatment of social deficits in neuropsychiatric disorders.

Functions of vasopressin and oxytocin in bone mass regulation

PubMed Central

Sun, Li; Tamma, Roberto; Yuen, Tony; Colaianni, Graziana; Ji, Yaoting; Cuscito, Concetta; Bailey, Jack; Dhawan, Samarth; Lu, Ping; Calvano, Cosima D.; Zhu, Ling-Ling; Zambonin, Carlo G.; Di Benedetto, Adriana; Stachnik, Agnes; Liu, Peng; Grano, Maria; Colucci, Silvia; Davies, Terry F.; New, Maria I.; Zallone, Alberta; Zaidi, Mone

2016-01-01

Prior studies show that oxytocin (Oxt) and vasopressin (Avp) have opposing actions on the skeleton exerted through high-affinity G protein-coupled receptors. We explored whether Avp and Oxtr can share their receptors in the regulation of bone formation by osteoblasts. We show that the Avp receptor 1α (Avpr1α) and the Oxt receptor (Oxtr) have opposing effects on bone mass: Oxtr−/− mice have osteopenia, and Avpr1α−/− mice display a high bone mass phenotype. More notably, this high bone mass phenotype is reversed by the deletion of Oxtr in Oxtr−/−:Avpr1α−/− double-mutant mice. However, although Oxtr is not indispensable for Avp action in inhibiting osteoblastogenesis and gene expression, Avp-stimulated gene expression is inhibited when the Oxtr is deleted in Avpr1α−/− cells. In contrast, Oxt does not interact with Avprs in vivo in a model of lactation-induced bone loss in which Oxt levels are high. Immunofluorescence microscopy of isolated nucleoplasts and Western blotting and MALDI-TOF of nuclear extracts show that Avp triggers Avpr1α localization to the nucleus. Finally, a specific Avpr2 inhibitor, tolvaptan, does not affect bone formation or bone mass, suggesting that Avpr2, which primarily functions in the kidney, does not have a significant role in bone remodeling. PMID:26699482

Vasopressin eliminates the expression of familiar odor bias in neonatal female mice through V1aR

PubMed Central

Hammock, Elizabeth A.D.; Law, Caitlin S.; Levitt, Pat

2014-01-01

Summary V1aR has a well established role in the neural regulation of adult mammalian social behavior. The role of V1aR in developmentally emerging social behavior is less well understood. We mapped V1aR at post-natal day 8 (P8) and demonstrate developmentally-specific expression in the neocortex and hippocampus. We tested the ability of male and female C57BL/6J mice to show orienting bias to a familiar odor at this age. We demonstrate that females, but not males, show an orienting bias for odors previously paired with the mother, which is eliminated by V1aR signaling. Arginine-vasopressin (AVP) and the vasopressin V1a receptor (V1aR) acting within the forebrain are involved in social behavior in adult animals. Much less is known about the function of V1aR in neurobehavioral development. In the present study, at post-natal day 8 (P8) in neonatal C57BL/6J mice, we map V1aR and use an olfactory exposure paradigm to assess a role for V1aR on olfactory preferences. In addition to V1aR in the lateral septum and ventral tegmental area, we observe V1aR in the neocortex and hippocampus, not typically observed in adult mice, implicating a developmental sensitive period for V1aR to modulate these brain areas in an experience-dependent manner. Males and females were tested on P8 for orienting preferences after exposure to a non-social odor, presented either when the mother was in the home cage (contingent) or when the mother had been removed from the home cage (not contingent). Wild-type female mice show a selective orienting bias toward the exposed odor, but only in the contingent condition. Males did not show orienting bias after either training condition. Female Avpr1a-/- mice showed strong familiar odor bias, regardless of the training condition. This finding led us to test the ability of AVP to diminish odor bias in females. Central application of AVP eliminated odor bias in Avpr1a+/+, but not Avpr1a-/- female mice. Together, these data indicate that AVP acting at V1aR eliminates the expression of familiar odor bias in neonatal mice. This suggests a developmental role for AVP on familiarity bias, which has implications for species-typical life history trajectories of social learning and natal dispersal. PMID:23261858

Effects of vasopressin on the isolated perfused human collecting tubule.

PubMed

Yanagawa, N; Trizna, W; Bar-Khayim, Y; Fine, L G

1981-05-01

Cortical collecting tubules (CCT) were dissected from the surviving normal tissue of human kidneys removed at operation for either carcinoma or calculus. These CCT's were perfused in vitro shortly after the nephrectomy was performed. Transtubular potential differences in different tubules varied from +3.2 to -2.0 mV and were reduced towards zero by lowering the temperature or by adding ouabain to the bath. In the absence of vasopressin, tubules were essentially impermeable to water with extremely low net water fluxes even in the presence of a transtubular osmotic gradient. Addition of vasopressin to the bath caused the transtubular osmotic water permeability coefficient to increase to values of 125, 175, and 155 X 10(-4) cm/sec in three tubules thus studied. These results demonstrate close similarities between the human CCT and the more extensively studied rabbit CCT.

Arginine-vasopressin directly promotes a thermogenic and pro-inflammatory adipokine expression profile in brown adipocytes.

PubMed

Küchler, Sebastian; Perwitz, Nina; Schick, Rafael Reinhold; Klein, Johannes; Westphal, Sören

2010-09-24

Arginine-vasopressin (AVP) - via activation of the hypothalamic-pituitary-adrenal (HPA) axis - may play a role in the regulation of energy homeostasis and related cardiovascular complications. Brown adipose tissue (BAT) - via dissipation of energy in the form of heat - contributes to whole body energy balance. BAT expresses vasopressin receptors. We investigated direct effects of AVP on brown adipose endocrine and metabolic functions. UCP-1 protein expression in differentiated brown adipocytes was induced after acute exposure of adipocytes to AVP. This effect was time-dependent with a maximum increase after 8h. AVP also induced a time- and dose-dependent increase in p38 MAP kinase phosphorylation. Pharmacological inhibition of p38 MAP kinase with SB 202190 abolished the induction of UCP-1 protein expression. Furthermore, while acute AVP treatment enhanced mRNA expression of MCP-1 and IL-6, adiponectin mRNA expression was reduced. Yet, on the level of intracellular glucose uptake, there was no AVP-induced change of adipose insulin-induced glucose uptake. Finally, there was no difference in lipid accumulation between control and AVP-treated cells. Taken together, our data demonstrate direct effects of AVP on thermogenic, inflammatory, and glucoregulatory gene expression in brown adipocytes, thus expanding the hitherto known spectrum of this neuropeptides's biological effects and suggesting a direct adipotropic role as a stress-promoting factor. Copyright 2010 Elsevier B.V. All rights reserved.

[Nocturnal polyuria, treatment with desmopressin].

PubMed

Zachoval, R; Krhut, J; Šottner, O; Hanuš, T; Martan, A; Horčička, L; Feyereisl, J; Halaška, M; Švabík, K; Krofta, L

2013-08-01

Nonpharmacologic and especially pharmacologic treatment options are available for nocturnal polyuria. Desmopressin represents the basis of pharmacologic treatment. Desmopressin acetate is a synthetic analogue of arginine vasopressin with high affinity to V2 receptors with antidiuretic effect. It is the only medicament currently registered for antidiuretic treatment. Desmopressin has not any relevant affinity to V1 receptors, and therefore there is no hypertensive effect in contrary to natural vasopressin. Desmopressin use before a bedtime leads to reduced production of urine during a sleep, therefore time between desires to void is prolonged and number of nocturia is reduced. Clinical effect, in a meaning of reduced urine production and increased osmolality of urine, lasts approximately 8-12 hours. In the treatment of nocturnal polyuria desmopressin is used orally one hour before a bedtime. It is essential to titrate an ideal dose, the initial dose is 60 µg of MELT formula (fast melting oral formulation) and it can be increased according to the clinical effect up to the maximal recommended daily dose 240 µg. Patients treated with desmopressin should cut down a fluid intake 1 hour before and 8 hours after the use of desmopressin. Total number of adverse events connected withdesmopressin treatment in clinical studies was higher compared to placebo but the side effects were mostly mild. The most common adverse events were headaches, nausea, diarrhoea, abdominal pain, dry mouth and hyponatremia both in the short-term and long-term clinical trials. Hyponatremia was observed mainly in patients over 65 year of age. Therefore treatment with desmopressin should not be commended in patients over 65 year of age without close monitoring of the natrium level in serum and all patients should be informed about the first symptoms of hyponatremia - headache, nausea and insomnia. According to Evidence Based Medicine, the level of evidence for treatment of nocturnal polyuria with desmopressin is 1b and the grade of recommendation for treatment is A. nocturnal polyuria - treatment - desmopressin.

Sex differences in the stress response in SD rats.

PubMed

Lu, Jing; Wu, Xue-Yan; Zhu, Qiong-Bin; Li, Jia; Shi, Li-Gen; Wu, Juan-Li; Zhang, Qi-Jun; Huang, Man-Li; Bao, Ai-Min

2015-05-01

Sex differences play an important role in depression, the basis of which is an excessive stress response. We aimed at revealing the neurobiological sex differences in the same study in acute- and chronically-stressed rats. Female Sprague-Dawley (SD) rats were randomly divided into 6 groups: chronic unpredictable mild stress (CUMS), acute foot shock (FS) and controls, animals in all 3 groups were sacrificed in proestrus or diestrus. Male SD rats were randomly divided into 3 groups: CUMS, FS and controls. Comparisons were made of behavioral changes in CUMS and control rats, plasma levels of corticosterone (CORT), testosterone (T) and estradiol (E2), and of the hypothalamic mRNA-expression of stress-related molecules, i.e. estrogen receptor α and β, androgen receptor, aromatase, mineralocorticoid receptor, glucocorticoid receptor, corticotropin-releasing hormone, arginine vasopressin and oxytocin. CUMS resulted in disordered estrus cycles, more behavioral and hypothalamic stress-related molecules changes and a stronger CORT response in female rats compared with male rats. Female rats also showed decreased E2 and T levels after FS and CUMS, while male FS rats showed increased E2 and male CUMS rats showed decreased T levels. Stress affects the behavioral, endocrine and the molecular response of the stress systems in the hypothalamus of SD rats in a clear sexual dimorphic way, which has parallels in human data on stress and depression. Copyright © 2015 Elsevier B.V. All rights reserved.

Combination decongestion therapy in hospitalized heart failure: loop diuretics, mineralocorticoid receptor antagonists and vasopressin antagonists.

PubMed

Vaduganathan, Muthiah; Mentz, Robert J; Greene, Stephen J; Senni, Michele; Sato, Naoki; Nodari, Savina; Butler, Javed; Gheorghiade, Mihai

2015-01-01

Congestion is the most common reason for admissions and readmissions for heart failure (HF). The vast majority of hospitalized HF patients appear to respond readily to loop diuretics, but available data suggest that a significant proportion are being discharged with persistent evidence of congestion. Although novel therapies targeting congestion should continue to be developed, currently available agents may be utilized more optimally to facilitate complete decongestion. The combination of loop diuretics, natriuretic doses of mineralocorticoid receptor antagonists and vasopressin antagonists represents a regimen of currently available therapies that affects early and persistent decongestion, while limiting the associated risks of electrolyte disturbances, hemodynamic fluctuations, renal dysfunction and mortality.

Vasopressin Receptor Signaling and Cycling of Water Channels in Renal Epithelia (HBC)

DTIC Science & Technology

1993-08-27

in the cellular ultrastructure that results in mucosal membrane reorganization to numerous microvilli from the normal phase of microridges ( DiBona ...a restructuring of the apical membrane microridges into numerous microvilli with an increase in membrane surface area ( DiBona , 1981; DiBona et aL...markers in freeze-fracture studies of toad urinary bladder. J. Histochem. Cytochem., 35, 1405-1414. DiBona , D.R. 1981. Vasopressin action on the

Methylphenidate-induced motor activity in rats: modulation by melatonin and vasopressin.

PubMed

Appenrodt, Edgar; Schwarzberg, Helmut

2003-04-01

Methylphenidate (MPH), a dopamine (DA) reuptake inhibitor, is well known to enhance motor activity, in part depending on the time of its application during the light-dark cycle. Moreover, after MPH administration, the hypothalamo-neurohypophysial axis including the neuropeptide vasopressin (AVP) was found influenced. Both the latter and behavioural effects of central AVP can also be modulated by the pineal gland with its light-dark-dependent activity. The present study was performed to investigate whether the pineal gland, its hormone melatonin (Mel), and AVP are involved in the MPH-evoked stimulation of activity. After application of 10 mg/kg MPH, the motor activity in pinealectomised (PE) rats was significantly higher than in sham-operated (SO) animals. After application of 250 microg Mel before MPH treatment, the stimulation of motor activity was diminished in PE rats and augmented in SO animals; however, when SO and PE rats were compared after Mel pretreatment, the reaction to MPH was nearly identical. Blocking the endogenous AVP by 25 or 1 microg of the V1a receptor antagonist d(CH(2))(5)[Tyr(Me)(2)]AVP (AAVP) before MPH treatment significantly augmented the motor activity in SO rats only and abolished the differences seen between SO and PE animals after MPH application. The present results indicate that the behavioural stimulation of MPH was modulated by both the pineal gland with its hormone Mel as well as the neuropeptide AVP.

Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism.

PubMed

Patrick, Rhonda P; Ames, Bruce N

2014-06-01

Serotonin and vitamin D have been proposed to play a role in autism; however, no causal mechanism has been established. Here, we present evidence that vitamin D hormone (calcitriol) activates the transcription of the serotonin-synthesizing gene tryptophan hydroxylase 2 (TPH2) in the brain at a vitamin D response element (VDRE) and represses the transcription of TPH1 in tissues outside the blood-brain barrier at a distinct VDRE. The proposed mechanism explains 4 major characteristics associated with autism: the low concentrations of serotonin in the brain and its elevated concentrations in tissues outside the blood-brain barrier; the low concentrations of the vitamin D hormone precursor 25-hydroxyvitamin D [25(OH)D3]; the high male prevalence of autism; and the presence of maternal antibodies against fetal brain tissue. Two peptide hormones, oxytocin and vasopressin, are also associated with autism and genes encoding the oxytocin-neurophysin I preproprotein, the oxytocin receptor, and the arginine vasopressin receptor contain VDREs for activation. Supplementation with vitamin D and tryptophan is a practical and affordable solution to help prevent autism and possibly ameliorate some symptoms of the disorder. © FASEB.

X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis.

PubMed Central

Bichet, D G; Arthus, M F; Lonergan, M; Hendy, G N; Paradis, A J; Fujiwara, T M; Morgan, K; Gregory, M C; Rosenthal, W; Didwania, A

1993-01-01

In X-linked nephrogenic diabetes insipidus (NDI) the urine of male patients is not concentrated after the administration of the antidiuretic hormone arginine-vasopressin. This disease is due to mutations in the V2 receptor gene that maps to chromosome region Xq28. In 1969, Bode and Crawford suggested that most NDI patients in North America shared common ancestors of Ulster Scot immigrants who arrived in Halifax in 1761 on the ship Hopewell. A link between this family and a large Utah kindred was also suggested. DNA was obtained from 17 affected male patients from the "Hopewell" kindred and from four additional families from Nova Scotia and New Brunswick who shared the same Xq28 NDI haplotype. The Utah kindred and two families (Q2, Q3) from Quebec were also studied. The "Hopewell" mutation, W71X, is a single base substitution (G-->A) that changes codon 71 from TGG (tryptophan) to TGA (stop). The W71X mutation was found in affected members of the Hopewell and of the four satellite families. The W71X mutation is the cause of X-linked NDI for the largest number of related male patients living in North America. Other families (Utah, Q2 and Q3) that are historically and ethnically unrelated bear other mutations in the V2 receptor gene. Images PMID:8104196

A Rare Case of Congenital Diabetes Insipidus

PubMed Central

Rege, Tanvi; Polsani, Srujana; Jim, Belinda

2015-01-01

Congenital nephrogenic diabetes insipidus (NDI) is a conformation disease resulting from protein misfolding. Ninety percent of mutations result from the inactivating mutations of the arginine vasopressin receptor 2 (AVPR2) gene transmitted in an X-linked fashion, blocking the response to vasopressin, resulting in the inability to concentrate urine. Clinical features include polyuria, polydispsia, dehydration, and hypernatremia. They are generally more severely in affected males but present variably in females due to skewed inactivation of the X chromosome. We describe a case of a 40-year-old woman with a history of Type 2 diabetes mellitus, hyperlipidemia, and obesity, who presents with debilitating polyuria since the age of 5 with no clear diagnosis. Interestingly, her son was diagnosed with NDI. Genetic testing revealed that she was heterozygous for the Val88Met mutation in the AVPR2 gene while her son was hemizygous for the same. The patient has since been successfully treated with diuretics and a low solute diet. We highlight that although X-linked NDI patients are mostly males, it should be considered in symptomatic females to prevent delays in the diagnosis. Conformational diseases such as NDI are presently the subject of research using pharmacological chaperones to restore proper receptor membrane localization and function. PMID:26217664

A Rare Case of Congenital Diabetes Insipidus.

PubMed

Rege, Tanvi; Polsani, Srujana; Jim, Belinda

2015-01-01

Congenital nephrogenic diabetes insipidus (NDI) is a conformation disease resulting from protein misfolding. Ninety percent of mutations result from the inactivating mutations of the arginine vasopressin receptor 2 (AVPR2) gene transmitted in an X-linked fashion, blocking the response to vasopressin, resulting in the inability to concentrate urine. Clinical features include polyuria, polydispsia, dehydration, and hypernatremia. They are generally more severely in affected males but present variably in females due to skewed inactivation of the X chromosome. We describe a case of a 40-year-old woman with a history of Type 2 diabetes mellitus, hyperlipidemia, and obesity, who presents with debilitating polyuria since the age of 5 with no clear diagnosis. Interestingly, her son was diagnosed with NDI. Genetic testing revealed that she was heterozygous for the Val88Met mutation in the AVPR2 gene while her son was hemizygous for the same. The patient has since been successfully treated with diuretics and a low solute diet. We highlight that although X-linked NDI patients are mostly males, it should be considered in symptomatic females to prevent delays in the diagnosis. Conformational diseases such as NDI are presently the subject of research using pharmacological chaperones to restore proper receptor membrane localization and function.

Signatures of positive selection in the cis-regulatory sequences of the human oxytocin receptor (OXTR) and arginine vasopressin receptor 1a (AVPR1A) genes.

PubMed

Schaschl, Helmut; Huber, Susanne; Schaefer, Katrin; Windhager, Sonja; Wallner, Bernard; Fieder, Martin

2015-05-13

The evolutionary highly conserved neurohypophyseal hormones oxytocin and arginine vasopressin play key roles in regulating social cognition and behaviours. The effects of these two peptides are meditated by their specific receptors, which are encoded by the oxytocin receptor (OXTR) and arginine vasopressin receptor 1a genes (AVPR1A), respectively. In several species, polymorphisms in these genes have been linked to various behavioural traits. Little, however, is known about whether positive selection acts on sequence variants in genes influencing variation in human behaviours. We identified, in both neuroreceptor genes, signatures of balancing selection in the cis-regulative acting sequences such as transcription factor binding and enhancer sequences, as well as in a transcriptional repressor sequence motif. Additionally, in the intron 3 of the OXTR gene, the SNP rs59190448 appears to be under positive directional selection. For rs59190448, only one phenotypical association is known so far, but it is in high LD' (>0.8) with loci of known association; i.e., variants associated with key pro-social behaviours and mental disorders in humans. Only for one SNP on the OXTR gene (rs59190448) was a sign of positive directional selection detected with all three methods of selection detection. For rs59190448, however, only one phenotypical association is known, but rs59190448 is in high LD' (>0.8), with variants associated with important pro-social behaviours and mental disorders in humans. We also detected various signatures of balancing selection on both neuroreceptor genes.

Autocrine feedback inhibition of plateau potentials terminates phasic bursts in magnocellular neurosecretory cells of the rat supraoptic nucleus

PubMed Central

Brown, Colin H; Bourque, Charles W

2004-01-01

Phasic activity in magnocellular neurosecretory cells is characterized by alternating periods of activity (bursts) and silence. During phasic bursts, action potentials are superimposed on plateau potentials that are generated by summation of depolarizing after-potentials. Dynorphin is copackaged in vasopressin neurosecretory vesicles that are exocytosed from magnocellular neurosecretory cell dendrites and terminals, and both peptides have been implicated in the generation of phasic activity. Here we show that somato-dendritic dynorphin release terminates phasic bursts by autocrine inhibition of plateau potentials in magnocellular neurosecretory cells recorded intracellularly from hypothalamic explants using sharp electrodes. Conditioning spike trains caused an activity-dependent reduction of depolarizing after-potential amplitude that was partially reversed by α-latrotoxin (which depletes neurosecretory vesicles) and by nor-binaltorphimine (κ-opioid receptor antagonist), but not by an oxytocin/vasopressin receptor antagonist or a μ-opioid receptor antagonist, indicating that activity-dependent inhibition of depolarizing after-potentials requires exocytosis of an endogenous κ-opioid peptide. κ-Opioid inhibition of depolarizing after-potentials was not mediated by actions on evoked after-hyperpolarizations since these were not affected by κ-opioid receptor agonists or antagonists. Evoked bursts were prolonged by antagonism of κ-opioid receptors with nor-binaltorphimine and by depletion of neurosecretory vesicles by α-latrotoxin, becoming everlasting in ∼50% of cells. Finally, spontaneously active neurones exposed to nor-binaltorphimine switched from phasic to continuous firing as plateau potentials became non-inactivating. Thus, dynorphin coreleased with vasopressin generates phasic activity through activity-dependent feedback inhibition of plateau potentials in magnocellular neurosecretory cells. PMID:15107473

Oxytocin (OT) and arginine-vasopressin (AVP) act on OT receptors and not AVP V1a receptors to enhance social recognition in adult Syrian hamsters (Mesocricetus auratus).

PubMed

Song, Zhimin; Larkin, Tony E; Malley, Maureen O'; Albers, H Elliott

2016-05-01

Social recognition is a fundamental requirement for all forms of social relationships. A majority of studies investigating the neural mechanisms underlying social recognition in rodents have investigated relatively neutral social stimuli such as juveniles or ovariectomized females over short time intervals (e.g., 2h). The present study developed a new testing model to study social recognition among adult males using a potent social stimulus. Flank gland odors are used extensively in social communication in Syrian hamsters and convey important information such as dominance status. We found that the recognition of flank gland odors after a 3min exposure lasted for at least 24h, substantially longer than the recognition of other social cues in rats and mice. Intracerebroventricular injections of OT and AVP prolonged the recognition of flank gland odor for up to 48h. Selective OTR but not V1aR agonists, mimicked these enhancing effects of OT and AVP. Similarly, selective OTR but not V1aR antagonists blocked recognition of the odors after 20min. In contrast, the recognition of non-social stimuli was not blocked by either the OTR or the V1aR antagonists. Our findings suggest both OT and AVP enhance social recognition via acting on OTRs and not V1aRs and that the recognition enhancing effects of OT and AVP are limited to social stimuli. Copyright © 2016 Elsevier Inc. All rights reserved.

Preclinical Efficacy of [V4Q5]dDAVP, a Second Generation Vasopressin Analog, on Metastatic Spread and Tumor-Associated Angiogenesis in Colorectal Cancer.

PubMed

Garona, Juan; Sobol, Natasha T; Pifano, Marina; Segatori, Valeria I; Gomez, Daniel E; Ripoll, Giselle V; Alonso, Daniel F

2018-06-01

Control of metastatic spread of colorectal cancer (CRC) remains as a major therapeutic challenge. [V4Q5]dDAVP is a vasopressin peptide analog with previously reported anticancer activity against carcinoma tumors. By acting as a selective agonist of AVPR2 present in endothelial and tumor cells, [V4Q5]dDAVP is able to impair tumor aggressiveness and distant spread. Our aim was to evaluate the potential therapeutic benefits of [V4Q5]dDAVP on highly aggressive CRC disease using experimental models with translational relevance. Murine CT-26 and human Colo-205 AVPR2-expressing CRC cell lines were used to test the preclinical efficacy of [V4Q5]dDAVP, both in vitro and in vivo. In syngeneic mice surgically implanted with CT-26 cells in the spleen, sustained i.v. treatment with [V4Q5]dDAVP (0.3 µg/kg) dramatically impaired metastatic progression to liver without overt signs of toxicity, and also reduced experimental lung colonization. The compound inhibited in vivo angiogenesis driven by Colo-205 cells in athymic mice, as well as in vitro endothelial cell migration and capillary tube formation. [V4Q5]dDAVP exerted AVPR2-dependent cytostatic activity in vitro (IC50 1.08 µM) and addition to 5-FU resulted in synergistic antiproliferative effects both in CT-26 and Colo-205 cells. The present preclinical study establishes for the first time the efficacy of [V4Q5]dDAVP on CRC. These encouraging results suggest that the novel second generation vasopressin analog could be used for the management of aggressive CRC as an adjuvant agent during surgery or to complement standard chemotherapy, limiting tumor angiogenesis and metastasis and thus protecting the patient from CRC recurrence.

Early life social stress induced changes in depression and anxiety associated neural pathways which are correlated with impaired maternal care.

PubMed

Murgatroyd, Christopher A; Peña, Catherine J; Podda, Giovanni; Nestler, Eric J; Nephew, Benjamin C

2015-08-01

Exposures to various types of early life stress can be robust predictors of the development of psychiatric disorders, including depression and anxiety. The objective of the current study was to investigate the roles of the translationally relevant targets of central vasopressin, oxytocin, ghrelin, orexin, glucocorticoid, and the brain-derived neurotrophic factor (BDNF) pathway in an early chronic social stress (ECSS) based rodent model of postpartum depression and anxiety. The present study reports novel changes in gene expression and extracellular signal related kinase (ERK) protein levels in the brains of ECSS exposed rat dams that display previously reported depressed maternal care and increased maternal anxiety. Decreases in oxytocin, orexin, and ERK proteins, increases in ghrelin receptor, glucocorticoid and mineralocorticoid receptor mRNA levels, and bidirectional changes in vasopressin underscore related work on the adverse long-term effects of early life stress on neural activity and plasticity, maternal behavior, responses to stress, and depression and anxiety-related behavior. The differences in gene and protein expression and robust correlations between expression and maternal care and anxiety support increased focus on these targets in animal and clinical studies of the adverse effects of early life stress, especially those focusing on depression and anxiety in mothers and the transgenerational effects of these disorders on offspring. Copyright © 2015 Elsevier B.V. All rights reserved.

Nephrogenic Diabetes Insipidus: Essential Insights into the Molecular Background and Potential Therapies for Treatment

PubMed Central

Rittig, Søren

2013-01-01

The water channel aquaporin-2 (AQP2), expressed in the kidney collecting ducts, plays a pivotal role in maintaining body water balance. The channel is regulated by the peptide hormone arginine vasopressin (AVP), which exerts its effects through the type 2 vasopressin receptor (AVPR2). Disrupted function or regulation of AQP2 or the AVPR2 results in nephrogenic diabetes insipidus (NDI), a common clinical condition of renal origin characterized by polydipsia and polyuria. Over several years, major research efforts have advanced our understanding of NDI at the genetic, cellular, molecular, and biological levels. NDI is commonly characterized as hereditary (congenital) NDI, arising from genetic mutations in the AVPR2 or AQP2; or acquired NDI, due to for exmple medical treatment or electrolyte disturbances. In this article, we provide a comprehensive overview of the genetic, cell biological, and pathophysiological causes of NDI, with emphasis on the congenital forms and the acquired forms arising from lithium and other drug therapies, acute and chronic renal failure, and disturbed levels of calcium and potassium. Additionally, we provide an overview of the exciting new treatment strategies that have been recently proposed for alleviating the symptoms of some forms of the disease and for bypassing G protein-coupled receptor signaling. PMID:23360744

Dehydration effects of a V2 antagonist on endolymphatic hydrops in guinea pigs.

PubMed

Egami, Naoya; Kakigi, Akinobu; Takeda, Taizo; Yamasoba, Tatsuya

2016-02-01

We investigated the influence of vasopressin type 2 receptor antagonist (OPC-41061; Tolvaptan) on experimentally induced endolymphatic hydrops (EH) in guinea pigs. In the first series, the endolymphatic sac (ES) of the left ear of all animals was electrocauterized. Four weeks after surgery, the animals were allocated to four groups: three systemic applications groups (saline, OPC 10 and 100 mg/kg) and a local round window (RW) OPC 1 mg/body application group. We examined the histopathology of the temporal bones and assessed volumetric changes of the endolymphatic space in the cochlea and saccule. In the second series, we investigated the effects of systemic and topical applications of OPC on plasma vasopressin (p-VP) concentrations and plasma osmolality (p-OSM). In the first series, we found that EH was reduced in the OPC 10 mg/kg systemic and OPC RW application groups. In contrast, EH increased in the OPC 100 mg/kg systemic application group. In the second series, neither p-VP levels nor p-OSM were significantly different among the non-OPC, OPC 10 mg/kg systemic, and OPC RW application groups. However, in the OPC 100 mg/kg systemic application group, the p-VP level was significantly higher than that in other groups, and p-OSM was higher than that in the non-OPC group. The systemic application of a low dose of OPC and topical application of OPC resulted in reduced EH in the face of minimal systemic effects (p-VP and p-OSM). These findings suggest that OPC-41061 may be one useful treatment option for EH. Copyright © 2015 Elsevier B.V. All rights reserved.

New aspects of firing pattern autocontrol in oxytocin and vasopressin neurones.

PubMed

Moos, F; Gouzènes, L; Brown, D; Dayanithi, G; Sabatier, N; Boissin, L; Rabié, A; Richard, P

1998-01-01

In the rat, oxytocin (OT) and vasopressin (AVP) neurones exhibit specific electrical activities which are controlled by OT and AVP released from soma and dendrites within the magnocellular hypothalamic nuclei. OT enhances amplitude and frequency of suckling-induced bursts, and changes basal firing characteristics: spike patterning becomes very irregular (spike clusters separated by long silences), firing rate is highly variable, oscillating before facilitated bursts. This unstable behaviour which markedly decreases during hyperosmotic stimulation (interrupting bursting) could be a prerequisite for bursting. The effects of AVP depend on the initial phasic pattern of AVP neurones: AVP excites weakly active neurones (increasing burst duration, decreasing silences) and inhibits highly active neurones; neurones with intermediate phasic activity are unaffected. Thus, AVP ensures all AVP neurones discharge with moderate phasic activity (bursts and silences lasting 20-40 s), known to optimise systemic AVP release. V1a-type receptors are involved in AVP actions. In conclusion, OT and AVP control their respective neurones in a complex manner to favour the patterns of activity which are the best suited for an efficient systemic hormone release.

Cardiovascular effects of substance P receptor stimulation in the ventrolateral medullary pressor and depressor areas.

PubMed

Urbanski, R W; Murugaian, J; Krieger, A J; Sapru, H N

1989-07-10

The pressor (VLPA) and the depressor (VLDA) areas in the ventrolateral medulla were identified with the microinjection of L-glutamate (1.77 nmol/site) in artificially ventilated urethane-anesthetized male Wistar rats. Bilateral microinjection of a stable substance P (SP) agonist [pGlu5, MePhe8, Sar9]-SP(5-11)], abbreviated as DiMe, into the VLPA (6-600 pmol/site) produced a dose-dependent increase in blood pressure (BP). The effects on heart rate (HR) were variable. Intravenous pretreatment with a ganglionic blocker chlorisondamine (3.0 mg/kg, i.v.), but not with a vasopressin antagonist, blocked these responses. Similar microinjection of DiMe (6-600 pmol/site) into the VLDA produced a dose-dependent decrease in HR but had no effect on BP levels. The DiMe-induced bradycardic response elicited from the VLDA was blocked by i.v. pretreatment with atropine methylbromide (0.5 mg/kg, i.v.). These findings indicate that there are SP receptors localized on sympathoexcitatory neurons in the VLPA and that SP may be an excitatory neurotransmitter in this area. In the VLDA, the SP receptors appear to be localized on a subpopulation of neurons that affect vagal, but not sympathetic, outflow to the heart.

Neural injury after use of vasopressin and adrenaline during porcine cardiopulmonary resuscitation.

PubMed

Halvorsen, Peter; Sharma, Hari Shanker; Basu, Samar; Wiklund, Lars

2015-03-01

Our aim was to investigate cerebral and cardiac tissue injury subsequent to use of vasopressin and adrenaline in combination compared with vasopressin alone during cardiopulmonary resuscitation (CPR). In a randomized, prospective, laboratory animal study 28 anesthetized piglets were subject to a 12-min untreated cardiac arrest and subsequent CPR. After 1 min of CPR, 10 of the piglets received 0.4 U/kg of arg(8)-vasopressin (V group), and 10 piglets received 0.4 U/kg of arg(8)-vasopressin, 1 min later followed by 20 µg/kg body weight of adrenaline, and another 1 min later continuous administration (10 µg/kg/min) of adrenaline (VA group). After 8 min of CPR, the piglets were defibrillated and monitored for another 3 h. Then they were killed and the brain immediately removed pending histological analysis. During CPR, the VA group had higher mean blood pressure and cerebral cortical blood flow (CCBF) but similar coronary perfusion pressure. After restoration of spontaneous circulation there was no difference in the pressure variables, but CCBF tended to be (36% ± 16%) higher in the V group. Neuronal injury and signs of a disrupted blood-brain barrier (BBB) were greater, 20% ± 4% and 21% ± 4%, respectively, in the VA group. In a background study of repeated single doses of adrenaline every third minute after 5 min arrest but otherwise the same protocol, histological measurements showed even worse neural injury and disruption of the BBB. Combined use of vasopressin and adrenaline caused greater signs of cerebral and cardiac injury than use of vasopressin alone during experimental cardiopulmonary resuscitation.

Pairing Increases Activation of V1aR, but not OTR, in Auditory Regions of Zebra Finches: The Importance of Signal Modality in Nonapeptide-Social Behavior Relationships.

PubMed

Tomaszycki, Michelle L; Atchley, Derek

2017-10-01

Social relationships are complex, involving the production and comprehension of signals, individual recognition, and close coordination of behavior between two or more individuals. The nonapeptides oxytocin and vasopressin are widely believed to regulate social relationships. These findings come largely from prairie voles, in which nonapeptide receptors in olfactory neural circuits drive pair bonding. This research is assumed to apply to all species. Previous reviews have offered two competing hypotheses. The work of Sarah Newman has implicated a common neural network across species, the Social Behavior Network. In contrast, others have suggested that there are signal modality-specific networks that regulate social behavior. Our research focuses on evaluating these two competing hypotheses in the zebra finch, a species that relies heavily on vocal/auditory signals for communication, specifically the neural circuits underlying singing in males and song perception in females. We have demonstrated that the quality of vocal interactions is highly important for the formation of long-term monogamous bonds in zebra finches. Qualitative evidence at first suggests that nonapeptide receptor distributions are very different between monogamous rodents (olfactory species) and monogamous birds (vocal/auditory species). However, we have demonstrated that social bonding behaviors are not only correlated with activation of nonapeptide receptors in vocal and auditory circuits, but also involve regions of the common Social Behavior Network. Here, we show increased Vasopressin 1a receptor, but not oxytocin receptor, activation in two auditory regions following formation of a pair bond. To our knowledge, this is the first study to suggest a role of nonapeptides in the auditory circuit in pair bonding. Thus, we highlight converging mechanisms of social relationships and also point to the importance of studying multiple species to understand mechanisms of behavior. © The Author 2017. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.

Reduced vasopressin receptors activation mediates the anti-depressant effects of fluoxetine and venlafaxine in bulbectomy model of depression.

PubMed

Poretti, María Belén; Sawant, Rahul S; Rask-Andersen, Mathias; de Cuneo, Marta Fiol; Schiöth, Helgi B; Perez, Mariela F; Carlini, Valeria Paola

2016-03-01

In response to stress, corticotropin releasing hormone (CRH) and vasopressin (AVP) are released from the hypothalamus, activate their receptors (CRHR1, CRHR2 or AVPr1b), and synergistically act to induce adrenocorticotropic hormone (ACTH) release from the anterior pituitary. Overstimulation of this system has been frequently associated with major depression states. The objective of the study is to assess the role of AVP and CRH receptors in fluoxetine and venlafaxine effects on the expression of depression-related behavior. In an animal model of depression (olfactory bulbectomy in mice, OB), we evaluated the effects of fluoxetine or venlafaxine (both 10 mg/kg/day) chronic administration on depression-related behavior in the tail suspension test. Plasma levels of AVP, CRH, and ACTH were determined as well as participation of their receptors in the expression of depression related-behavior and gene expression of AVP and CRH receptors (AVPr1b, CRHR1, and CRHR2) in the pituitary gland. The expression of depressive-like behavior in OB animals was reversed by treatment with both antidepressants. Surprisingly, OB-saline mice exhibited increased AVP and ACTH plasma levels, with no alterations in CRH levels when compared to sham mice. Chronic fluoxetine or venlafaxine reversed these effects. In addition, a significant increase only in AVPr1b gene expression was found in OB-saline. The antidepressant therapy used seems to be more likely related to a reduced activation of AVP rather than CRH receptors, since a positive correlation between AVP levels and depressive-like behavior was observed in OB animals. Furthermore, a full restoration of depressive behavior was observed in OB-fluoxetine- or venlafaxine-treated mice only when AVP was centrally administered but not CRH.

Polymorphism at the avpr1a locus in male prairie voles correlated with genetic but not social monogamy in field populations.

PubMed

Solomon, N G; Richmond, A R; Harding, P A; Fries, A; Jacquemin, S; Schaefer, R L; Lucia, K E; Keane, B

2009-11-01

Integrative studies of genetics, neurobiology and behaviour indicate that polymorphism in specific genes contributes to variation observed in some complex social behaviours. The neuropeptide arginine vasopressin plays an important role in the regulation of a variety of social behaviours, including social attachment of males to females, through its action on the vasopressin 1a receptor (V1aR). In socially monogamous prairie voles (Microtus ochrogaster), polymorphism in the length of microsatellite DNA within the regulatory region of the gene (avpr1a) encoding the V1aR predicts differences among males in neural expression of V1aRs and partner preference under laboratory conditions. However, understanding the extent to which V1aR mediates variation in prairie vole social and reproductive behaviour observed in nature requires investigating the consequences of avpr1a polymorphism and environmental influences under ecologically relevant conditions. We examined the relationship between avpr1a length polymorphism and monogamy among male prairie voles living in 0.1 ha enclosures during a time similar to their natural lifespan. We found no evidence that avpr1a genotype of males predicts variation in social monogamy measured in the field but some indices of social monogamy were affected by population density. Parentage data indicated that a male's avpr1a genotype significantly influenced the number of females with which he sired offspring and the total number of offspring sired. Total brain concentrations of V1aR mRNA were not associated with either male behaviour or avpr1a genotype. These data show that melding ecological field studies with neurogenetics can substantially augment our understanding of the effects of genes and environment on social behaviours.

Simultaneous Anterior and Posterior Serosal Mapping of Gastric Slow Wave Dysrhythmias Induced by Vasopressin

PubMed Central

Du, Peng; O'Grady, Greg; Paskaranandavadivel, Niranchan; Tang, Shou-jiang; Abell, Thomas; Cheng, Leo K

2016-01-01

Background High-resolution (HR) mapping enables mechanistic insights into gastric slow wave dysrhythmias and is now achieving clinical translation. However, previous studies have focused mainly on dysrhythmias occurring on the anterior gastric wall. The present study simultaneously mapped the anterior and posterior gastric serosa during episodes of dysrhythmias induced by vasopressin to aid understanding of dysrhythmia initiation, maintenance and termination.. Methods HR mapping (8×16 electrodes on each serosa; 20-74 cm2) was performed in anesthetized subjects. Baseline recordings (21±8 min) were followed by intravenous vasopressin infusion (0.1-0.5 IU/mL at 60-190 mL/hour) and further recordings (22±13 min). Slow wave activation maps, amplitudes, velocity, interval, and frequency were calculated, and differences compared between baseline and post-infusion. Results All subjects demonstrated and increased prevalence of dysrhythmic events following infusion of vasopressin (17% vs 51%).Both amplitude and velocity demonstrated significant differences (baseline vs. post-infusion: 3.6 vs. 2.2 mV; 7.7 vs. 6.5 mm s−1; P < 0.05 for both). Dysrhythmias occurred simultaneously or independently on anterior and posterior serosa, and then interacted according to frequency dynamics. A number of persistent dysrhythmias were compared, including: ectopic activation (n=2 subjects), conduction block (n=1), rotor (n=2), retrograde (n=3), collision/merge of wavefronts (n=2). Conclusions Infusion of vasopressin induces gastric dysrhythmias, which occurred across a heterogeneous range of frequencies and patterns. The results demonstrated that different classes of gastric dysrhythmias may arise simultaneously or independently in one or both surfaces of the serosa, then interact according to their relative frequencies. These results will help inform clinical dysrhythmia interpretations. PMID:27265885

SR-121463. Sanofi-Synthélabo.

PubMed

Martinez-Castelao, A

2001-10-01

Sanofi-Synthélabo (formerly Sanofi) is developing SR-121463, a vasopressin V, receptor antagonist, as a potential treatment for cardiovascular indications such as congestive heart failure (CHF) and hypertension [330073], [341858]. By September 2001, it had entered phase IIa trials for these indications [421268]. SR-121463 was in phase I clinical trials for CHF and hypertension in June 2001 [359231], [413342]. It was also being evaluated for the potential treatment of glaucoma but its development has been discontinued for this indication [367094]. In October 1999, Lehman Brothers predicted a 5% chance of the compound reaching market, with a launch anticipated in 2004 and potential peak sales of $100 million in 2012 [346267].

Use of LC-MS/MS and Bayes' theorem to identify protein kinases that phosphorylate aquaporin-2 at Ser256.

PubMed

Bradford, Davis; Raghuram, Viswanathan; Wilson, Justin L L; Chou, Chung-Lin; Hoffert, Jason D; Knepper, Mark A; Pisitkun, Trairak

2014-07-15

In the renal collecting duct, binding of AVP to the V2 receptor triggers signaling changes that regulate osmotic water transport. Short-term regulation of water transport is dependent on vasopressin-induced phosphorylation of aquaporin-2 (AQP2) at Ser256. The protein kinase that phosphorylates this site is not known. We use Bayes' theorem to rank all 521 rat protein kinases with regard to the likelihood of a role in Ser256 phosphorylation on the basis of prior data and new experimental data. First, prior probabilities were estimated from previous transcriptomic and proteomic profiling data, kinase substrate specificity data, and evidence for kinase regulation by vasopressin. This ranking was updated using new experimental data describing the effects of several small-molecule kinase inhibitors with known inhibitory spectra (H-89, KN-62, KN-93, and GSK-650394) on AQP2 phosphorylation at Ser256 in inner medullary collecting duct suspensions. The top-ranked kinase was Ca2+/calmodulin-dependent protein kinase II (CAMK2), followed by protein kinase A (PKA) and protein kinase B (AKT). Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based in vitro phosphorylation studies compared the ability of three highly ranked kinases to phosphorylate AQP2 and other inner medullary collecting duct proteins, PKA, CAMK2, and serum/glucocorticoid-regulated kinase (SGK). All three proved capable of phosphorylating AQP2 at Ser256, although CAMK2 and PKA were more potent than SGK. The in vitro phosphorylation experiments also identified candidate protein kinases for several additional phosphoproteins with likely roles in collecting duct regulation, including Nedd4-2, Map4k4, and 3-phosphoinositide-dependent protein kinase 1. We conclude that Bayes' theorem is an effective means of integrating data from multiple data sets in physiology.

Oxytocin, vasopressin and estrogen receptor gene expression in relation to social recognition in female mice

PubMed Central

Clipperton-Allen, Amy E.; Lee, Anna W.; Reyes, Anny; Devidze, Nino; Phan, Anna; Pfaff, Donald W.; Choleris, Elena

2012-01-01

Inter- and intra-species differences in social behavior and recognition-related hormones and receptors suggest that different distribution and/or expression patterns may relate to social recognition. We used qRT-PCR to investigate naturally occurring differences in expression of estrogen receptor-alpha (ERα), ER-beta (ERβ), progesterone receptor (PR), oxytocin (OT) and receptor, and vasopressin (AVP) and receptors in proestrous female mice. Following four 5 min exposures to the same two conspecifics, one was replaced with a novel mouse in the final trial (T5). Gene expression was examined in mice showing high (85–100%) and low (40–60%) social recognition scores (i.e., preferential novel mouse investigation in T5) in eight socially-relevant brain regions. Results supported OT and AVP involvement in social recognition, and suggest that in the medial preoptic area, increased OT and AVP mRNA, together with ERα and ERβ gene activation, relate to improved social recognition. Initial social investigation correlated with ERs, PR and OTR in the dorsolateral septum, suggesting that these receptors may modulate social interest without affecting social recognition. Finally, increased lateral amygdala gene activation in the LR mice may be associated with general learning impairments, while decreased lateral amygdala activity may indicate more efficient cognitive mechanisms in the HR mice. PMID:22079582

Neural injury after use of vasopressin and adrenaline during porcine cardiopulmonary resuscitation

PubMed Central

Halvorsen, Peter; Sharma, Hari Shanker; Basu, Samar

2015-01-01

Background Our aim was to investigate cerebral and cardiac tissue injury subsequent to use of vasopressin and adrenaline in combination compared with vasopressin alone during cardiopulmonary resuscitation (CPR). Methods In a randomized, prospective, laboratory animal study 28 anesthetized piglets were subject to a 12-min untreated cardiac arrest and subsequent CPR. After 1 min of CPR, 10 of the piglets received 0.4 U/kg of arg8-vasopressin (V group), and 10 piglets received 0.4 U/kg of arg8-vasopressin, 1 min later followed by 20 µg/kg body weight of adrenaline, and another 1 min later continuous administration (10 µg/kg/min) of adrenaline (VA group). After 8 min of CPR, the piglets were defibrillated and monitored for another 3 h. Then they were killed and the brain immediately removed pending histological analysis. Results During CPR, the VA group had higher mean blood pressure and cerebral cortical blood flow (CCBF) but similar coronary perfusion pressure. After restoration of spontaneous circulation there was no difference in the pressure variables, but CCBF tended to be (36% ± 16%) higher in the V group. Neuronal injury and signs of a disrupted blood–brain barrier (BBB) were greater, 20% ± 4% and 21% ± 4%, respectively, in the VA group. In a background study of repeated single doses of adrenaline every third minute after 5 min arrest but otherwise the same protocol, histological measurements showed even worse neural injury and disruption of the BBB. Conclusion Combined use of vasopressin and adrenaline caused greater signs of cerebral and cardiac injury than use of vasopressin alone during experimental cardiopulmonary resuscitation. PMID:25645317

Vasopressin excites interneurons to suppress hippocampal network activity across a broad span of brain maturity at birth

PubMed Central

Spoljaric, Albert; Seja, Patricia; Spoljaric, Inkeri; Virtanen, Mari A.; Lindfors, Jenna; Uvarov, Pavel; Summanen, Milla; Crow, Ailey K.; Hsueh, Brian; Puskarjov, Martin; Ruusuvuori, Eva; Voipio, Juha; Deisseroth, Karl; Kaila, Kai

2017-01-01

During birth in mammals, a pronounced surge of fetal peripheral stress hormones takes place to promote survival in the transition to the extrauterine environment. However, it is not known whether the hormonal signaling involves central pathways with direct protective effects on the perinatal brain. Here, we show that arginine vasopressin specifically activates interneurons to suppress spontaneous network events in the perinatal hippocampus. Experiments done on the altricial rat and precocial guinea pig neonate demonstrated that the effect of vasopressin is not dependent on the level of maturation (depolarizing vs. hyperpolarizing) of postsynaptic GABAA receptor actions. Thus, the fetal mammalian brain is equipped with an evolutionarily conserved mechanism well-suited to suppress energetically expensive correlated network events under conditions of reduced oxygen supply at birth. PMID:29183979

Interaction between vasopressin and angiotensin II in vivo and in vitro: effect on aquaporins and urine concentration

PubMed Central

Wang, Weidong; Li, Chunling; Summer, Sandra; Falk, Sandor

2010-01-01

The study was undertaken to examine the potential cross talk between vasopressin and angiotensin II (ANG II) intracellular signaling pathways. We investigated in vivo and in vitro whether vasopressin-induced water reabsorption could be attenuated by ANG II AT1 receptor blockade (losartan). On a low-sodium diet (0.5 meq/day) dDAVP-treated animals with or without losartan exhibited comparable renal function [creatinine clearance 1.2 ± 0.1 in dDAVP+losartan (LSDL) vs. 1.1 ± 0.1 ml·100 g−1·day−1 in dDAVP alone (LSD), P > 0.05] and renal blood flow (6.3 ± 0.5 in LSDL vs. 6.8 ± 0.5 ml/min in LSD, P > 0.05). The urine output, however, was significantly increased in LSDL (2.5 ± 0.2 vs. 1.8 ± 0.2 ml·100 g−1·day−1, P < 0.05) in association with decreased urine osmolality (2,600 ± 83 vs. 3,256 ± 110 mosmol/kgH2O, P < 0.001) compared with rats in LSD. Immunoblotting revealed significantly decreased expression of medullary AQP2 (146 ± 6 vs. 176 ± 10% in LSD, P < 0.01), p-AQP2 (177 ± 13 vs. 214 ± 12% in LSD, P < 0.05), and AQP3 (134 ± 14 vs. 177 ± 11% in LSD, P < 0.05) in LSDL compared with LSD. The expressions of AQP1, the α1- and γ-subunits of Na-K-ATPase, and the Na-K-2Cl cotransporter were not different among groups. In vitro studies showed that ANG II or dDAVP treatment was associated with increased AQP2 expression and cAMP levels, which were potentiated by cotreatment with ANG II and dDAVP and were inhibited by AT1 blockade. In conclusion, ANG II AT1 receptor blockade in dDAVP-treated rats on a low-salt diet was associated with decreased urine concentration and decreased inner medullary AQP2, p-AQP2, and AQP3 expression, suggesting that AT1 receptor activation plays a significant role in regulating aquaporin expression and modulating urine concentration in vivo. Studies in collecting duct cells were confirmatory. PMID:20576679

Vasopressin, cortisol, and catecholamine concentrations in dogs with dilated cardiomyopathy.

PubMed

Tidholm, Anna; Häggström, Jens; Hansson, Kerstin

2005-10-01

To evaluate plasma concentrations and urinary excretion of vasopressin and cortisol and urinary excretion of catecholamines in dogs with dilated cardiomyopathy (DCM). 15 dogs with clinical signs of DCM, 15 dogs with preclinical DCM, and 15 control dogs. Physical examinations, thoracic radiography, ECG, and echocardiography were performed on all dogs. Blood and urine samples were collected. Plasma concentration of vasopressin and the urine cortisol-to-urine creatinine ratio were significantly increased in dogs with clinical signs of DCM and dogs with preclinical DCM, compared with control dogs. Plasma vasopressin concentration was significantly higher in dogs with clinical signs of DCM, compared with dogs with preclinical DCM. Urine vasopressin-to-urine creatinine ratio was significantly increased in dogs with clinical signs of DCM, compared with dogs with preclinical DCM and control dogs. Urine epinephrine-to-urine creatinine ratio and urine norepinephrine-to-urine creatinine ratio were significantly increased in dogs with clinical signs of DCM, compared with control dogs. Plasma concentration of cortisol and urine dopamine-to-urine creatinine ratio did not differ significantly among groups. According to this study, the neuroendocrine pattern is changed in dogs with preclinical DCM. These changes are even more pronounced in dogs with clinical signs of DCM. Analysis of concentrations of vasopressin, cortisol, and catecholamines may aid in identification of the clinical stages of DCM. These findings may also provide a basis for additional studies of the possible beneficial effects of vasopressin antagonists and beta-adrenergic receptor antagonists in the treatment of dogs with congestive heart failure and DCM.

Congenital nephrogenic diabetes insipidus: the current state of affairs.

PubMed

Wesche, Daniel; Deen, Peter M T; Knoers, Nine V A M

2012-12-01

The anti-diuretic hormone arginine vasopressin (AVP) is released from the pituitary upon hypovolemia or hypernatremia, and regulates water reabsorption in the renal collecting duct principal cells. Binding of AVP to the arginine vasopressin receptor type 2 (AVPR2) in the basolateral membrane leads to translocation of aquaporin 2 (AQP2) water channels to the apical membrane of the collecting duct principal cells, inducing water permeability of the membrane. This results in water reabsorption from the pro-urine into the medullary interstitium following an osmotic gradient. Congenital nephrogenic diabetes insipidus (NDI) is a disorder associated with mutations in either the AVPR2 or AQP2 gene, causing the inability of patients to concentrate their pro-urine, which leads to a high risk of dehydration. This review focuses on the current knowledge regarding the cell biological aspects of congenital X-linked, autosomal-recessive and autosomal-dominant NDI while specifically addressing the latest developments in the field. Based on deepened mechanistic understanding, new therapeutic strategies are currently being explored, which we also discuss here.

Hyaluronan Production by Renomedullary Interstitial Cells: Influence of Endothelin, Angiotensin II and Vasopressin

PubMed Central

Palm, Fredrik; Takahashi, Tomoko; Ikegami-Kawai, Mayumi; Friederich-Persson, Malou; Hansell, Peter

2017-01-01

The content of hyaluronan (HA) in the interstitium of the renal medulla changes in relation to body hydration status. We investigated if hormones of central importance for body fluid homeostasis affect HA production by renomedullary interstitial cells in culture (RMICs). Simultaneous treatment with vasopressin and angiotensin II (Ang II) reduced HA by 69%. No change occurred in the mRNA expressions of hyaluronan synthase 2 (HAS2) or hyaluronidases (Hyals), while Hyal activity in the supernatant increased by 67% and CD44 expression reduced by 42%. The autocoid endothelin (ET-1) at low concentrations (10−10 and 10−8 M) increased HA 3-fold. On the contrary, at a high concentration (10−6 M) ET-1 reduced HA by 47%. The ET-A receptor antagonist BQ123 not only reversed the reducing effect of high ET-1 on HA, but elevated it to the same level as low concentration ET-1, suggesting separate regulating roles for ET-A and ET-B receptors. This was corroborated by the addition of ET-B receptor antagonist BQ788 to low concentration ET-1, which abolished the HA increase. HAS2 and Hyal2 mRNA did not alter, while Hyal1 mRNA was increased at all ET-1 concentrations tested. Hyal activity was elevated the most by high ET-1 concentration, and blockade of ET-A receptors by BQ123 prevented about 30% of this response. The present study demonstrates an important regulatory influence of hormones involved in body fluid balance on HA handling by RMICs, thereby supporting the concept of a dynamic involvement of interstitial HA in renal fluid handling. PMID:29236055

Nutritional State-Dependent Ghrelin Activation of Vasopressin Neurons via Retrograde Trans-Neuronal–Glial Stimulation of Excitatory GABA Circuits

PubMed Central

Haam, Juhee; Halmos, Katalin C.; Di, Shi

2014-01-01

Behavioral and physiological coupling between energy balance and fluid homeostasis is critical for survival. The orexigenic hormone ghrelin has been shown to stimulate the secretion of the osmoregulatory hormone vasopressin (VP), linking nutritional status to the control of blood osmolality, although the mechanism of this systemic crosstalk is unknown. Here, we show using electrophysiological recordings and calcium imaging in rat brain slices that ghrelin stimulates VP neurons in the hypothalamic paraventricular nucleus (PVN) in a nutritional state-dependent manner by activating an excitatory GABAergic synaptic input via a retrograde neuronal–glial circuit. In slices from fasted rats, ghrelin activation of a postsynaptic ghrelin receptor, the growth hormone secretagogue receptor type 1a (GHS-R1a), in VP neurons caused the dendritic release of VP, which stimulated astrocytes to release the gliotransmitter adenosine triphosphate (ATP). ATP activation of P2X receptors excited presynaptic GABA neurons to increase GABA release, which was excitatory to the VP neurons. This trans-neuronal–glial retrograde circuit activated by ghrelin provides an alternative means of stimulation of VP release and represents a novel mechanism of neuronal control by local neuronal–glial circuits. It also provides a potential cellular mechanism for the physiological integration of energy and fluid homeostasis. PMID:24790191

Variation in Mothers’ Arginine Vasopressin Receptor 1a and Dopamine Receptor D4 Genes Predict Maternal Sensitivity via Social Cognition

PubMed Central

Leerkes, Esther M.; Su, Jinni; Calkins, Susan; Henrich, Vincent C.; Smolen, Andrew

2016-01-01

We examined the extent to which the arginine vasopressin receptor 1a (AVPR1a) and dopamine receptor d4 (DRD4) were related to sensitive maternal behavior directly or indirectly via maternal social cognition. Participants were 207 (105 European American, 102 African American) mothers and their children (52% female). Sensitive maternal behavior was rated and aggregated across a series of tasks when infants were 6 months, 1 year, and 2 years old. At 6 months, mothers were interviewed about their empathy, attributions about infant behavior, and beliefs about crying to assess their parenting-related social cognition. Mothers with long alleles for AVPR1a and DRD4 engaged in more mother-oriented social cognition (i.e., negative attributions and beliefs about their infants’ crying), β = .13, p < .05 and β = .16, p < .05, respectively, which in turn predicted less sensitive maternal behavior, β = −.23, p < .01. Both indirect effects were statistically significant independent of one another and covariates; 95% CI [−.22, −.03] and β = −.03 for AVPR; 95% CI [−.20, −.03] and β = −.04 for DRD4. There were no significant direct effects of AVPR1a or DRD4 on maternal sensitivity, β = .02, ns and β = −.10, ns, respectively. The results did not vary for African American and European American mothers (Δχ2 = 18.76, Δdf = 16, p = .28). Results support the view that one mechanism by which maternal genes are associated with parental behavior is via social cognition. PMID:27581946

Genotypic differences in intruder-evoked immediate early gene activation in male, but not female, vasopressin 1b receptor knockout mice.

PubMed

Witchey, Shannah K; Stevenson, Erica L; Caldwell, Heather K

2016-11-24

The neuropeptide arginine vasopressin (Avp) modulates social behaviors via its two centrally expressed receptors, the Avp 1a receptor and the Avp 1b receptor (Avpr1b). Recent work suggests that, at least in mice, Avp signaling through Avpr1b within the CA2 region of the hippocampus is critical for normal aggressive behaviors and social recognition memory. However, this brain area is just one part of a larger neural circuit that is likely to be impacted in Avpr1b knockout (-/-) mice. To identify other brain areas that are affected by altered Avpr1b signaling, genotypic differences in immediate early gene activation, i.e. c-FOS and early growth response factor 1 (EGR-1), were quantified using immunocytochemistry following a single exposure to an intruder. In females, no genotypic differences in intruder-evoked c-FOS or EGR-1 immunoreactivity were observed in any of the brain areas measured. In males, while there were no intruder-evoked genotypic differences in c-FOS immunoreactivity, genotypic differences were observed in EGR-1 immunoreactivity within the ventral bed nucleus of the stria terminalis and the anterior hypothalamus; with Avpr1b -/- males having less EGR-1 immunoreactivity in these regions than controls. These data are the first to identify specific brain areas that may be a part of a neural circuit that includes Avpr1b-expressing cells in the CA2 region of the hippocampus. It is thought that this circuit, when working properly, plays a role in how an animal evaluates its social context.

Trichostatin A (TSA) facilitates formation of partner preference in male prairie voles (Microtus ochrogaster).

PubMed

Duclot, F; Wang, H; Youssef, C; Liu, Y; Wang, Z; Kabbaj, M

2016-05-01

In the socially monogamous prairie voles (Microtus ochrogaster), the development of a social bonding is indicated by the formation of partner preference, which involves a variety of environmental and neurochemical factors and brain structures. In a most recent study in female prairie voles, we found that treatment with the histone deacetylase inhibitor trichostatin A (TSA) facilitates the formation of partner preference through up-regulation of oxytocin receptor (OTR) and vasopressin V1a receptor (V1aR) genes expression in the nucleus accumbens (NAcc). In the present study, we tested the hypothesis that TSA treatment also facilitates partner preference formation and alters OTR and V1aR genes expression in the NAcc in male prairie voles. We thus observed that central injection of TSA dose-dependently promoted the formation of partner preference in the absence of mating in male prairie voles. Interestingly, TSA treatment up-regulated OTR, but not V1aR, gene expression in the NAcc similarly as they were affected by mating - an essential process for naturally occurring partner preference. These data, together with others, not only indicate the involvement of epigenetic events but also the potential role of NAcc oxytocin in the regulation of partner preference in both male and female prairie voles. Copyright © 2016 Elsevier Inc. All rights reserved.

Profound and Rapid Reduction in Body Temperature Induced by the Melanocortin Receptor Agonists

PubMed Central

Xu, Yuanzhong; Kim, Eun Ran; Fan, Shengjie; Xia, Yan; Xu, Yong; Huang, Cheng; Tong, Qingchun

2014-01-01

The melanocortin receptor 4 (MC4R) plays a major role in body weight regulation and its agonist MTII has been widely used to study the role of MC4Rs in energy expenditure promotion and feeding reduction. Unexpectedly, we observed that intraperitoneal (i.p.) administration of MTII induced a rapid reduction in both body temperature and energy expenditure, which was independent of its effect on feeding and followed by a prolonged increase in energy expenditure. The rapid reduction was at least partly mediated by brain neurons since intracerebroventricular (icv) administration of alpha melanocyte-stimulating hormone, an endogenous melanocortin receptor agonist, produced a similar response. In addition, the body temperature-lowering effect of MTII was independent of the presence of MC4Rs, but in a similar fashion to the previously shown effect on body temperature by 5′AMP. Moreover, β-adrenergic receptors (β-ARs) were required for the recovery from low body temperature induced by MTII and further pharmacological studies showed that the MTII’s effect on body temperature may be partially mediated by the vasopressin V1a receptors. Collectively, our results reveal a previously unappreciated role for the melanocortin pathway in rapidly lowering body temperature. PMID:25065745

Membrane Protein Stability Analyses by Means of Protein Energy Profiles in Case of Nephrogenic Diabetes Insipidus

PubMed Central

Heinke, Florian; Labudde, Dirk

2012-01-01

Diabetes insipidus (DI) is a rare endocrine, inheritable disorder with low incidences in an estimated one per 25,000–30,000 live births. This disease is characterized by polyuria and compensatory polydypsia. The diverse underlying causes of DI can be central defects, in which no functional arginine vasopressin (AVP) is released from the pituitary or can be a result of defects in the kidney (nephrogenic DI, NDI). NDI is a disorder in which patients are unable to concentrate their urine despite the presence of AVP. This antidiuretic hormone regulates the process of water reabsorption from the prourine that is formed in the kidney. It binds to its type-2 receptor (V2R) in the kidney induces a cAMP-driven cascade, which leads to the insertion of aquaporin-2 water channels into the apical membrane. Mutations in the genes of V2R and aquaporin-2 often lead to NDI. We investigated a structure model of V2R in its bound and unbound state regarding protein stability using a novel protein energy profile approach. Furthermore, these techniques were applied to the wild-type and selected mutations of aquaporin-2. We show that our results correspond well to experimental water ux analysis, which confirms the applicability of our theoretical approach to equivalent problems. PMID:22474537

Vasopressin function in familial cranial diabetes insipidus.

PubMed Central

Baylis, P. H.; Robertson, G. L.

1981-01-01

A family suffering from cranial diabetes insipidus, that extends over 4 generations, is described. Inheritance of polyuria was autosomal dominant. Vasopressin function was studied in members of the last 2 generations, 4 of whom had polyuria. Osmoregulation of vasopressin secretion was assessed by infusion of hypertonic saline. Plasma vasopressin remained undetectable in one patient, while 2 others had very blunted vasopressin responses to osmotic stimulation. Three non-osmotic stimuli were applied. Controlled hypotension produced by trimetaphan infusion and insulin-induced hypoglycaemia did not increase plasma vasopressin but apomorphine-induced nausea caused a minimal rise in plasma vasopressin to 0.7 pg/ml. Polyuria and thirst resolved with antidiuretic therapy in all patients studied. Congenital absence of vasopressin as in Brattleboro rats is unlikely to account for diabetes insipidus in this disorder since small increases in vasopressin have been demonstrated in these patients. In view of previous post-mortem findings, familial cranial diabetes insipidus is most likely to be due to degeneration of vasopressin-synthesizing neurones. PMID:7279821

Genes Related to Oxytocin and Arginine-Vasopressin Pathways: Associations with Autism Spectrum Disorders.

PubMed

Zhang, Rong; Zhang, Hong-Feng; Han, Ji-Sheng; Han, Song-Ping

2017-04-01

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorders characterized by impaired social interactions, communication deficits, and repetitive behavior. Although the mechanisms underlying its etiology and manifestations are poorly understood, several lines of evidence from rodent and human studies suggest involvement of the evolutionarily highly-conserved oxytocin (OXT) and arginine-vasopressin (AVP), as these neuropeptides modulate various aspects of mammalian social behavior. As far as we know, there is no comprehensive review of the roles of the OXT and AVP systems in the development of ASD from the genetic aspect. In this review, we summarize the current knowledge regarding associations between ASD and single-nucleotide variants of the human OXT-AVP pathway genes OXT, AVP, AVP receptor 1a (AVPR1a), OXT receptor (OXTR), the oxytocinase/vasopressinase (LNPEP), and ADP-ribosyl cyclase (CD38).

GABAergic inhibition through synergistic astrocytic neuronal interaction transiently decreases vasopressin neuronal activity during hypoosmotic challenge.

PubMed

Wang, Yu-Feng; Sun, Min-Yu; Hou, Qiuling; Hamilton, Kathryn A

2013-04-01

The neuropeptide vasopressin is crucial to mammalian osmotic regulation. Local hypoosmotic challenge transiently decreases and then increases vasopressin secretion. To investigate mechanisms underlying this transient response, we examined the effects of hypoosmotic challenge on the electrical activity of rat hypothalamic supraoptic nucleus (SON) vasopressin neurons using patch-clamp recordings. We found that 5 min exposure of hypothalamic slices to hypoosmotic solution transiently increased inhibitory postsynaptic current (IPSC) frequency and reduced the firing rate of vasopressin neurons. Recovery occurred by 10 min of exposure, even though the osmolality remained low. The γ-aminobutyric acid (GABA)A receptor blocker, gabazine, blocked the IPSCs and the hypoosmotic suppression of firing. The gliotoxin l-aminoadipic acid blocked the increase in IPSC frequency at 5 min and the recovery of firing at 10 min, indicating astrocytic involvement in hypoosmotic modulation of vasopressin neuronal activity. Moreover, β-alanine, an osmolyte of astrocytes and GABA transporter (GAT) inhibitor, blocked the increase in IPSC frequency at 5 min of hypoosmotic challenge. Confocal microscopy of immunostained SON sections revealed that astrocytes and magnocellular neurons both showed positive staining of vesicular GATs (VGAT). Hypoosmotic stimulation in vivo reduced the number of VGAT-expressing neurons, and increased co-localisation and molecular association of VGAT with glial fibrillary acidic protein that increased significantly by 10 min. By 30 min, neuronal VGAT labelling was partially restored, and astrocytic VGAT was relocated to the ventral portion while it decreased in the somatic zone of the SON. Thus, synergistic astrocytic and neuronal GABAergic inhibition could ensure that vasopressin neuron firing is only transiently suppressed under hypoosmotic conditions. © 2013 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Developmental effects of vasotocin and nonapeptide receptors on early social attachment and affiliative behavior in the zebra finch.

PubMed

Baran, Nicole M; Sklar, Nathan C; Adkins-Regan, Elizabeth

2016-02-01

Zebra finches demonstrate selective affiliation between juvenile offspring and parents, which, like affiliation between pair partners, is characterized by proximity, vocal communication and contact behaviors. This experiment tested the hypothesis that the nonapeptide arginine vasotocin (AVT, avian homologue of vasopressin) and nonapeptide receptors play a role prior to fledging in the development of affiliative behavior. Zebra finch hatchlings of both sexes received daily intracranial injections (post-hatch days 2-8) of either AVT, Manning Compound (MC, a potent V1a receptor antagonist) or saline (vehicle control). The social development of both sexes was assessed by measuring responsiveness to isolation from the family and subsequent reunion with the male parent after fledging. In addition, we assessed the changes in affiliation with the parents, unfamiliar males, and unfamiliar females each week throughout juvenile development. Compared to controls, MC subjects showed decreased attachment to the parents and MC males did not show the normal increase in affiliative interest in opposite sex individuals as they reached reproductive maturity. In contrast, AVT subjects showed a sustained affiliative interest in parents throughout development, and males showed increased interest in opposite sex conspecifics as they matured. These results provide the first evidence suggesting that AVT and nonapeptide receptors play organizational roles in social development in a bird. Copyright © 2015 Elsevier Inc. All rights reserved.

Oxytocin, vasopressin and estrogen receptor gene expression in relation to social recognition in female mice.

PubMed

Clipperton-Allen, Amy E; Lee, Anna W; Reyes, Anny; Devidze, Nino; Phan, Anna; Pfaff, Donald W; Choleris, Elena

2012-02-28

Inter- and intra-species differences in social behavior and recognition-related hormones and receptors suggest that different distribution and/or expression patterns may relate to social recognition. We used qRT-PCR to investigate naturally occurring differences in expression of estrogen receptor-alpha (ERα), ER-beta (ERβ), progesterone receptor (PR), oxytocin (OT) and receptor, and vasopressin (AVP) and receptors in proestrous female mice. Following four 5 min exposures to the same two conspecifics, one was replaced with a novel mouse in the final trial (T5). Gene expression was examined in mice showing high (85-100%) and low (40-60%) social recognition scores (i.e., preferential novel mouse investigation in T5) in eight socially-relevant brain regions. Results supported OT and AVP involvement in social recognition, and suggest that in the medial preoptic area, increased OT and AVP mRNA, together with ERα and ERβ gene activation, relate to improved social recognition. Initial social investigation correlated with ERs, PR and OTR in the dorsolateral septum, suggesting that these receptors may modulate social interest without affecting social recognition. Finally, increased lateral amygdala gene activation in the LR mice may be associated with general learning impairments, while decreased lateral amygdala activity may indicate more efficient cognitive mechanisms in the HR mice. Copyright © 2011 Elsevier Inc. All rights reserved.

The Septic Shock 3.0 Definition and Trials: A Vasopressin and Septic Shock Trial Experience.

PubMed

Russell, James A; Lee, Terry; Singer, Joel; Boyd, John H; Walley, Keith R

2017-06-01

The Septic Shock 3.0 definition could alter treatment comparisons in randomized controlled trials in septic shock. Our first hypothesis was that the vasopressin versus norepinephrine comparison and 28-day mortality of patients with Septic Shock 3.0 definition (lactate > 2 mmol/L) differ from vasopressin versus norepinephrine and mortality in Vasopressin and Septic Shock Trial. Our second hypothesis was that there are differences in plasma cytokine levels in Vasopressin and Septic Shock Trial for lactate less than or equal to 2 versus greater than 2 mmol/L. Retrospective analysis of randomized controlled trial. Multicenter ICUs. We compared vasopressin-to-norepinephrine group 28- and 90-day mortality in Vasopressin and Septic Shock Trial in lactate subgroups. We measured 39 cytokines to compare patients with lactate less than or equal to 2 versus greater than 2 mmol/L. Patients with septic shock with lactate greater than 2 mmol/L or less than or equal to 2 mmol/L, randomized to vasopressin or norepinephrine. Concealed vasopressin (0.03 U/min.) or norepinephrine infusions. The Septic Shock 3.0 definition would have decreased sample size by about half. The 28- and 90-day mortality rates were 10-12 % higher than the original Vasopressin and Septic Shock Trial mortality. There was a significantly (p = 0.028) lower mortality with vasopressin versus norepinephrine in lactate less than or equal to 2 mmol/L but no difference between treatment groups in lactate greater than 2 mmol/L. Nearly all cytokine levels were significantly higher in patients with lactate greater than 2 versus less than or equal to 2 mmol/L. The Septic Shock 3.0 definition decreased sample size by half and increased 28-day mortality rates by about 10%. Vasopressin lowered mortality versus norepinephrine if lactate was less than or equal to 2 mmol/L. Patients had higher plasma cytokines in lactate greater than 2 versus less than or equal to 2 mmol/L, a brisker cytokine response to infection. The Septic Shock 3.0 definition and our findings have important implications for trial design in septic shock.

Milrinone and esmolol decrease cardiac damage after resuscitation from prolonged cardiac arrest.

PubMed

Zoerner, F; Lennmyr, F; Wiklund, L; Martijn, C; Semenas, E

2015-04-01

Long-term survival after cardiac arrest (CA) due to shock-refractory ventricular fibrillation (VF) is low. Clearly, there is a need for new pharmacological interventions in the setting of cardiopulmonary resuscitation (CPR) to improve outcome. Here, hemodynamic parameters and cardiac damage are compared between the treatment group (milrinone, esmolol and vasopressin) and controls (vasopressin only) during resuscitation from prolonged CA in piglets. A total of 26 immature male piglets were subjected to 12-min VF followed by 8-min CPR. The treatment group (n=13) received i.v. (intravenous) boluses vasopressin 0.4 U/kg, esmolol 250 μg/kg and milrinone 25 μg/kg after 13 min, followed by i.v. boluses esmolol 375 μg/kg and milrinone 25 μg/kg after 18 min and continuous esmolol 15 μg/kg/h infusion during 180 min reperfusion, whereas controls (n=13) received equal amounts of vasopressin and saline. A 200 J monophasic counter-shock was delivered to achieve resumption of spontaneous circulation (ROSC) after 8 min CPR. If ROSC was not achieved, another 200 J defibrillation and bolus vasopressin 0.4 U/kg would be administered in both groups. Direct current shocks at 360 J were applied as one shot per minute over maximally 5 min. Hemodynamic variables and troponin I as a marker of cardiac injury were recorded. Troponin I levels after 180 min reperfusion were lower in the treatment group than in controls (P<0.05). The treatment group received less norepinephrine (P<0.01) and had greater diuresis (P<0.01). There was no difference in survival between groups. The combination of milrinone, esmolol and vasopressin decreased cardiac injury compared with vasopressin alone. © 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Effectiveness and adverse events of tolvaptan in octogenarians with heart failure. Interim analyses of Samsca Post-Marketing Surveillance In Heart faiLurE (SMILE study).

PubMed

Kinugawa, Koichiro; Inomata, Takayuki; Sato, Naoki; Yasuda, Moriyoshi; Shimakawa, Toshiyuki; Bando, Kosuke; Mizuguchi, Kazuki

2015-01-01

The vasopressin receptor 2 (V2) receptor antagonist tolvaptan is an aquaretic agent that has been found to improve symptoms in patients with congestive heart failure. In this study (SMILE study), we administered tolvaptan to patients aged ≥ 80 years with heart failure accompanied by congestive symptoms and compared its effectiveness and safety profiles in this group with those in patients < 80 years (U-80). The results showed that the effectiveness of tolvaptan in the aged patients was similar to that in U-80 patients. In the safety profile, the incidence rate of thirst was lower in the aged patients than that in U-80 patients (9.6% versus 11.6%, P = 0.0023). Furthermore, the incidence of hypernatremia, defined as ≥ 150 mEq/L in aged patients, was comparable with that in U-80 patients (2.9% versus 3.6%, respectively, P = 0.3657). Based on these findings, tolvaptan has similar effectiveness and safety profiles in aged patients compared with U-80 patients. In addition, we found that a higher starting dose of tolvaptan was markedly associated with the occurrence of hypernatremia exclusively in the aged population; therefore, we recommend that tolvaptan should be started at lower doses in aged patients.

Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: a neurobehavioral model of autism.

PubMed

Sala, Mariaelvina; Braida, Daniela; Lentini, Daniela; Busnelli, Marta; Bulgheroni, Elisabetta; Capurro, Valeria; Finardi, Annamaria; Donzelli, Andrea; Pattini, Linda; Rubino, Tiziana; Parolaro, Daniela; Nishimori, Katsuhiko; Parenti, Marco; Chini, Bice

2011-05-01

Oxytocin (OT) has been suggested as a treatment to improve social behavior in autistic patients. Accordingly, the OT (Oxt(-/-)) and the OT receptor null mice (Oxtr(-/-)) display autistic-like deficits in social behavior, increased aggression, and reduced ultrasonic vocalization. Oxtr(-/-) mice were characterized for general health, sociability, social novelty, cognitive flexibility, aggression, and seizure susceptibility. Because vasopressin (AVP) and OT cooperate in controlling social behavior, learning, and aggression, they were tested for possible rescue of the impaired behaviors. Primary hyppocampal cultures from Oxtr(+/+) and Oxtr(-/-) mouse embryos were established to investigate the balance between gamma-aminobutyric acid (GABA) and glutamate synapses and the expression levels of OT and AVP (V1a) receptors were determined by autoradiography. Oxtr(-/-) mice display two additional, highly relevant, phenotypic characteristics: 1) a resistance to change in a learned pattern of behavior, comparable to restricted interests and repetitive behavior in autism, and 2) an increased susceptibility to seizures, a frequent and clinically relevant symptom of autism. We also show that intracerebral administration of both OT and AVP lowers aggression and fully reverts social and learning defects by acting on V1a receptors and that seizure susceptibility is antagonized by peripherally administered OT. Finally, we detect a decreased ratio of GABA-ergic versus total presynapses in hippocampal neurons of Oxtr(-/-) mice. Autistic-like symptoms are rescued on administration of AVP and OT to young Oxtr(-/-) adult animals. The Oxtr(-/-) mouse is thus instrumental to investigate the neurochemical and synaptic abnormalities underlying autistic-like disturbances and to test new strategies of pharmacologic intervention. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Endothelin and vasopressin influence splanchnic blood flow distribution during and after cardiopulmonary bypass.

PubMed

Bomberg, Hagen; Bierbach, Benjamin; Flache, Stephan; Wagner, Isabell; Gläser, Lena; Groesdonk, Heinrich V; Menger, Michael D; Schäfers, Hans-Joachim

2013-02-01

Gastrointestinal blood flow can be compromised during and after cardiopulmonary bypass. Endothelin has been shown to be involved in the intestinal microcirculatory disturbance of sepsis. The aim of the present study was to analyze the involvement of the endothelin system on intestinal blood flow regulation during cardiopulmonary bypass and the effect of vasopressin given during cardiopulmonary bypass. A total of 24 pigs were studied in 4 groups (n = 6): group I, sham; group II, ischemia/reperfusion with 1 hour of superior mesenteric artery occlusion; group III, cardiopulmonary bypass for 1 hour; and group IV, 1 hour of cardiopulmonary bypass plus vasopressin administration, maintaining the baseline arterial pressure. All the pigs were reperfused for 90 minutes. During the experiment, the hemodynamics and jejunal microcirculation were measured continuously. The jejunal mucosal expression of endothelin-1 and its receptor subtypes A and B were determined using polymerase chain reaction. During cardiopulmonary bypass, superior mesenteric artery flow was preserved but marked jejunal microvascular impairment occurred compared with baseline (mucosal capillary density, 192.2 ± 5.4 vs 150.8 ± 5.1 cm/cm(2); P = .005; tissue blood flow, 501.7 ± 39.3 vs 332.3 ± 27.9 AU; P = .025). The expression of endothelin-1 after cardiopulmonary bypass (3.2 ± 0.4 vs 12.2 ± 0.8 RQ, P = .006) and endothelin subtype A (0.7 ± 0.2 vs 2.4 ± 0.6 RQ; P = .01) was significantly increased compared to the sham group. Vasopressin administration during cardiopulmonary bypass led to normal capillary density (189.9 ± 3.9 vs 178.0 ± 6.3; P = .1) and tissue blood flow (501.7 ± 39.3 vs 494.7 ± 44.4 AU; P = .4) compared with baseline. The expression of endothelin-1 (3.2 ± 0.4 vs 1.8 ± 0.3 RQ; P = .3) and endothelin subtype A (0.7 ± 0.2 vs 0.9 ± 0.2 RQ; P = .5) was not different from the sham group. Cardiopulmonary bypass leads to microvascular impairment of jejunal microcirculation, which is associated with the upregulation of endothelin-1 and endothelin subtype A. The administration of vasopressin minimizes these cardiopulmonary bypass-associated alterations. Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Stabilizing selection on microsatellite allele length at arginine vasopressin 1a receptor and oxytocin receptor loci

PubMed Central

Kallio, Eva R.; Koskela, Esa; Lonn, Eija

2017-01-01

The loci arginine vasopressin receptor 1a (avpr1a) and oxytocin receptor (oxtr) have evolutionarily conserved roles in vertebrate social and sexual behaviour. Allelic variation at a microsatellite locus in the 5′ regulatory region of these genes is associated with fitness in the bank vole Myodes glareolus. Given the low frequency of long and short alleles at these microsatellite loci in wild bank voles, we used breeding trials to determine whether selection acts against long and short alleles. Female bank voles with intermediate length avpr1a alleles had the highest probability of breeding, while male voles whose avpr1a alleles were very different in length had reduced probability of breeding. Moreover, there was a significant interaction between male and female oxtr genotypes, where potential breeding pairs with dissimilar length alleles had reduced probability of breeding. These data show how genetic variation at microsatellite loci associated with avpr1a and oxtr is associated with fitness, and highlight complex patterns of selection at these loci. More widely, these data show how stabilizing selection might act on allele length frequency distributions at gene-associated microsatellite loci. PMID:29237850

Human maternal behaviour is associated with arginine vasopressin receptor 1A gene.

PubMed

Avinun, Reut; Ebstein, Richard P; Knafo, Ariel

2012-10-23

Parenting is one of the main influences on children's early development, and yet its underlying genetic mechanisms have only recently begun to be explored, with many studies neglecting to control for possible child effects. This study focuses on maternal behaviour and on an allele at the RS3 promoter region of the arginine vasopressin receptor 1A (AVPR1A) gene, previously associated with autism and with higher amygdala activation in a face-matching task. Mothers were observed during a free-play session with each of their 3.5-year-old twins. Multilevel regression analyses revealed that mothers who are carriers of the AVPR1A RS3 allele tend to show less structuring and support throughout the interaction independent of the child's sex and RS3 genotype. This finding advances our understanding of the genetic influences on human maternal behaviour.

Tolvaptan for the treatment of liver cirrhosis oedema.

PubMed

Sakaida, Isao

2014-07-01

No alternative therapeutic option exists if liver cirrhosis patients have insufficient response to conventional diuretics and/or experience conventional diuretic-related adverse events. In 2013, tolvaptan (7.5 mg/day), an arginine vasopressin V2 receptor antagonist, was approved in Japan for the treatment of liver cirrhosis with oedema. Short-term use of tolvaptan produced decreases in body weight, reduction in ascites volume and increases in urine volume when compared to placebo, despite the use of conventional diuretics. Additionally, approximately 60% of patients with oedema-related symptoms improved. Low-dose tolvaptan, 3.75 mg, was also efficacious. Even in patients with low serum albumin (<2.5 g/dL), decrease in body weight was greater with tolvaptan than with placebo. For future research, the efficacy and safety of lower tolvaptan doses for the treatment of liver cirrhosis patients with oedema should be confirmed in Japan. The results of this research could be used as an indicator or a guideline for physicians around the world.

A history of diabetes insipidus: paving the road to internal water balance.

PubMed

Eknoyan, Garabed

2010-12-01

Diabetes insipidus is an ancient disease considered under the rubric of diabetes, the Greek descriptive term for polyuria, which was unrecognized even after the sweetness of urine was reported as a characteristic of diabetes mellitus in the 17th century. It would be another century before diabetes insipidus was identified from the insipid rather than saccharine taste of urine in cases of polyuria. After its increased recognition, pathologic observations and experimental studies connected diabetes insipidus to the pituitary gland in the opening decades of the 20th century. Simultaneously, posterior pituitary lobe extracts were shown to be vasoconstrictive (vasopressin) and antidiuretic (antidiuretic hormone). As vasopressin was purified and synthesized and its assay became available, it was shown to be released in response to both osmotic and volume stimuli that are integrated in the hypothalamus, and vasopressin thereby was essential to maintaining internal water balance. The antidiuretic properties of vasopressin to treat the rare cases of diabetes insipidus were of limited clinical utility until its vasoconstrictive effects were resuscitated in the 1970s, with the consequent increasing wider use of vasopressin for the treatment of compromised hemodynamic states. In addition, the discovery of antidiuretic hormone receptor blockers has led to their increasing use in managing hypo-osmolar states. Copyright © 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

A novel AVPR2 gene mutation of X-linked congenital nephrogenic diabetes insipidus in an Asian pedigree

PubMed Central

Guo, Wei-Hong; Li, Qiang; Wei, Hong-Yan; Lu, Hong-Yan; Qu, Hui-Qi

2016-01-01

Polyuria and polydipsia are the characteristics of congenital nephrogenic diabetes insipidus (CNDI). Approximately 90% of all patients with CNDI have X-linked hereditary disease, which is due to a mutation of the arginine vasopressin receptor 2 (AVPR2) gene. This case report describes a 54-year-old male with polyuria and polydipsia and several male members of his pedigree who had the same symptoms. The proband was diagnosed with diabetes insipidus using a water-deprivation and arginine vasopressin stimulation test. Genomic DNA from the patient and his family members was extracted and the AVPR2 gene was sequenced. A novel missense mutation of a cytosine to guanine transition at position 972 (c.972C > G) was found, which resulted in the substitution of isoleucine for methionine at amino acid position 324 (p.I324M) in the seventh transmembrane domain of the protein. The proband’s mother and daughter were heterozygous for this mutation. The novel mutation of the AVPR2 gene further broadens the phenotypic spectrum of the AVPR2 gene. PMID:27565746

A novel AVPR2 gene mutation of X-linked congenital nephrogenic diabetes insipidus in an Asian pedigree.

PubMed

Guo, Wei-Hong; Li, Qiang; Wei, Hong-Yan; Lu, Hong-Yan; Qu, Hui-Qi; Zhu, Mei

2016-10-01

Polyuria and polydipsia are the characteristics of congenital nephrogenic diabetes insipidus (CNDI). Approximately 90% of all patients with CNDI have X-linked hereditary disease, which is due to a mutation of the arginine vasopressin receptor 2 ( AVPR2) gene. This case report describes a 54-year-old male with polyuria and polydipsia and several male members of his pedigree who had the same symptoms. The proband was diagnosed with diabetes insipidus using a water-deprivation and arginine vasopressin stimulation test. Genomic DNA from the patient and his family members was extracted and the AVPR2 gene was sequenced. A novel missense mutation of a cytosine to guanine transition at position 972 (c.972C > G) was found, which resulted in the substitution of isoleucine for methionine at amino acid position 324 (p.I324M) in the seventh transmembrane domain of the protein. The proband's mother and daughter were heterozygous for this mutation. The novel mutation of the AVPR2 gene further broadens the phenotypic spectrum of the AVPR2 gene.

Interplay of oxytocin, vasopressin, and sex hormones in the regulation of social recognition.

PubMed

Gabor, Christopher S; Phan, Anna; Clipperton-Allen, Amy E; Kavaliers, Martin; Choleris, Elena

2012-02-01

Social Recognition is a fundamental skill that forms the basis of behaviors essential to the proper functioning of pair or group living in most social species. We review here various neurobiological and genetic studies that point to an interplay of oxytocin (OT), arginine-vasopressin (AVP), and the gonadal hormones, estrogens and testosterone, in the mediation of social recognition. Results of a number of studies have shown that OT and its actions at the medial amygdala seem to be essential for social recognition in both sexes. Estrogens facilitate social recognition, possibly by regulating OT production in the hypothalamus and the OT receptors at the medial amygdala. Estrogens also affect social recognition on a rapid time scale, likely through nongenomic actions. The mechanisms of these rapid effects are currently unknown but available evidence points at the hippocampus as the possible site of action. Male rodents seem to be more dependent on AVP acting at the level of the lateral septum for social recognition than female rodents. Results of various studies suggest that testosterone and its metabolites (including estradiol) influence social recognition in males primarily through the AVP V1a receptor. Overall, it appears that gonadal hormone modulation of OT and AVP regulates and fine tunes social recognition and those behaviors that depend upon it (e.g., social bonds, social hierarchies) in a sex specific manner. This points at an important role for these neuroendocrine systems in the regulation of the sex differences that are evident in social behavior and of sociality as a whole.

Functionality of promoter microsatellites of arginine vasopressin receptor 1A (AVPR1A): implications for autism.

PubMed

Tansey, Katherine E; Hill, Matthew J; Cochrane, Lynne E; Gill, Michael; Anney, Richard Jl; Gallagher, Louise

2011-03-31

Arginine vasopressin (AVP) has been hypothesized to play a role in aetiology of autism based on a demonstrated involvement in the regulation of social behaviours. The arginine vasopressin receptor 1A gene (AVPR1A) is widely expressed in the brain and is considered to be a key receptor for regulation of social behaviour. Moreover, genetic variation at AVPR1A has been reported to be associated with autism. Evidence from non-human mammals implicates variation in the 5'-flanking region of AVPR1A in variable gene expression and social behaviour. We examined four tagging single nucleotide polymorphisms (SNPs) (rs3803107, rs1042615, rs3741865, rs11174815) and three microsatellites (RS3, RS1 and AVR) at the AVPR1A gene for association in an autism cohort from Ireland. Two 5'-flanking region polymorphisms in the human AVPR1A, RS3 and RS1, were also tested for their effect on relative promoter activity. The short alleles of RS1 and the SNP rs11174815 show weak association with autism in the Irish population (P = 0.036 and P = 0.008, respectively). Both RS1 and RS3 showed differences in relative promoter activity by length. Shorter repeat alleles of RS1 and RS3 decreased relative promoter activity in the human neuroblastoma cell line SH-SY5Y. These aligning results can be interpreted as a functional route for this association, namely that shorter alleles of RS1 lead to decreased AVPR1A transcription, which may proffer increased susceptibility to the autism phenotype.

UPLC/MS-MS assay development for estimation of mozavaptan in plasma and its pharmacokinetic study in rats.

PubMed

Ezzeldin, Essam; Mostafa, Gamal Ae; Iqbal, Muzaffar; Al-Rashood, Khalid A; Asiri, Yousef; El-Nahhas, Toqa

2018-05-10

Mozavaptan is a nonpeptide vasopressin receptor antagonist approved for the treatment of ectopic antidiuretic hormone secretion syndrome. A simple, rapid and fully validated UPLC/MS-MS method was developed for the quantitation of mozavaptan in rat plasma. The chromatographic separation was conducted on an Acquity UPLC BEH™ C 18 column with an optimum mobile phase of 10 mM ammonium acetate buffer and 0.1% formic acid in acetonitrile (30:70 v/v) at a flow rate of 0.3 ml/min. The multiple reaction monitoring transitions were performed at m/z 428.16→119.03 for mozavaptan and m/z 237.06→179.10 for carbamazepine (internal standard). The method was effectively applied for the determination of mozavaptan pharmacokinetic parameters after the oral administration of 3 mg/kg mozavaptan in rats.

High salt intake increases blood pressure via BDNF-mediated downregulation of KCC2 and impaired baroreflex inhibition of vasopressin neurons.

PubMed

Choe, Katrina Y; Han, Su Y; Gaub, Perrine; Shell, Brent; Voisin, Daniel L; Knapp, Blayne A; Barker, Philip A; Brown, Colin H; Cunningham, J Thomas; Bourque, Charles W

2015-02-04

The mechanisms by which dietary salt promotes hypertension are unknown. Previous work established that plasma [Na(+)] and osmolality rise in proportion with salt intake and thus promote release of vasopressin (VP) from the neurohypophysis. Although high levels of circulating VP can increase blood pressure, this effect is normally prevented by a potent GABAergic inhibition of VP neurons by aortic baroreceptors. Here we show that chronic high salt intake impairs baroreceptor inhibition of rat VP neurons through a brain-derived neurotrophic factor (BDNF)-dependent activation of TrkB receptors and downregulation of KCC2 expression, which prevents inhibitory GABAergic signaling. We show that high salt intake increases the spontaneous firing rate of VP neurons in vivo and that circulating VP contributes significantly to the elevation of arterial pressure under these conditions. These results provide the first demonstration that dietary salt can affect blood pressure through neurotrophin-induced plasticity in a central homeostatic circuit. Copyright © 2015 Elsevier Inc. All rights reserved.

Angiotensin (1-7) contributes to nitric oxide tonic inhibition of vasopressin release during hemorrhagic shock in acute ethanol intoxicated rodents

PubMed Central

Whitaker, Annie M.; Molina, Patricia E.

2013-01-01

Aims Acute ethanol intoxication (AEI) attenuates the arginine vasopressin (AVP) response to hemorrhage leading to impaired hemodynamic counter-regulation and accentuated hemodynamic stability. Previously we identified that the ethanol-induced impairment of circulating AVP concentrations in response to hemorrhage was the result of augmented central nitric oxide (NO) inhibition. The aim of the current study was to examine the mechanisms underlying ethanol-induced up-regulation of paraventricular nucleus (PVN) NO concentration. Angiotensin (ANG) (1-7) is an important mediator of NO production through activation of the Mas receptor. We hypothesized that Mas receptor inhibition would decrease central NO concentration and thus restore the rise in circulating AVP levels during hemorrhagic shock in AEI rats. Main Methods Conscious male Sprague Dawley rats (300-325 g) received a 15h intra-gastric infusion of ethanol (2.5g/kg + 300mg/kg/h) or dextrose prior to a fixed-pressure (~40mmHg) 60 minute hemorrhage. The Mas receptor antagonist A-779 was injected through an intracerebroventricular (ICV) cannula 15 min prior to hemorrhage. Key Findings PVN NOS activity and NO were significantly higher in AEI compared to DEX-treated controls at the completion of hemorrhage. ICV A-779 administration decreased NOS activity and NO concentration, partially restoring the rise in circulating AVP levels completion of hemorrhage in AEI rats. Significance These results suggest that Mas receptor activation contributes to the NO-mediated inhibitory tone of AVP release in the ethanol-intoxicated hemorrhaged host. PMID:24002017

Profound and rapid reduction in body temperature induced by the melanocortin receptor agonists.

PubMed

Xu, Yuanzhong; Kim, Eun Ran; Fan, Shengjie; Xia, Yan; Xu, Yong; Huang, Cheng; Tong, Qingchun

2014-08-22

The melanocortin receptor 4 (MC4R) plays a major role in body weight regulation and its agonist MTII has been widely used to study the role of MC4Rs in energy expenditure promotion and feeding reduction. Unexpectedly, we observed that intraperitoneal (i.p.) administration of MTII induced a rapid reduction in both body temperature and energy expenditure, which was independent of its effect on feeding and followed by a prolonged increase in energy expenditure. The rapid reduction was at least partly mediated by brain neurons since intracerebroventricular (icv) administration of alpha melanocyte-stimulating hormone, an endogenous melanocortin receptor agonist, produced a similar response. In addition, the body temperature-lowering effect of MTII was independent of the presence of MC4Rs, but in a similar fashion to the previously shown effect on body temperature by 5'AMP. Moreover, β-adrenergic receptors (β-ARs) were required for the recovery from low body temperature induced by MTII and further pharmacological studies showed that the MTII's effect on body temperature may be partially mediated by the vasopressin V1a receptors. Collectively, our results reveal a previously unappreciated role for the melanocortin pathway in rapidly lowering body temperature. Copyright © 2014 Elsevier Inc. All rights reserved.

Regulation of Vasopressin Action by Prostaglandins

PubMed Central

Kirschenbaum, Michael A.; Lowe, Andrew G.; Trizna, Walter; Fine, Leon G.

1982-01-01

The present studies examined whether vasopressin increases prostaglandin biosynthesis in isolated rabbit cortical collecting tubules (CCT) and whether endogenous prostaglandin biosynthesis plays a role in modulating the response of this nephron segment to vasopressin. Three groups of studies were performed. In the first group, CCT and proximal straight tubules (PST) were incubated with [3H]arachidonic acid, and metabolites were separated and identified using silica gel thin-layer chromatography. CCT were capable of producing all of the major prostaglandins (PG) (PGE2 > thromboxane B2[TxB2] > PGF2α > PGI2). PST produced significantly lesser quantities of these lipids. In the second group, radiolabeled arachidonic acid was incorporated into the phospholipid pool of both CCT and PST, vasopressin was added to the incubation medium, and metabolities were separated and identified as above. Vasopressin stimulated the release of all of the major prostaglandins in CCT but had no effect on PST. PGE release into the incubation medium, as assessed by a radioreceptor assay, increased 108%, and a vasopressin analogue, 1-desamino-8-d-arginine vasopressin, had a quantitatively similar effect. In the third group, a submaximal dose of vasopressin was administered to isolated, perfused CCT studied in the presence and absence of indomethacin to assess whether endogenous prostaglandins play a role in modulating the antidiuretic response to vasopressin. Studies were performed in rabbits on a normal diet and in desoxycorticosterone acetate (DOCA)- or KCl-loaded animals. In the state of mineralocorticoid excess, basal prostaglandin synthesis was 63% lower, and vasopressin-stimulated prostaglandin synthesis 76% lower, than the synthesis observed in rabbits on a normal diet. Cyclooxygenase inhibition exposed a significant hydroosmotic response to a submaximal dose of vasopressin in CCT from DOCA- or KCl-loaded animals. With arachidonic acid in the bath, the same dose of vasopressin failed to elicit a hydroosmotic response in CCT from rabbits on a normal diet even in the presence of a cyclooxygenase inhibitor. However, removal of exogenous arachidonic acid, with a consequently lower rate of prostaglandin synthesis, allowed the cyclooxygenase inhibitor to enhance the hydroosmotic response to vasopressin in these tubules. We conclude from these studies that the rabbit CCT has the capacity to synthesize all of the major prostaglandins and that the rate of synthesis of these lipids is enhanced by vasopessin. Prostaglandin synthesis by the CCT is postulated to modulate the antidiuretic action of vasopressin via a closed feedback loop. The effectiveness of this feedback regulation is dependent upon the mineralocorticoid status of the animal, which determines the level of basal and vasopressin-stimulated prostaglandin synthesis by the CCT. PMID:7174790

Anxiety-like behavior and neuropeptide receptor expression in male and female prairie voles: The effects of stress and social buffering.

PubMed

Donovan, Meghan; Liu, Yan; Wang, Zuoxin

2018-04-16

Strong social support can negate negative health outcomes - an effect defined as 'social buffering'. In the present study, using the socially monogamous prairie vole (Microtus ochrogaster), we examined whether the presence of a bonded partner during a stressful event can reduce stress responses. Adult, pair-bonded female and male voles were assigned into experimental groups that were either handled (Control), experienced a 1-h immobilization (IMO) stress alone (IMO-Alone), or experienced IMO with their partner (IMO-Partner). Thereafter, subjects were tested for anxiety-like behavior, and brain sections were subsequently processed for oxytocin receptor (OTR) and vasopressin V1a-type receptor (V1aR) binding. Our data indicate that while IMO stress significantly decreased the time that subjects spent in the open arms of an elevated plus maze, partner's presence prevented this behavioral change - this social buffering on anxiety-like behavior was the same for both male and female subjects. Further, IMO stress decreased OTR binding in the nucleus accumbens (NAcc), but a partner's presence dampened this effect. No effects were found in V1aR binding. These data suggest that the neuropeptide- and brain region-specific OTR alterations in the NAcc may be involved in both the mediation and social buffering of stress responses. Some sex differences in the OTR and V1aR binding were also found in selected brain regions, offering new insights into the sexually dimorphic roles of the two neuropeptides. Overall, our results suggest a potential preventative approach in which the presence of social interactions during a stressor may buffer typical negative outcomes. Copyright © 2018 Elsevier B.V. All rights reserved.

A POC Clinical Trial for PTSD with a First-In-Class Vasopressin 1a Receptor Antagonist

DTIC Science & Technology

2017-10-01

the major objective will be to continue to recruit and enroll subjects to participate in the clinical study that will test the effect of SRX246, a...8 9. Quad Chart…………………………………………………………… 9 1. INTRODUCTION: The project will test the clinical efficacy of a novel, first-in-class vasopressin 1a...in 42 PTSD patients. In addition, the study also will test in PTSD patients i) the safety and tolerability of SRX246 (160 mg PO BID) and ii) the

Analysis of argentinated peptide complexes using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry: Peptide = oxytocin, arg(8) -vasopressin, bradykinin, bombesin, somatostatin, neurotensin.

PubMed

Gupta, Shyam L; Dhiman, Vikas; Jayasekharan, T; Sahoo, N K

2016-06-15

The increased use of silver nanoparticles (AgNPs) for various biological applications, and over-expression of various peptide receptors in different tumors/cancer cells, necessitate the need for dedicated investigations on the intrinsic binding ability of Ag with various biologically important peptides for better understanding of AgNPs-peptide interactions and for the future development of contrasting agents as well as drugs for imaging/biomedical applications. The [M+(Ag)n ](+) complexes are prepared and characterized using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS). Silver complexes of the peptides [M+(Ag)n ](+) , where M = oxytocin, arg(8) -vasopressin, bradykinin, bombesin, somatostatin, and neurotensin, have been investigated for their intrinsic Ag(+) -binding ability. Unusual binding of up to seven Ag(+) with these small peptides is observed. The mass spectra show n = 1-5 for bombesin and somatostatin, n = 1-6 for bradykinin and arg(8) -vasopressin, and n = 1-7 for oxytocin and neurotensin. In addition, oxytocin and arg(8) -vasopressin show the formation of dimers and their complexes [M2 +(Ag)n ](+) with n = 1-8 and n = 1-5, respectively. The possible amino acid residues responsible for Ag(+) binding in each peptide have been identified on the basis of density functional theory (DFT)-calculated binding energy values of Ag(+) towards individual amino acids. Mass spectrometric evidence indicates that the peptides, viz., oxytocin, arg(8) -vasopressin, bradykinin, bombesin, somatostatin, and neurotensin, show greater affinity for Ag(+) . Hence, they may be used as carriers for AgNPs in targeted drug delivery as well as an alternative for iodinated contrasting agents in dual energy X-ray imaging techniques. Radio-labeled Ag with these peptides can also be used in radio-pharmaceuticals for diagnostic and therapeutic applications. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

[Response of vasopressin and tyrosine hydroxylase expressing neurons of the rat supraoptic nucleus to chronic osmotic stimulation].

PubMed

Abramova, M A; Calas, A; Maiily, P; Thibault, J; Ugriumov, M V

1999-06-01

This study has evaluated the dynamic of intracellular vasopressin and tyrosine hydroxylase contents in the neuron cell bodies in the supraoptic nucleus and in the axons of the posterior lobe in rats drinking 2% NaCl for 1, 2, and 3 weeks. The number of vasopressin-immunoreactive neurons increased by the end of the second week of osmotic stimulation that might be explained by the onset of vasopressin synthesis in the neurons which do not synthesize this neurohormone under normal physiological conditions. The concentration of vasopressin fell down continuously during the first two weeks of salt-loading, apparently, due to predominance of the vasopressin release over its synthesis. Over the third week of salt-loading, the intracellular concentration of vasopressin was not changed significantly suggesting the establishment of the dynamic equilibrium between the vasopressin synthesis and release. The number of tyrosine hydroxylase-immunoreactive neurons and the amount of tyrosine hydroxylase in cell bodies and the large axonal swellings, Herring bodies, increased gradually showing that the rate of tyrosine hydroxylase synthesis prevailed over that of its enzymatic degradation. Thus, the chronic stimulation of vasopressin neurons is accompanied by a number of the adaptive reactions; the most important is related to the onset of vasopressin and tyrosine hydroxylase synthesis in the neurons which do not synthetize both of them under normal conditions.

Association testing of vasopressin receptor 1a microsatellite polymorphisms in non-clinical autism spectrum phenotypes.

PubMed

Procyshyn, Tanya L; Hurd, Peter L; Crespi, Bernard J

2017-05-01

Variation in the AVPR1a gene, which codes for a receptor for the neurohormone vasopressin, has been found to relate to autism risk. Interestingly, variation in this gene also relates to differences in social behaviour in non-clinical populations. Variation in this gene may affect expression of AVPR1a receptors in brain areas involved in social behaviour. Here, we tested whether AVPR1a variation was associated with Autism Quotient (AQ) scores, a questionnaire that measures non-clinical manifestations of autism, in a population of 873 healthy university students. The AVPR1a RS1 and RS3 microsatellites were examined, and variants were categorized as "long" or "short". The RS3 long/long genotype was significantly associated with a higher AQ score (i.e., a more autistic-like phenotype) for the combined population and for females only. Further examination showed that this relationship was due to a specific RS3 variant, termed the "target allele", which previous research has linked to reduced altruism and increased marital problems in healthy individuals. We also observed that the relationship between RS3 genotype and AQ score was mainly due to the "attention switching" (the ability to shift attention from one task to another) component of the questionnaire; this ability is commonly impaired in autism spectrum disorders. Overall, our study establishes continuity between the existing AVPR1a research in clinical and non-clinical populations. Our results suggest that vasopressin may exert its effects on social behaviour in part by modulating attentional focus between social and non-social cues. Autism Res 2017, 10: 750-756. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Identification of Phosphorylation Codes for Arrestin Recruitment by G Protein-Coupled Receptors.

PubMed

Zhou, X Edward; He, Yuanzheng; de Waal, Parker W; Gao, Xiang; Kang, Yanyong; Van Eps, Ned; Yin, Yanting; Pal, Kuntal; Goswami, Devrishi; White, Thomas A; Barty, Anton; Latorraca, Naomi R; Chapman, Henry N; Hubbell, Wayne L; Dror, Ron O; Stevens, Raymond C; Cherezov, Vadim; Gurevich, Vsevolod V; Griffin, Patrick R; Ernst, Oliver P; Melcher, Karsten; Xu, H Eric

2017-07-27

G protein-coupled receptors (GPCRs) mediate diverse signaling in part through interaction with arrestins, whose binding promotes receptor internalization and signaling through G protein-independent pathways. High-affinity arrestin binding requires receptor phosphorylation, often at the receptor's C-terminal tail. Here, we report an X-ray free electron laser (XFEL) crystal structure of the rhodopsin-arrestin complex, in which the phosphorylated C terminus of rhodopsin forms an extended intermolecular β sheet with the N-terminal β strands of arrestin. Phosphorylation was detected at rhodopsin C-terminal tail residues T336 and S338. These two phospho-residues, together with E341, form an extensive network of electrostatic interactions with three positively charged pockets in arrestin in a mode that resembles binding of the phosphorylated vasopressin-2 receptor tail to β-arrestin-1. Based on these observations, we derived and validated a set of phosphorylation codes that serve as a common mechanism for phosphorylation-dependent recruitment of arrestins by GPCRs. Copyright © 2017 Elsevier Inc. All rights reserved.

Physiology and pathophysiology of the vasopressin-regulated renal water reabsorption

PubMed Central

Boone, Michelle

2008-01-01

To prevent dehydration, terrestrial animals and humans have developed a sensitive and versatile system to maintain their water homeostasis. In states of hypernatremia or hypovolemia, the antidiuretic hormone vasopressin (AVP) is released from the pituitary and binds its type-2 receptor in renal principal cells. This triggers an intracellular cAMP signaling cascade, which phosphorylates aquaporin-2 (AQP2) and targets the channel to the apical plasma membrane. Driven by an osmotic gradient, pro-urinary water then passes the membrane through AQP2 and leaves the cell on the basolateral side via AQP3 and AQP4 water channels. When water homeostasis is restored, AVP levels decline, and AQP2 is internalized from the plasma membrane, leaving the plasma membrane watertight again. The action of AVP is counterbalanced by several hormones like prostaglandin E2, bradykinin, dopamine, endothelin-1, acetylcholine, epidermal growth factor, and purines. Moreover, AQP2 is strongly involved in the pathophysiology of disorders characterized by renal concentrating defects, as well as conditions associated with severe water retention. This review focuses on our recent increase in understanding of the molecular mechanisms underlying AVP-regulated renal water transport in both health and disease. PMID:18431594

A non-invasive test for receptor binding applied to nephrogenic diabetes insipidus.

PubMed Central

Britton, K. E.; Tedder, R. S.; Khokhar, A. M.; Brown, N. J.; Davison, A.; Slater, J. D.

1977-01-01

Studies in animals have determined the importance of specific receptors to the action of many hormones and drugs. In man, a non-invasive external counting technique has been used and absence of receptor function has been demonstrated in a patient with nephrogenic diabetes insipidus using radioactively labelled arginine vasopressin. This is in contrast to the findings in a patient with pituitary diabetes insipidus and a normal control. These results suggest a model for the study of hormone and drug kinetics in man avoiding multiple samplings of biological fluids. PMID:196275

Oxytocin and vasopressin modulation of the neural correlates of motivation and emotion: results from functional MRI studies in awake rats.

PubMed

Febo, Marcelo; Ferris, Craig F

2014-09-11

Oxytocin and vasopressin modulate a range of species typical behavioral functions that include social recognition, maternal-infant attachment, and modulation of memory, offensive aggression, defensive fear reactions, and reward seeking. We have employed novel functional magnetic resonance mapping techniques in awake rats to explore the roles of these neuropeptides in the maternal and non-maternal brain. Results from the functional neuroimaging studies that are summarized here have directly and indirectly confirmed and supported previous findings. Oxytocin is released within the lactating rat brain during suckling stimulation and activates specific subcortical networks in the maternal brain. Both vasopressin and oxytocin modulate brain regions involved unconditioned fear, processing of social stimuli and the expression of agonistic behaviors. Across studies there are relatively consistent brain networks associated with internal motivational drives and emotional states that are modulated by oxytocin and vasopressin. This article is part of a Special Issue entitled Oxytocin and Social Behav. Copyright © 2014 Elsevier B.V. All rights reserved.

Continuous and selective measurement of oxytocin and vasopressin using boron-doped diamond electrodes

NASA Astrophysics Data System (ADS)

Asai, Kai; Ivandini, Tribidasari A.; Einaga, Yasuaki

2016-09-01

The electrochemical detection of oxytocin using boron-doped diamond (BDD) electrodes was studied. Cyclic voltammetry of oxytocin in a phosphate buffer solution exhibits an oxidation peak at +0.7 V (vs. Ag/AgCl), which is attributable to oxidation of the phenolic group in the tyrosyl moiety. Furthermore, the linearity of the current peaks obtained in flow injection analysis (FIA) using BDD microelectrodes over the oxytocin concentration range from 0.1 to 10.0 μM with a detection limit of 50 nM (S/N = 3) was high (R2 = 0.995). Although the voltammograms of oxytocin and vasopressin observed with an as-deposited BDD electrode, as well as with a cathodically-reduced BDD electrode, were similar, a clear distinction was observed with anodically-oxidized BDD electrodes due to the attractive interaction between vasopressin and the oxidized BDD surface. By means of this distinction, selective measurements using chronoamperometry combined with flow injection analysis at an optimized potential were demonstrated, indicating the possibility of making selective in situ or in vivo measurements of oxytocin.

Endogenous opioids inhibit oxytocin release during nicotine-stimulated secretion of vasopressin in man.

PubMed

Seckl, J R; Johnson, M; Shakespear, C; Lightman, S L

1988-05-01

The effects of the opioid antagonist naloxone on the vasopressin (AVP) and oxytocin (OT) responses to nicotine were studied in male non-smokers (21-30 years old). Either saline (n = 6) or naloxone (4 mg bolus + 6 mg/h, n = 6) was infused i.v. during the study. After 60 min infusion the subjects smoked one high-nicotine content cigarette. Naloxone infusion for 60 min did not alter basal plasma AVP or OT levels. Smoking led to a significant rise in plasma vasopressin in both saline and naloxone-infused subjects (P less than 0.05). There was no significant difference in the plasma AVP response to smoking between the two groups. Saline-infused subjects did not show any change in plasma OT in response to smoking. Naloxone infusion was associated with a significant rise in OT from 1.3 +/- 0.1 pmol/l to 4.3 +/- 2.4 pmol/l 5 min after smoking (P less than 0.05). We conclude that there is endogenous opioid-mediated inhibition of OT which prevents its release when AVP is secreted in response to nicotine in man.

ASD and Genetic Associations with Receptors for Oxytocin and Vasopressin-AVPR1A, AVPR1B, and OXTR.

PubMed

Francis, Sunday M; Kim, Soo-Jeong; Kistner-Griffin, Emily; Guter, Stephen; Cook, Edwin H; Jacob, Suma

2016-01-01

Background: There are limited treatments available for autism spectrum disorder (ASD). Studies have reported significant associations between the receptor genes of oxytocin (OT) and vasopressin (AVP) and ASD diagnosis, as well as ASD-related phenotypes. Researchers have also found the manipulation of these systems affects social and repetitive behaviors, core characteristics of ASD. Consequently, research involving the oxytocin/vasopressin pathways as intervention targets has increased. Therefore, further examination into the relationship between these neuropeptides and ASD was undertaken. In this study, we examined associations between variants in the receptor genes of vasopressin ( AVPR1A, AVPR1B ), oxytocin ( OXTR ), and ASD diagnosis along with related subphenotypes. Methods: Probands were assessed using Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, and clinical DSM-IV-TR criteria. Single nucleotide polymorphisms (SNPs) in AVPR1B and OXTR , and microsatellites in AVPR1A were genotyped in ~200 families with a proband with ASD. Family-based association testing (FBAT) was utilized to determine associations between variants and ASD. Haplotypes composed of OXTR SNPs (i.e., rs53576-rs2254298-rs2268493) were also analyzed due to previously published associations. Results: Using the additive inheritance model in FBAT we found associations between AVPR1B SNPs (rs28632197, p = 0.005, rs35369693, p = 0.025) and diagnosis. As in other studies, OXTR rs2268493 ( p = 0.050) was associated with diagnosis. rs2268493 was also associated with ASD subphenotypes of social withdrawal ( p = 0.013) and Insistence on Sameness ( p = 0.039). Further analyses demonstrated that the haplotype, rs2254298-rs2268493 was found to be significantly associated with diagnosis (A-T; p = 0.026). FBAT was also used to analyze AVPR1A microsatellites (RS1 and RS3). Both length variants were found to be associated with restrictive, repetitive behaviors, but not overall diagnosis. Correction for multiple comparisons was performed for SNPs tested in each gene region, only AVPR1B SNPs remained significantly associated with ASD diagnosis. Conclusions: Autism is a heterogeneous disorder with many genes and pathways that contribute to its development. SNPs and microsatellites in the receptor genes of OT and AVP are associated with ASD diagnosis and measures of social behavior as well as restricted repetitive behaviors. We reported a novel association with ASD and AVPR1B SNPs. Understanding of genotype-phenotype relationships may be helpful in the development of pharmacological interventions for the OT/AVP system.

Nephrogenic Diabetes Insipidus (NDI): Clinical, Laboratory and Genetic Characterization of Five Brazilian Patients

PubMed Central

Vaisbich, Maria Helena; Carneiro, Juliana; Bóson, Wolfanga; Resende, Bruna; De Marco, Luiz; Honjo, Rachel S; Kim, Chong Ae; Koch, Vera H

2009-01-01

INTRODUCTION: Nephrogenic diabetes insipidus is characterized by a lack of response in the distal nephron to the antidiuretic hormone arginine vasopressin. Manifestations include polyuria, polydipsia, hyposthenuria, recurrent episodes of dehydration and fever and growth failure. Most cases are caused by mutations in the AVPR2 gene. The mutant receptors are trapped intracellularly. METHOD: We studied five boys using clinical, laboratory and molecular data. The mean age at diagnosis was 14.6 months (range 6 to 24) and 12.2 years (7.8 to 19) after the follow-up period. The mean period of follow-up was 132.2 ± 50.9 months. RESULTS: The geometric means of the z-scores of weight and stature were −4.5 and −3.6, respectively, at diagnosis. At the last medical appointment, the z-scores of weight and stature were −0.3 and −0.9, respectively. Three patients were diagnosed with ureterohydronephrosis and exhibited increased post-void urine volume. Mutations in the AVPR2 gene were found in all patients, and the carrier status was confirmed in four of five cases. Two unrelated children presented identical mutations (S167L) in arginine vasopressin R2. Two of the patients had a mutation that has already been described in other Brazilian families (R337X), and one patient showed a de novo mutation (Y128D) in arginine vasopressin R2, since his mother’s molecular analysis was normal. The recurrence risk for this family was significantly reduced. CONCLUSION: This study reports the clinical and laboratory characterization of Nephrogenic diabetes insipidus and reiterates the importance of the genetic basis that underlies the disease diagnosis and genetic counseling. PMID:19488606

Role of vasopressin in regulation of renal kinin excretion in Long-Evans and diabetes insipidus rats.

PubMed Central

Kauker, M L; Crofton, J T; Share, L; Nasjletti, A

1984-01-01

To study the relationship between vasopressin and the renal kallikrein-kinin system we measured the rate of excretion of kinins into the urine of anesthetized rats during conditions of increased and decreased vasopressin level. The excretion of immunoreactive kinins in Brattleboro rats with hereditary diabetes insipidus (DI) (24 +/- 3 pg min-1 kg-1) was lower than in the control Long Evans (LE) rats (182 +/- 22 pg min-1 kg-1; P less than 0.05). The DI rats also exhibited negligible urinary excretion of immunoreactive vasopressin, reduced urine osmolality, and increased urine flow and kininogenase excretion. In LE rats, volume expansion by infusion of 0.45% NaCl-2.5% dextrose to lower vasopressin secretion reduced (P less than 0.05) kinin excretion, vasopressin excretion, and urine osmolality to 41, 26, and 15% of their respective control values, while increasing (P less than 0.05) urine flow and kininogenase excretion. On the other hand, the infusion of 5% NaCl, which promotes vasopressin secretion, increased (P less than 0.05) the urinary excretion of kinins and vasopressin to 165 and 396% of control, while increasing (P less than 0.05) urine flow and kininogenase excretion. Infusion of vasopressin (1.2 mU/h, intravenous) enhanced (P less than 0.05) kinin excretion by two to threefold in DI rats and in LE rats during volume expansion with 0.45% NaCl-2.5% dextrose, while decreasing urine flow and increasing urine osmolality. This study demonstrates that the urinary excretion of immunoreactive kinins varies in relation to the urinary level of vasopressin, irrespective of urine volume and osmolality and of the urinary excretions of sodium and kininogenase. The study suggests a role for vasopressin in promoting the activity of the renal kallikrein-kinin system in the rat. PMID:6561201

Magnesium sulphate attenuates arterial pressure increase during laparoscopic cholecystectomy.

PubMed

Jee, D; Lee, D; Yun, S; Lee, C

2009-10-01

Magnesium is well known to inhibit catecholamine release and attenuate vasopressin-stimulated vasoconstriction. We investigated whether i.v. magnesium sulphate attenuates the haemodynamic stress responses to pneumoperitoneum by changing neurohumoral responses during laparoscopic cholecystectomy. Thirty-two patients undergoing laparoscopic cholecystectomy were randomly assigned to two groups; a control group was given saline, and a magnesium group received magnesium sulphate 50 mg kg(-1) immediately before pneumoperitoneum. Arterial pressure, heart rate, serum magnesium, plasma renin activity (PRA), and catecholamine, cortisol, and vasopressin levels were measured. Systolic and diastolic arterial pressures were greater in the control group (P<0.05) than in the magnesium group at 10, 20, and 30 min post-pneumoperitoneum. Norepinephrine or epinephrine levels [pg ml(-1), mean (SD)] were higher in the control group than in the magnesium group at 5 [211 (37) vs 138 (18)] or 10 min [59 (19) vs 39 (9)] post-pneumoperitoneum, respectively (P<0.05). In the control group, vasopressin levels [pg ml(-1), mean (SD)] were higher compared with the magnesium group at 5 [64 (18) vs 35 (9), P<0.01] and 10 min [65 (18) vs 47 (11), P<0.05] post-pneumoperitoneum. There were no significant differences between the groups in PRA and cortisol levels. I.V. magnesium sulphate before pneumoperitoneum attenuates arterial pressure increases during laparoscopic cholecystectomy. This attenuation is apparently related to reductions in the release of catecholamine, vasopressin, or both.

A randomised, double-blind, multi-centre trial comparing vasopressin and adrenaline in patients with cardiac arrest presenting to or in the Emergency Department.

PubMed

Ong, Marcus Eng Hock; Tiah, Ling; Leong, Benjamin Sieu-Hon; Tan, Elaine Ching Ching; Ong, Victor Yeok Kein; Tan, Elizabeth Ai Theng; Poh, Bee Yen; Pek, Pin Pin; Chen, Yuming

2012-08-01

To compare vasopressin and adrenaline in the treatment of patients with cardiac arrest presenting to or in the Emergency Department (ED). A randomised, double-blind, multi-centre, parallel-design clinical trial in four adult hospitals. Eligible cardiac arrest patients (confirmed by the absence of pulse, unresponsiveness and apnea) aged >16 (aged>21 for one hospital) were randomly assigned to intravenous adrenaline (1mg) or vasopressin (40 IU) at ED. Patients with traumatic cardiac arrest or contraindication for cardiopulmonary resuscitation (CPR) were excluded. Patients received additional open label doses of adrenaline as per current guidelines. Primary outcome was survival to hospital discharge (defined as participant discharged alive or survival to 30 days post-arrest). The study recruited 727 participants (adrenaline = 353; vasopressin = 374). Baseline characteristics of the two groups were comparable. Eight participants (2.3%) from adrenaline and 11 (2.9%) from vasopressin group survived to hospital discharge with no significant difference between groups (p = 0.27, RR = 1.72, 95% CI = 0.65-4.51). After adjustment for race, medical history, bystander CPR and prior adrenaline given, more participants survived to hospital admission with vasopressin (22.2%) than with adrenaline (16.7%) (p = 0.05, RR = 1.43, 95% CI = 1.02-2.04). Sub-group analysis suggested improved outcomes for vasopressin in participants with prolonged arrest times. Combination of vasopressin and adrenaline did not improve long term survival but seemed to improve survival to admission in patients with prolonged cardiac arrest. Further studies on the effect of vasopressin combined with therapeutic hypothermia on patients with prolonged cardiac arrest are needed. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Vasopressin-induced changes in splanchnic blood flow and hepatic and portal venous pressures in liver resection.

PubMed

Bown, L Sand; Ricksten, S-E; Houltz, E; Einarsson, H; Söndergaard, S; Rizell, M; Lundin, S

2016-05-01

To minimize blood loss during hepatic surgery, various methods are used to reduce pressure and flow within the hepato-splanchnic circulation. In this study, the effect of low- to moderate doses of vasopressin, a potent splanchnic vasoconstrictor, on changes in portal and hepatic venous pressures and splanchnic and hepato-splanchnic blood flows were assessed in elective liver resection surgery. Twelve patients were studied. Cardiac output (CO), stroke volume (SV), mean arterial (MAP), central venous (CVP), portal venous (PVP) and hepatic venous pressures (HVP) were measured, intraoperatively, at baseline and during vasopressin infusion at two infusion rates (2.4 and 4.8 U/h). From arterial and venous blood gases, the portal (splanchnic) and hepato-splanchnic blood flow changes were calculated, using Fick's equation. CO, SV, MAP and CVP increased slightly, but significantly, while systemic vascular resistance and heart rate remained unchanged at the highest infusion rate of vasopressin. PVP was not affected by vasopressin, while HVP increased slightly. Vasopressin infusion at 2.4 and 4.8 U/h reduced portal blood flow (-26% and -37%, respectively) and to a lesser extent hepato-splanchnic blood flow (-9% and -14%, respectively). The arterial-portal vein lactate gradient was not significantly affected by vasopressin. Postoperative serum creatinine was not affected by vasopressin. Short-term low to moderate infusion rates of vasopressin induced a splanchnic vasoconstriction without metabolic signs of splanchnic hypoperfusion or subsequent renal impairment. Vasopressin caused a centralization of blood volume and increased cardiac output. Vasopressin does not lower portal or hepatic venous pressures in this clinical setting. © 2016 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Simultaneous anterior and posterior serosal mapping of gastric slow-wave dysrhythmias induced by vasopressin.

PubMed

Du, Peng; O'Grady, Gregory; Paskaranandavadivel, Niranchan; Tang, Shou-Jiang; Abell, Thomas; Cheng, Leo K

2016-06-06

What is the central question of this study? This study aimed to provide the first comparison of simultaneous high-resolution mapping of anterior and posterior gastric serosa over sustained periods. What is the main finding and its importance? Episodes of spontaneous gastric slow-wave dysrhythmias increased significantly following intravenous infusion of vasopressin compared with the baseline state. A number of persistent dysrhythmias were defined, including ectopic activation, conduction block, rotor, retrograde and collision/merger of wavefronts. Slow-wave dysrhythmias could occur either simultaneously or independently on the anterior and posterior gastric serosa, and interacted depending on activation-repolarization and frequency dynamics. High-resolution mapping enables mechanistic insights into gastric slow-wave dysrhythmias and is now achieving clinical translation. However, previous studies have focused mainly on dysrhythmias occurring on the anterior gastric wall. The present study simultaneously mapped the anterior and posterior gastric serosa during episodes of dysrhythmias induced by vasopressin to aid understanding of dysrhythmia initiation, maintenance and termination. High-resolution mapping (8 × 16 electrodes on each serosa; 20-74 cm 2 ) was performed in anaesthetized dogs. Baseline recordings (21 ± 8 min) were followed by intravenous infusion of vasopressin (0.1-0.5 IU ml -1 at 60-190 ml h -1 ) and further recordings (22 ± 13 min). Slow-wave activation maps, amplitudes, velocity, interval and frequency were calculated, and differences compared between baseline and postinfusion. All dogs demonstrated an increased prevalence of dysrhythmic events following infusion of vasopressin (17 versus 51%). Both amplitude and velocity demonstrated significant differences (baseline versus postinfusion: 3.6 versus 2.2 mV; 7.7 versus 6.5 mm s -1 ; P < 0.05 for both). Dysrhythmias occurred simultaneously or independently on the anterior and posterior serosa, and then interacted according to frequency dynamics. A number of persistent dysrhythmias were compared, including the following: ectopic activation (n = 2 animals), conduction block (n = 1), rotor (n = 2), retrograde (n = 3) and collision/merger of wavefronts (n = 2). We conclude that infusion of vasopressin induces gastric dysrhythmias, which occur across a heterogeneous range of frequencies and patterns. The results demonstrate that different classes of gastric dysrhythmias may arise simultaneously or independently in one or both surfaces of the serosa, then interact according to their relative frequencies. These results will help to inform interpretation of clinical dysrhythmia. © 2016 The Authors. Experimental Physiology © 2016 The Physiological Society.

Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial.

PubMed

Gordon, Anthony C; Mason, Alexina J; Thirunavukkarasu, Neeraja; Perkins, Gavin D; Cecconi, Maurizio; Cepkova, Magda; Pogson, David G; Aya, Hollmann D; Anjum, Aisha; Frazier, Gregory J; Santhakumaran, Shalini; Ashby, Deborah; Brett, Stephen J

2016-08-02

Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative. To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock. Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103). The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes. A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, -2.3% [95% CI, -13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to -24) in the vasopressin group and 13 days (IQR, 1 to -25) in the norepinephrine group (difference, -4 days [95% CI, -11 to 5]). There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group (25.4% for vasopressin vs 35.3% for norepinephrine; difference, -9.9% [95% CI, -19.3% to -0.6%]). There was no significant difference in mortality rates between groups. In total, 22 of 205 patients (10.7%) had a serious adverse event in the vasopressin group vs 17 of 204 patients (8.3%) in the norepinephrine group (difference, 2.5% [95% CI, -3.3% to 8.2%]). Among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days. Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation, the confidence interval included a potential clinically important benefit for vasopressin, and larger trials may be warranted to assess this further. clinicaltrials.gov Identifier: ISRCTN 20769191.

ANG II receptor subtype 1a gene knockdown in the subfornical organ prevents increased drinking behavior in bile duct-ligated rats.

PubMed

Walch, Joseph D; Nedungadi, T Prashant; Cunningham, J Thomas

2014-09-15

Bile duct ligation (BDL) causes congestive liver failure that initiates hemodynamic changes, resulting in dilutional hyponatremia due to increased water intake and vasopressin release. This project tested the hypothesis that angiotensin signaling at the subfornical organ (SFO) augments drinking behavior in BDL rats. A genetically modified adeno-associated virus containing short hairpin RNA (shRNA) for ANG II receptor subtype 1a (AT1aR) gene was microinjected into the SFO of rats to knock down expression. Two weeks later, BDL or sham surgery was performed. Rats were housed in metabolic chambers for measurement of fluid and food intake and urine output. The rats were euthanized 28 days after BDL surgery for analysis. A group of rats was perfused for immunohistochemistry, and a second group was used for laser-capture microdissection for analysis of SFO AT1aR gene expression. BDL rats showed increased water intake that was attenuated in rats that received SFO microinjection of AT1aR shRNA. Among BDL rats treated with scrambled (control) and AT1aR shRNA, we observed an increased number of vasopressin-positive cells in the supraoptic nucleus that colocalized with ΔFosB staining, suggesting increased vasopressin release in both groups. These results indicate that angiotensin signaling through the SFO contributes to increased water intake, but not dilutional hyponatremia, during congestive liver failure. Copyright © 2014 the American Physiological Society.

[Nephrogenic diabetes insipidus].

PubMed

Velásquez-Jones, Luis; Medeiros-Domingo, Mara

The anti-diuretic hormone arginine-vasopressin (AVP) is released from the pituitary and regulates water reabsorption in the principal cells of the kidney collecting duct. Binding of AVP to the arginine-vasopressin receptor type-2 in the basolateral membrane leads to translocation of aquaporin-2 water channels to the apical membrane of the principal cells of the collecting duct, inducing water permeability of the membrane. This results in water reabsorption in the collecting duct of the nephron following an osmotic gradient. Nephrogenic diabetes insipidus is caused by partial or complete renal resistance to the effects of AVP. Congenital nephrogenic diabetes insipidus is a disorder associated with mutations in either the AVPR2 or AQP2 gene, causing the inability of patients to concentrate their urine. Acquired nephrogenic diabetes insipidus can be caused by electrolyte imbalances (e.g., hypercalcemia, hypokalemia), renal/extra-renal diseases and drugs (e.g., lithium toxicity). This article reviews the causes, clinical manifestations, diagnosis and treatment of patients with nephrogenic diabetes insipidus. Based on more in-depth mechanistic understanding, new therapeutic strategies are current being explored. Copyright © 2014 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

Effect of maternal renin-angiotensin-aldosterone system activation on social coping strategies and gene expression of oxytocin and vasopressin in the brain of rat offspring in adulthood.

PubMed

Senko, Tomáš; Svitok, Pavel; Kršková, Lucia

2017-10-01

The intrauterine condition in which the mammalian foetus develops has an important role in prenatal programming. The aim of this study was to determine the extent to which activation of the maternal renin-angiotensin-aldosterone system (RAAS) could influence social behaviour strategies in offspring via changes in social neurotransmitters in the brain. Pregnant female Wistar rats were implanted with osmotic minipumps which continually released angiotensin II for 14 days at concentration of 2 μg/kg/h. The adult offspring (angiotensin and control groups) underwent a social interaction test. The mRNA expression of vasopressin, oxytocin and the oxytocin receptor in selected brain areas was measured by in situ hybridisation. Prenatal exposure to higher levels of angiotensin II resulted in a strong trend toward decreased total social interaction time and significantly decreased time spent in close proximity and frequency of mutual sniffing. The angiotensin group showed no changes in oxytocin mRNA expression in the hypothalamic paraventricular or supraoptic nuclei, but this group had reduced vasopressin mRNA expression in the same areas. We concluded that maternal activation of RAAS (via higher levels of angiotensin II) caused inhibition of some socio-cohesive indicators and decreased vasopressinergic activity of offspring. Taken together, these results suggest a reactive rather than proactive social coping strategy.

Distinct Effects of Estrogen on Mouse Maternal Behavior: The Contribution of Estrogen Synthesis in the Brain

PubMed Central

Murakami, Gen

2016-01-01

Estrogen surge following progesterone withdrawal at parturition plays an important role in initiating maternal behavior in various rodent species. Systemic estrogen treatment shortens the latency to onset of maternal behavior in nulliparous female rats that have not experienced parturition. In contrast, nulliparous laboratory mice show rapid onset of maternal behavior without estrogen treatment, and the role of estrogen still remains unclear. Here the effect of systemic estrogen treatment (for 2 h, 1 day, 3 days, and 7 days) after progesterone withdrawal was examined on maternal behavior of C57BL/6 mice. This estrogen regimen led to different effects on nursing, pup retrieval, and nest building behaviors. Latency to nursing was shortened by estrogen treatment within 2 h. Moreover, pup retrieval and nest building were decreased. mRNA expression was also investigated for estrogen receptor α (ERα) and for genes involved in regulating maternal behavior, specifically, the oxytocin receptor (OTR) and vasopressin receptor in the medial amygdala (MeA) and medial preoptic area (MPOA). Estrogen treatment led to decreased ERα mRNA in both regions. Although OTR mRNA was increased in the MeA, OTR and vasopressin receptor mRNA were reduced in the MPOA, showing region-dependent transcription regulation. To determine the mechanisms for the actions of estrogen treatment, the contribution of estrogen synthesis in the brain was examined. Blockade of estrogen synthesis in the brain by systemic letrozole treatment in ovariectomized mice interfered with pup retrieval and nest building but not nursing behavior, indicating different contributions of estrogen synthesis to maternal behavior. Furthermore, letrozole treatment led to an increase in ERα mRNA in the MeA but not in the MPOA, suggesting that involvement of estrogen synthesis is brain region dependent. Altogether, these results suggest that region-dependent estrogen synthesis leads to differential transcriptional activation due to exogenous estrogen treatment, and thereby results in different effects on maternal behavior. PMID:27007402

Vasopressin, Sepsis, and Renal Perfusion - A VASST Deficit in Our Understanding

DTIC Science & Technology

2014-06-01

including the Pediatric Subgroup: Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care...JUN 2014 2. REPORT TYPE N/A 3. DATES COVERED - 4. TITLE AND SUBTITLE Vasopressin, Sepsis , and Renal PerfusionâA VASST Deficit in Our...AKI with vasopressin. The current Surviving Sepsis Campaign Guidelines (3), based largely on the results of the VASST trial (4), recommend vasopressin

Phenotypic regulation of the sphingosine 1-phosphate receptor miles apart by G protein-coupled receptor kinase 2.

PubMed

Burczyk, Martina; Burkhalter, Martin D; Blätte, Tamara; Matysik, Sabrina; Caron, Marc G; Barak, Lawrence S; Philipp, Melanie

2015-01-27

The evolutionarily conserved DRY motif at the end of the third helix of rhodopsin-like, class-A G protein-coupled receptors (GPCRs) is a major regulator of receptor stability, signaling activity, and β-arrestin-mediated internalization. Substitution of the DRY arginine with histidine in the human vasopressin receptor results in a loss-of-function phenotype associated with diabetes insipidus. The analogous R150H substitution of the DRY motif in zebrafish sphingosine-1 phosphate receptor 2 (S1p2) produces a mutation, miles apart m(93) (mil(m93)), that not only disrupts signaling but also impairs heart field migration. We hypothesized that constitutive S1p2 desensitization is the underlying cause of this strong zebrafish developmental defect. We observed in cell assays that the wild-type S1p2 receptor is at the cell surface whereas in distinct contrast the S1p2 R150H receptor is found in intracellular vesicles, blocking G protein but not arrestin signaling activity. Surface S1p2 R150H expression could be restored by inhibition of G protein-coupled receptor kinase 2 (GRK2). Moreover, we observed that β-arrestin 2 and GRK2 colocalize with S1p2 in developing zebrafish embryos and depletion of GRK2 in the S1p2 R150H miles apart zebrafish partially rescued cardia bifida. The ability of reduced GRK2 activity to reverse a developmental phenotype associated with constitutive desensitization supports efforts to genetically or pharmacologically target this kinase in diseases involving biased GPCR signaling.

Phenotypic Regulation of the Sphingosine 1-Phosphate Receptor Miles Apart by G Protein-Coupled Receptor Kinase 2

PubMed Central

2016-01-01

The evolutionarily conserved DRY motif at the end of the third helix of rhodopsin-like, class-A G protein-coupled receptors (GPCRs) is a major regulator of receptor stability, signaling activity, and β-arrestin-mediated internalization. Substitution of the DRY arginine with histidine in the human vasopressin receptor results in a loss-of-function phenotype associated with diabetes insipidus. The analogous R150H substitution of the DRY motif in zebrafish sphingosine-1 phosphate receptor 2 (S1p2) produces a mutation, miles apart m93 (milm93), that not only disrupts signaling but also impairs heart field migration. We hypothesized that constitutive S1p2 desensitization is the underlying cause of this strong zebrafish developmental defect. We observed in cell assays that the wild-type S1p2 receptor is at the cell surface whereas in distinct contrast the S1p2 R150H receptor is found in intracellular vesicles, blocking G protein but not arrestin signaling activity. Surface S1p2 R150H expression could be restored by inhibition of G protein-coupled receptor kinase 2 (GRK2). Moreover, we observed that β-arrestin 2 and GRK2 colocalize with S1p2 in developing zebrafish embryos and depletion of GRK2 in the S1p2 R150H miles apart zebrafish partially rescued cardia bifida. The ability of reduced GRK2 activity to reverse a developmental phenotype associated with constitutive desensitization supports efforts to genetically or pharmacologically target this kinase in diseases involving biased GPCR signaling. PMID:25555130

Oxytocin and Vasopressin Receptor Gene Polymorphisms: Role in Social and Psychiatric Traits

PubMed Central

Aspé-Sánchez, Mauricio; Moreno, Macarena; Rivera, Maria Ignacia; Rossi, Alejandra; Ewer, John

2016-01-01

Oxytocin (OXT) and arginine-vasopressin (AVP) are two phylogenetically conserved neuropeptides that have been implicated in a wide range of social behaviors. Although a large body of research, ranging from rodents to humans, has reported on the effects of OXT and AVP administration on affiliative and trust behaviors, and has highlighted the genetic contributions of OXT and AVP receptor polymorphisms to both social behaviors and to diseases related to social deficits, the consequences of peptide administration on psychiatric symptoms, and the impact of receptor polymorphisms on receptor function, are still unclear. Despite the exciting advances that these reports have brought to social neuroscience, they remain preliminary and suffer from the problems that are inherent to monogenetic linkage and association studies. As an alternative, some studies are using polygenic approaches, and consider the contributions of other genes and pathways, including those involving DA, 5-HT, and reelin, in addition to OXT and AVP; a handful of report are also using genome-wide association studies. This review summarizes findings on the associations between OXT and AVP receptor polymorphism, social behavior, and psychiatric diseases. In addition, we discuss reports on the interactions of OXT and AVP receptor genes and genes involved in other pathways (such as those of dopamine, serotonin, and reelin), as well as research that has shed some light on the impact of gene polymorphisms on the volume, connectivity, and activation of specific neural structures, differential receptor expression, and plasma levels of the OXT and AVP peptides. We hope that this effort will be helpful for understanding the studies performed so far, and for encouraging the inclusion of other candidate genes not explored to date. PMID:26858594

Oxytocin and Vasopressin Receptor Gene Polymorphisms: Role in Social and Psychiatric Traits.

PubMed

Aspé-Sánchez, Mauricio; Moreno, Macarena; Rivera, Maria Ignacia; Rossi, Alejandra; Ewer, John

2015-01-01

Oxytocin (OXT) and arginine-vasopressin (AVP) are two phylogenetically conserved neuropeptides that have been implicated in a wide range of social behaviors. Although a large body of research, ranging from rodents to humans, has reported on the effects of OXT and AVP administration on affiliative and trust behaviors, and has highlighted the genetic contributions of OXT and AVP receptor polymorphisms to both social behaviors and to diseases related to social deficits, the consequences of peptide administration on psychiatric symptoms, and the impact of receptor polymorphisms on receptor function, are still unclear. Despite the exciting advances that these reports have brought to social neuroscience, they remain preliminary and suffer from the problems that are inherent to monogenetic linkage and association studies. As an alternative, some studies are using polygenic approaches, and consider the contributions of other genes and pathways, including those involving DA, 5-HT, and reelin, in addition to OXT and AVP; a handful of report are also using genome-wide association studies. This review summarizes findings on the associations between OXT and AVP receptor polymorphism, social behavior, and psychiatric diseases. In addition, we discuss reports on the interactions of OXT and AVP receptor genes and genes involved in other pathways (such as those of dopamine, serotonin, and reelin), as well as research that has shed some light on the impact of gene polymorphisms on the volume, connectivity, and activation of specific neural structures, differential receptor expression, and plasma levels of the OXT and AVP peptides. We hope that this effort will be helpful for understanding the studies performed so far, and for encouraging the inclusion of other candidate genes not explored to date.

Developmental Perspectives on Oxytocin and Vasopressin

PubMed Central

Hammock, Elizabeth A D

2015-01-01

The related neuropeptides oxytocin and vasopressin are involved in species-typical behavior, including social recognition behavior, maternal behavior, social bonding, communication, and aggression. A wealth of evidence from animal models demonstrates significant modulation of adult social behavior by both of these neuropeptides and their receptors. Over the last decade, there has been a flood of studies in humans also implicating a role for these neuropeptides in human social behavior. Despite popular assumptions that oxytocin is a molecule of social bonding in the infant brain, less mechanistic research emphasis has been placed on the potential role of these neuropeptides in the developmental emergence of the neural substrates of behavior. This review summarizes what is known and assumed about the developmental influence of these neuropeptides and outlines the important unanswered questions and testable hypotheses. There is tremendous translational need to understand the functions of these neuropeptides in mammalian experience-dependent development of the social brain. The activity of oxytocin and vasopressin during development should inform our understanding of individual, sex, and species differences in social behavior later in life. PMID:24863032

Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills

PubMed Central

Skuse, David H.; Lori, Adriana; Cubells, Joseph F.; Lee, Irene; Conneely, Karen N.; Puura, Kaija; Lehtimäki, Terho; Binder, Elisabeth B.; Young, Larry J.

2014-01-01

The neuropeptides oxytocin and vasopressin are evolutionarily conserved regulators of social perception and behavior. Evidence is building that they are critically involved in the development of social recognition skills within rodent species, primates, and humans. We investigated whether common polymorphisms in the genes encoding the oxytocin and vasopressin 1a receptors influence social memory for faces. Our sample comprised 198 families, from the United Kingdom and Finland, in whom a single child had been diagnosed with high-functioning autism. Previous research has shown that impaired social perception, characteristic of autism, extends to the first-degree relatives of autistic individuals, implying heritable risk. Assessments of face recognition memory, discrimination of facial emotions, and direction of gaze detection were standardized for age (7–60 y) and sex. A common SNP in the oxytocin receptor (rs237887) was strongly associated with recognition memory in combined probands, parents, and siblings after correction for multiple comparisons. Homozygotes for the ancestral A allele had impairments in the range −0.6 to −1.15 SD scores, irrespective of their diagnostic status. Our findings imply that a critical role for the oxytocin system in social recognition has been conserved across perceptual boundaries through evolution, from olfaction in rodents to visual memory in humans. PMID:24367110

Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills.

PubMed

Skuse, David H; Lori, Adriana; Cubells, Joseph F; Lee, Irene; Conneely, Karen N; Puura, Kaija; Lehtimäki, Terho; Binder, Elisabeth B; Young, Larry J

2014-02-04

The neuropeptides oxytocin and vasopressin are evolutionarily conserved regulators of social perception and behavior. Evidence is building that they are critically involved in the development of social recognition skills within rodent species, primates, and humans. We investigated whether common polymorphisms in the genes encoding the oxytocin and vasopressin 1a receptors influence social memory for faces. Our sample comprised 198 families, from the United Kingdom and Finland, in whom a single child had been diagnosed with high-functioning autism. Previous research has shown that impaired social perception, characteristic of autism, extends to the first-degree relatives of autistic individuals, implying heritable risk. Assessments of face recognition memory, discrimination of facial emotions, and direction of gaze detection were standardized for age (7-60 y) and sex. A common SNP in the oxytocin receptor (rs237887) was strongly associated with recognition memory in combined probands, parents, and siblings after correction for multiple comparisons. Homozygotes for the ancestral A allele had impairments in the range -0.6 to -1.15 SD scores, irrespective of their diagnostic status. Our findings imply that a critical role for the oxytocin system in social recognition has been conserved across perceptual boundaries through evolution, from olfaction in rodents to visual memory in humans.

Common α2A and α2C adrenergic receptor polymorphisms do not affect plasma membrane trafficking.

PubMed

Hurt, Carl M; Sorensen, Matt W; Angelotti, Timothy

2014-06-01

Various naturally occurring polymorphic forms of human G protein-coupled receptors (GPCRs) have been identified and linked to diverse pathological diseases, including receptors for vasopressin type 2 (nephrogenic diabetes insipidus) and gonadotropin releasing hormone (hypogonadotropic hypogonadism). In most cases, polymorphic amino acid mutations disrupt protein folding, altering receptor function as well as plasma membrane expression. Other pathological GPCR variants have been found that do not alter receptor function, but instead affect only plasma membrane trafficking (e.g., delta opiate and histamine type 1 receptors). Thus, altered membrane trafficking with retained receptor function may be another mechanism causing polymorphic GPCR dysfunction. Two common human α2A and α2C adrenergic receptor (AR) variants have been identified (α2A N251K and α2C Δ322-325 ARs), but pharmacological analysis of ligand binding and second messenger signaling has not consistently demonstrated altered receptor function. However, possible alterations in plasma membrane trafficking have not been investigated. We utilized a systematic approach previously developed for the study of GPCR trafficking motifs and accessory proteins to assess whether these α2 AR variants affected intracellular trafficking or plasma membrane expression. By combining immunofluorescent microscopy, glycosidic processing analysis, and quantitative fluorescent-activated cell sorting (FACS), we demonstrate that neither variant receptor had altered intracellular localization, glycosylation, nor plasma membrane expression compared to wild-type α2 ARs. Therefore, pathopharmacological properties of α2A N251K and α2C Δ322-325 ARs do not appear to be due to altered receptor pharmacology or plasma membrane trafficking, but may involve interactions with other intracellular signaling cascades or proteins.

Hormonal regulation of hepatic glycogenolysis in the carp, Cyprinus carpio

DOE Office of Scientific and Technical Information (OSTI.GOV)

Janssens, P.A.; Lowrey, P.

1987-04-01

Carp (Cyprinus carpio) liver maintained normal glycogen content and enzyme complement for several days in organ culture. Epinephrine-stimulated glycogenolysis, phosphorylase activation, and cyclic AMP (cAMP) accumulation in a concentration-dependent manner with EC/sub 50/s of 100, 100, and 500 nM, respectively. These actions were blocked by the ..beta..-adrenergic antagonist, propranolol, but not by the ..cap alpha..-adrenergic antagonist phentolamine. Glycogenolysis and tissue cAMP were uninfluenced by 10/sup -6/ M arginine vasotocin, arginine vasopressin, lysine vasotocin, lysine vasopressin, mesotocin, or oxytocin, but were slightly increased by 10/sup -5/ M isotocin and slightly decreased by 10/sup -6/ M angiotensin II. (/sup 125/I)-iodocyanopindolol (ICP), amore » ..beta..-adrenergic ligand, bound to isolated carp liver membranes with a K/sub D/ of 83 pM. Maximum binding of 45 fmol/mg protein was at 600 pM. Propranolol, isoprenaline, epinephrine, phenylephrine, norepinephrine, and phenoxybenzamine displaced ICP with K/sub D/s of 100 nM, 2, 20, 20, 60, and 200 ..mu..M, respectively. The ..cap alpha..-adrenergic antagonists, yohimbine and prazosin, showed no specific binding. These data provide evidence that catecholamines act via ..beta..-adrenergic receptors in carp liver and that ..cap alpha..-adrenergic receptors are not present. Vasoactive peptides play no significant role in regulation of carp liver glycogenolysis.« less

Effects of electrical stimulation of ventral septal area on firing rates of pyrogen-treated thermosensitive neurons in preoptic anterior hypothalamus from rabbits.

PubMed

Dong, Jun; Xie, Xin-Hua; Lu, Da-Xiang; Fu, Yong-Mei

2007-01-09

Although there is considerable evidence supporting that fever evolved as a host defense response, it is important that the rise in body temperature would not be too high. Many endogenous cryogens or antipyretics that limit the rise in body temperature have been identified. Endogenous antipyretics attenuate fever by influencing the thermoregulatory neurons in the preoptic anterior hypothalamus (POAH) and in adjacent septal areas including ventral septal area (VSA). Our previous study showed that intracerebroventricular (I.C.V.) injection of interleukin-1beta (IL-1beta) affected electrophysiological activities of thermosensitive neurons in VSA regions, and electrical stimulation of POAH reversed the effect of IL-1beta. To further investigate the functional electrophysiological connection between POAH and VSA and its mechanisms in thermoregulation, the firing rates of thermosensitive neurons in POAH of forty-seven unit discharge were recorded by using extracellular microelectrode technique in New Zealand white rabbits. Our results show that the firing rates of the warm-sensitive neurons decreased significantly and those of the cold-sensitive neurons increased in POAH when the pyrogen (IL-1beta) was injected I.C.V. The effects of IL-1beta on firing rates in thermosensitive neurons of POAH were reversed by electrical stimulation of VSA. An arginine vasopressin (AVP) V1 antagonist abolished the regulatory effects of VSA on the firing rates in thermosensitive neurons of POAH evoked by IL-1beta. However, an AVP V2 antagonist had no effects. These data indicated that VSA regulates the activities of the thermosensitive neurons of POAH through AVP V1 but not AVP V2 receptor.

DDAVP in Treatment of Vasopressin-Sensitive Diabetes Insipidus

PubMed Central

Ward, M. K.; Fraser, T. Russell

1974-01-01

In 11 patients with vasopressin-sensitive diabetes insipidus the effectiveness of the vasopressin analogue 1-desamino-8-D-arginine vasopressin (DDAVP) for controlling diabetes insipidus has been compared with that of lysine vasopressin. DDAVP in equivalent intravenous dosage has been found to be at least as potent and to have a more prolonged action, lasting 13-22 hours instead of 1-2 hours. Twice-daily intranasal DDAVP effected satisfactory control in all these patients, without side effects, and all the patients preferred this to their previous treatment. Single daily intramuscular injections of DDAVP were found to offer excellent control for any subject unable to manage intranasal administration. PMID:4851464

Chronic anabolic-androgenic steroid treatment during adolescence increases anterior hypothalamic vasopressin and aggression in intact hamsters.

PubMed

Harrison, R J; Connor, D F; Nowak, C; Nash, K; Melloni, R H

2000-05-01

The present study examines the hypothesis that exposure to anabolic-androgenic steroids (AAS) during adolescent development predisposes hamsters to heightened levels of aggressive behavior by influencing the anterior hypothalamic-arginine vasopressin (AH-AVP) neural system. To test this, adolescent male hamsters (Mesocricetus auratus) were treated with high doses of AAS, tested for offensive aggression in the absence or presence of AH-AVP receptor antagonists, and then examined for changes in AH-AVP expression and neural organization. AAS exposure during adolescence significantly increased aggression intensity (number of attacks and bites) and initiation (latency to the first bite). Yet, only increases in aggression intensity were inhibited by AH-AVP receptor antagonism. Adolescent AAS-treated hamsters showed significant increases in AH-AVP fiber density and peptide content. However, no alterations in AH-AVP neuronal organization or mRNA expression were found. Together, these data suggest that adolescent AAS exposure increase aggression intensity by altering AH-AVP expression and activity, providing direct evidence for a causal role of AH-AVP expression and function in early onset AAS-stimulated aggression.

Species, Sex and Individual Differences in the Vasotocin/Vasopressin System: Relationship to Neurochemical Signaling in the Social Behavior Neural Network

PubMed Central

Albers, H. Elliott

2014-01-01

Arginine-vasotocin(AVT)/arginine vasopressin (AVP) are members of the AVP/oxytocin (OT) superfamily of peptides that are involved in the regulation of social behavior, social cognition and emotion. Comparative studies have revealed that AVT/AVP and their receptors are found throughout the “Social Behavior Neural Network” and display the properties expected from a signaling system that controls social behavior (i.e., species, sex and individual differences and modulation by gonadal hormones and social factors). Neurochemical signaling within the SBNN likely involves a complex combination of synaptic mechanisms that co-release multiple chemical signals (e.g., classical neurotransmitters and AVT/AVP as well as other peptides) and non-synaptic mechanisms (i.e., volume transmission). Crosstalk between AVP/OT peptides and receptors within the SBNN is likely. A better understanding of the functional properties of neurochemical signaling in the SBNN will allow for a more refined examination of the relationships between this peptide system and species, sex and individual differences in sociality. PMID:25102443

Functional polymorphisms affecting the clinically important arginine-137 residue of AVPR2 do not influence serum sodium concentration at the population level

PubMed Central

Fu, Yi; Cheetham, Tim; Bourn, David; Orwoll, Eric

2013-01-01

The protein product of the AVPR2 gene, coding for the arginine vasopressin receptor type 2, is essential for vasopressin-dependent concentration of the urine. The arginine residue at position 137 in the protein product of this gene is uniquely pivotal for function. The R137H mutant inactivates the receptor conferring congenital nephrogenic diabetes insipidus, whereas activating mutations at this same residue (i.e., R137C and R137L) confer pathological water retention in the nephrogenic syndrome of inappropriate antidiuresis. These mutations were discovered in human subjects with conspicuous phenotypes in clinical water balance. Prevalence of these polymorphisms among asymptomatic individuals has not been assessed, nor has their contribution to broad interindividual variation in serum sodium concentration; no data addressing minor allele frequency are available. We genotyped two large cohorts using a validated high-throughput Pyrosequencing-based assay that we designed to capture the totality of pathological variation at this important residue. In the Osteoporotic Fractures in Men (MrOS) Study, all participants were male (i.e., hemizygous for AVPR2 gene on the X-chromosome), and participants were oversampled at the extremes of the population distribution for serum sodium concentration. In the Offspring Cohort of the Framingham Heart Study, male and female participants were genotyped. No pathological variants affecting R137 were detected among the 5,142 AVPR2 alleles successfully genotyped. Even at the population extremes of serum sodium distribution, we estimate minor allele frequency < 0.06%. We conclude that these disease-associated variants are exceedingly uncommon and do not contribute broadly to interindividual variability in serum sodium concentration or to its heritability. PMID:23362144

Quantification of extracellular levels of corticosterone in the basolateral amygdaloid complex of freely-moving rats: a dialysis study of circadian variation and stress-induced modulation.

PubMed

Bouchez, Gaëlle; Millan, Mark J; Rivet, Jean-Michel; Billiras, Rodolphe; Boulanger, Raphaël; Gobert, Alain

2012-05-03

Corticosterone influences emotion and cognition via actions in a diversity of corticolimbic structures, including the amygdala. Since extracellular levels of corticosterone in brain have rarely been studied, we characterized a specific and sensitive enzymatic immunoassay for microdialysis quantification of corticosterone in the basolateral amygdaloid complex of freely-moving rats. Corticosterone levels showed marked diurnal variation with an evening (dark phase) peak and stable, low levels during the day (light phase). The "anxiogenic agents", FG7142 (20 mg/kg) and yohimbine (10 mg/kg), and an environmental stressor, 15-min forced-swim, induced marked and sustained (1-3 h) increases in dialysis levels of corticosterone in basolateral amygdaloid complex. They likewise increased dialysis levels of dopamine and noradrenaline, but not serotonin and GABA. As compared to basal corticosterone levels of ~200-300 pg/ml, the elevation provoked by forced-swim was ca. 20-fold and this increase was abolished by adrenalectomy. Interestingly, stress-induced rises of corticosterone levels in basolateral amygdaloid complex were abrogated by combined but not separate administration of the corticotrophin releasing factor(1) (CRF(1)) receptor antagonist, CP154,526, and the vasopressin(1b) (V(1b)) receptor antagonist, SSR149,415. Underpinning their specificity, they did not block forced-swim-induced elevations in dopamine and noradrenaline. In conclusion, extracellular levels of corticosterone in the basolateral amygdaloid complex display marked diurnal variation. Further, they are markedly elevated by acute stressors, the effects of which are mediated (in contrast to concomitant elevations in levels of monoamines) by co-joint recruitment of CRF(1) and V(1b) receptors. Copyright © 2012 Elsevier B.V. All rights reserved.

Commissural NTS lesions enhance the pressor response to central cholinergic and adrenergic activation.

PubMed

Vieira, Alexandre A; De Luca, Laurival A; Colombari, Eduardo; Colombari, Debora S A; Menani, José V

2012-07-11

Electrolytic lesions of the commissural nucleus of the solitary tract (commNTS) in rats enhance the pressor response to bilateral carotid occlusion or to intravenous infusion of hypertonic NaCl without changing baroreflex responses. In an opposite direction, commNTS lesions abolish the pressor responses to peripheral chemoreflex activation. These opposite effects of commNTS lesions apparently result from an impairment of sympathetic activation in one case and in a facilitation of vasopressin secretion in the others. In the present study, we investigated the effects of the electrolytic lesions of the commNTS in the pressor responses that depend on sympathetic activation and vasopressin secretion produced by central cholinergic or adrenergic activation with intracerebroventricular (i.c.v.) injections of carbachol or noradrenaline, respectively, in unanesthetized rats. Male Holtzman rats (280-320 g, n=8-15/group) with acute (1 day) or chronic (21 days) sham or commNTS lesions (1 mA×10 s) and a stainless steel cannula implanted in the lateral ventricle were used. Acute commNTS lesions increased the pressor response to i.c.v. injection of carbachol (0.5 nmol/1μ1) (52 ± 2, vs. sham: 37 ± 2mm Hg) or noradrenaline (80 nmol/1μl) (45 ± 6, vs. sham: 30 ± 3 mm Hg), whereas chronic commNTS lesions did not affect the pressor responses to the same treatments. Lesions of the commNTS impaired chemoreflex responses produced by intravenous KCN, without changing baroreflex responses. The results suggest that commNTS-dependent inhibitory signals are involved in the modulation of the pressor responses to central cholinergic and adrenergic activation, probably limiting vasopressin secretion. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

A Review of Oxytocin and Arginine-Vasopressin Receptors and Their Modulation of Autism Spectrum Disorder

PubMed Central

Cataldo, Ilaria; Azhari, Atiqah; Esposito, Gianluca

2018-01-01

Oxytocin (OXT) and arginine-vasopressin (AVP) play a key regulatory part in social and affiliative behaviors; two aspects highly compromised in Autism Spectrum Disorder (ASD). Furthermore, variants in the adjacent oxytocin-vasopressin gene regions have been found to be associated with ASD diagnosis and endophenotypes. This review focuses mainly on common OXTr single nucleotide polymorphisms (SNPs), AVPR1a microsatellites and AVPR1b polymorphisms in relation to the development of autism. Although these genes did not surface in genome-wide association studies, evidence supports the hypothesis that these receptors and their polymorphisms are widely involved in the regulation of social behavior, and in modulating neural and physiological pathways contributing to the etiology of ASD. With a specific focus on variants considered to be among the most prevalent in the development of ASD, these issues will be discussed in-depth and suggestions to approach inconsistencies in the present literature will be provided. Translational implications and future directions are deliberated from a short-term and a forward-looking perspective. While the scientific community has made significant progress in enhancing our understanding of ASD, more research is required for the ontology of this disorder to be fully elucidated. By supplementing information related to genetics, highlighting the differences across male and female sexes, this review provides a wider view of the current state of knowledge of OXTr and AVPr mechanisms of functioning, eventually addressing future research in the identification of further risk factors, to build new strategies for early interventions. PMID:29487501

Neuroprotective Effects of Drug-Induced Therapeutic Hypothermia in Central Nervous System Diseases.

PubMed

Ma, Junwei; Wang, Yibin; Wang, Zhong; Li, Haiying; Wang, Zhimin; Chen, Gang

2017-01-01

This review article focuses on the neuroprotective effect of drug-induced hypothermia in cerebrovascular diseases and discusses its related side effects. A systematic literature search was performed using Pubmed and Embase electronic databases for a retrospective analysis. Experimental studies have shown that drug-induced hypothermia alleviates brain damage and plays a neuroprotective role, thereby reducing mortality and ameliorating neurological deficits. Therefore, drug-induced hypothermia has an important research value and is worth further consideration in the clinical setting. However, drug-induced hypothermia is also associated with side effects, such as ventricular tachycardia, ventricular fibrillation, suppressed immune function, infection, electrolyte imbalance, glucose metabolism disorders, and skeletal muscle tremor. Existing drugs with cooling effects belong to the following categories: (1) dopamine receptor agonists; (2) cannabis; (3) opioid receptors; (4) vanilloid receptors; (5) vasopressins (potent neurotensin receptor agonists); (6) thyroid drugs; (7) adenosine drugs; and (8) purine drugs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Dopamine D2 Receptors Act Upstream of AVP in the Latero-Anterior Hypothalamus to Modulate Adolescent Anabolic/Androgenic Steroid-Induced Aggression in Syrian Hamsters

PubMed Central

Morrison, Thomas R.; Ricci, Lesley A.; Melloni, Richard H.

2015-01-01

In pubertal male Syrian hamsters, exposure to anabolic/androgenic steroids (AAS) during adolescence facilitates a high level of offensive aggression modulated by the enhanced development and activity of the vasopressin (AVP) and dopamine (DA) neural systems within the latero-anterior hypothalamus (LAH), i.e., a brain region implicated in the control of aggression. The present studies provide a detailed report of the pharmacologic interactions between AVP and DA D2 receptor signaling within the LAH in the control of adolescent AAS-induced offensive aggression. Male Syrian hamsters were treated with AAS throughout adolescence and tested for aggression after local infusion of the DA D2 receptor antagonist eticlopride (ETIC) alone, or in combination with AVP in the LAH in an effort to determine the influence of DA D2 receptors relative to AVP-receptor mediated aggression mechanisms. As previously shown, ETIC infusion into the LAH suppressed adolescent AAS-induced aggressive responding; however, the AAS-induced aggressive phenotype was rescued by the co-infusion of AVP into the LAH. These behavioral data indicate that interactions between AVP and DA neural systems within the LAH modulate the control of aggression following adolescent exposure to AAS and that DA D2 receptor signaling functions upstream of AVP in the LAH to control this behavioral response. PMID:25798632

Vasopressin, renin, and cortisol responses to hemorrhage during acute blockade of cardiac nerves in conscious dogs

NASA Technical Reports Server (NTRS)

O'Donnell, C. P.; Keil, L. C.; Thrasher, T. N.

1993-01-01

The effect of acute cardiac nerve blockade (CNB) on the increases in plasma renin activity (PRA), arginine vasopressin (AVP), and cortisol in response to a 30 ml/kg hemorrhage was determined in conscious dogs (n = 9). Procaine was infused into the pericardial space to produce acute reversible CNB, or saline was infused in the control hemorrhage. Blood was removed from the inferior vena cava at a rate of 1 ml.kg-1.min-1. In the control hemorrhage, plasma AVP increased from 1.8 +/- 0.3 to 219 +/- 66 pg/ml, PRA increased from 0.63 +/- 0.20 to 3.08 +/- 0.91 ng angiotensin I (ANG I).ml-1.3 h-1, and cortisol increased from 1.4 +/- 0.2 to 4.0 +/- 0.7 micrograms/dl. When the hemorrhage was repeated during acute CNB, plasma AVP increased from 2.8 +/- 1.6 to 185 +/- 59 pg/ml, PRA increased from 0.44 +/- 0.14 to 2.24 +/- 0.27 ng ANG I.ml-1.3 h-1, and cortisol increased from 1.9 +/- 0.3 to 5.4 +/- 0.6 micrograms/dl, and none of the increases differed significantly from the responses during the control hemorrhage. Left atrial pressure fell significantly after removal of 6 ml/kg of blood, but mean arterial pressure was maintained at control levels until blood loss reached 20 ml/kg during pericardial infusion of either saline or procaine. The declines in MAP at the 30 ml/kg level of hemorrhage in both treatments were similar. These results demonstrate that acutely blocking input from cardiac receptors does not reduce the increases in plasma AVP, cortisol, and PRA in response to a 30 ml/kg hemorrhage. The results of this study do not support the hypothesis that input from cardiac receptors is required for a normal AVP response to hemorrhage and suggest that other receptors, presumably arterial baroreceptors, can stimulate AVP and cortisol secretion in the absence of signals from the heart.

Absence of specific binding of several putative neuro-transmitters to human fibroblasts.

PubMed

Berrettini, W H; Nadi, N S; Gershon, E S

1983-01-01

Fibroblasts were examined for specific binding sites of ten putative neurotransmitters to determine whether this tissue could be used in receptor studies of neurologic and psychiatric disorders. Stereospecific saturable binding was not found for any of the ligands: arginine vasopressin, neurotensin, somatostatin, angiotensin II, thyrotropin-releasing hormone (TRH), alpha-bungarotoxin, LSD, dihydromorphine, muscimol and spiperone.

Pharmacokinetics and Pharmacodynamics of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Phase 2 Trials for Dose Selection in the Pivotal Phase 3 Trial

PubMed Central

Chapman, Arlene B.; Torres, Vicente E.; Ouyang, John; Czerwiec, Frank S.

2017-01-01

Abstract In the pivotal TEMPO 3:4 trial, the arginine vasopressin V2‐receptor antagonist tolvaptan reduced the rate of kidney growth in patients with autosomal dominant polycystic kidney disease. Tolvaptan was initiated as daily morning/afternoon doses of 45/15 mg, and uptitrated weekly to 60/30 mg and 90/30 mg according to patient‐reported tolerability. The current report describes 3 phase 2 trials in adult autosomal dominant polycystic kidney disease subjects that were the basis for the titrated split‐dose regimen: a single ascending‐dose trial (tolvaptan 15 to 120 mg; n = 11), a multiple split‐dose trial (tolvaptan 15/15 mg, 30/0 mg, 30/15 mg, and 30/30 mg; n = 37), and an 8‐week open‐label safety and efficacy trial in 46 of the 48 subjects who participated in the prior 2 trials (tolvaptan 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg). Urine osmolality (Uosm) was chosen as the biomarker of V2 receptor inhibition. Two tolvaptan doses per day were necessary to suppress Uosm to <300 mOsm/kg for 24 hours. The 45/15‐mg regimen was well tolerated and effective in suppressing Uosm in >50% of subjects. Therefore, this regimen was selected as the starting regimen for the TEMPO 3:4 trial. The 90/30‐mg regimen suppressed Uosm in 85% of subjects tested; however, only 28/46 subjects agreed to uptitrate to 90/30 mg due to tolerability. Higher concentrations of tolvaptan were less well tolerated, resulting in adverse events of pollakiuria, thirst, polyuria, nocturia, and a higher number of times out of bed to urinate. Subjects who agreed to uptitrate to 90/30 mg had lower eGFR than those who did not uptitrate. PMID:28218410

Transient central diabetes insipidus induced by ketamine infusion.

PubMed

Hatab, Sarah Z; Singh, Arun; Felner, Eric I; Kamat, Pradip

2014-12-01

Report a case of central diabetes insipidus (DI) associated with ketamine infusion. A 2-year-old girl with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and stable hypertrophic cardiomyopathy was admitted to the pediatric intensive care with pneumonia. She subsequently developed respiratory failure and required intubation. Continuous ketamine infusion was used for the sedation and facilitation of mechanical ventilation. Shortly after infusion of ketamine, the patient developed DI and responded appropriately to vasopressin. The Naranjo adverse drug reaction probability scale indicated a probable relationship between the development of central DI and ketamine. The most likely mechanism involves ketamine's antagonist action on N-methyl-d-aspartate receptors, resulting in inhibition of glutamate-stimulated arginine vasopressin release from the neurohypophysis. This is the second case report of ketamine-induced central DI and the only report in children. Clinicians who sedate children with continuous ketamine infusions should monitor patients for developing signs and symptoms of DI by measuring serum sodium and urine output prior to, during, and after ketamine infusion in order to make a timely diagnosis of this potentially serious complication. © The Author(s) 2014.

New insights into the dynamic regulation of water and acid-base balance by renal epithelial cells.

PubMed

Brown, Dennis; Bouley, Richard; Păunescu, Teodor G; Breton, Sylvie; Lu, Hua A J

2012-05-15

Maintaining tight control over body fluid and acid-base homeostasis is essential for human health and is a major function of the kidney. The collecting duct is a mosaic of two cell populations that are highly specialized to perform these two distinct processes. The antidiuretic hormone vasopressin (VP) and its receptor, the V2R, play a central role in regulating the urinary concentrating mechanism by stimulating accumulation of the aquaporin 2 (AQP2) water channel in the apical membrane of collecting duct principal cells. This increases epithelial water permeability and allows osmotic water reabsorption to occur. An understanding of the basic cell biology/physiology of AQP2 regulation and trafficking has informed the development of new potential treatments for diseases such as nephrogenic diabetes insipidus, in which the VP/V2R/AQP2 signaling axis is defective. Tubule acidification due to the activation of intercalated cells is also critical to organ function, and defects lead to several pathological conditions in humans. Therefore, it is important to understand how these "professional" proton-secreting cells respond to environmental and cellular cues. Using epididymal proton-secreting cells as a model system, we identified the soluble adenylate cyclase (sAC) as a sensor that detects luminal bicarbonate and activates the vacuolar proton-pumping ATPase (V-ATPase) via cAMP to regulate tubular pH. Renal intercalated cells also express sAC and respond to cAMP by increasing proton secretion, supporting the hypothesis that sAC could function as a luminal sensor in renal tubules to regulate acid-base balance. This review summarizes recent advances in our understanding of these fundamental processes.

New insights into the dynamic regulation of water and acid-base balance by renal epithelial cells

PubMed Central

Bouley, Richard; Pǎunescu, Teodor G.; Breton, Sylvie; Lu, Hua A. J.

2012-01-01

Maintaining tight control over body fluid and acid-base homeostasis is essential for human health and is a major function of the kidney. The collecting duct is a mosaic of two cell populations that are highly specialized to perform these two distinct processes. The antidiuretic hormone vasopressin (VP) and its receptor, the V2R, play a central role in regulating the urinary concentrating mechanism by stimulating accumulation of the aquaporin 2 (AQP2) water channel in the apical membrane of collecting duct principal cells. This increases epithelial water permeability and allows osmotic water reabsorption to occur. An understanding of the basic cell biology/physiology of AQP2 regulation and trafficking has informed the development of new potential treatments for diseases such as nephrogenic diabetes insipidus, in which the VP/V2R/AQP2 signaling axis is defective. Tubule acidification due to the activation of intercalated cells is also critical to organ function, and defects lead to several pathological conditions in humans. Therefore, it is important to understand how these “professional” proton-secreting cells respond to environmental and cellular cues. Using epididymal proton-secreting cells as a model system, we identified the soluble adenylate cyclase (sAC) as a sensor that detects luminal bicarbonate and activates the vacuolar proton-pumping ATPase (V-ATPase) via cAMP to regulate tubular pH. Renal intercalated cells also express sAC and respond to cAMP by increasing proton secretion, supporting the hypothesis that sAC could function as a luminal sensor in renal tubules to regulate acid-base balance. This review summarizes recent advances in our understanding of these fundamental processes. PMID:22460710

Efficacy and safety of tolvaptan in heart failure patients with volume overload despite the standard treatment with conventional diuretics: a phase III, randomized, double-blind, placebo-controlled study (QUEST study).

PubMed

Matsuzaki, Masunori; Hori, Masatsugu; Izumi, Tohru; Fukunami, Masatake

2011-12-01

Diuretics are recommended to treat volume overload with heart failure (HF), however, they may cause serum electrolyte imbalance, limiting their use. Moreover, patients with advanced HF could poorly respond to these diuretics. In this study, we evaluated the efficacy and safety of Tolvaptan, a competitive vasopressin V2-receptor antagonist developed as a new drug to treat volume overload in HF patients. A phase III, multicenter, randomized, double-blind, placebo-controlled parallel study was performed to assess the efficacy and safety of tolvaptan in treating HF patients with volume overload despite the use of conventional diuretics. One hundred and ten patients were randomly assigned to receive either placebo or 15 mg/day tolvaptan for 7 consecutive days. Compared with placebo, tolvaptan administered for 7 days significantly reduced body weight and improved symptoms associated with volume overload. The safety profile of tolvaptan was considered acceptable for clinical use with minimal adverse effects. Tolvaptan reduced volume overload and improved congestive symptoms associated with HF by a potent water diuresis (aquaresis).

Plasma volume, osmolality, vasopressin, and renin activity during graded exercise in man

NASA Technical Reports Server (NTRS)

Convertino, V. A.; Keil, L. C.; Bernauer, E. M.; Greenleaf, J. E.

1981-01-01

The influence of work intensity on plasma volume, osmolality, vasopressin and renin activity and the interrelationships between these responses are investigated. Plasma volume, renin activity and osmotic, sodium and arginine vasopressin concentrations were measured in venous blood samples taken from 15 healthy male subjects before and after six minutes of bicycle ergometer exercise at 100, 175 and 225 W. Plasma volume is found to decrease significantly with increasing work intensity, while increases in Na(+) concentration, osmolality and vasopressin are only observed to be significant when the work intensity exceeds 40% maximal aerobic capacity and plasma resin activity increased linearly at all work levels. In addition, significant correlations are observed between plasma volume and osmolality and sodium changes, and between vasopressin and osmolality and sodium content changes. Data thus support the hypotheses that (1) vasopressin may be the primary controlling endocrine for fluid and electrolyte levels following exercise; (2) an exercise intensity greater than 40% maximal aerobic capacity is required to stimulate vasopressin release through changes in plasma osmolality; and (3) the stimulation of the renin-angiotensin system is a more general stress response.

The vasopressin V(1b) receptor antagonist SSR149415 in the treatment of major depressive and generalized anxiety disorders: results from 4 randomized, double-blind, placebo-controlled studies.

PubMed

Griebel, Guy; Beeské, Sandra; Stahl, Stephen M

2012-11-01

These studies were designed to evaluate the efficacy and tolerability of the first nonpeptide vasopressin V(1b) receptor antagonist, SSR149415, in the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD). Studies were randomized 8-week, double-blind, placebo-controlled trials evaluating 100- and 250-mg twice daily doses of SSR149415, placebo, and escitalopram 10 mg/day or paroxetine 20 mg/day, conducted from August 2006 through February 2008. Participants met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for MDD or GAD. Baseline Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HDRS) total scores were ≥ 24 and 18, respectively, and in the GAD trial baseline Hamilton Anxiety Rating Scale (HARS) score was ≥ 22. Primary efficacy variables included changes from baseline in total score on HDRS or HARS and MADRS, and the secondary variable included changes in the Clinical Global Impressions-Severity of Illness score (CGI-S). A 4-week, double-blind, placebo-controlled study evaluating the effect of 100- and 250-mg twice daily doses of SSR149415 on the hypothalamic-pituitary-adrenal (HPA) axis in MDD patients was also conducted. In the GAD trial, SSR149415 did not separate from placebo on the primary (HARS-100 mg: P = .29; 250 mg: P = .21) and secondary (CGI-S-100 mg: P = .18; 250 mg: P = .24) outcome measures, while paroxetine demonstrated efficacy (HARS: P = .003; CGI-S: P = .01). In 2 MDD trials, SSR149415-treated patients did not show significant improvement from baseline on any outcome measure compared with placebo-treated patients (HDRS-100 mg: P = .21 and .48, respectively; 250 mg: P = .22 and P = .46, respectively; CGI-S-100 mg: P = .64 and P = .82, respectively; 250 mg: P = .33 and P = .08, respectively). In the third MDD study, SSR149415 250 mg (P = .04), but not escitalopram (P = .15), demonstrated significant improvement compared to placebo on the HDRS total score at week 8. SSR149415 had no deleterious effects on the HPA axis. These studies demonstrate that SSR149415 may not be useful for the treatment of GAD and that its antidepressant potential needs to be further evaluated. ClinicalTrials.gov identifiers: NCT00374166 (Sanofi ID number: DFI5880), NCT00361491 (Sanofi ID number: DFI5879), NCT00358631 (Sanofi ID number: DFI5878), NCT01606384 (Sanofi ID number: PDY5467). © Copyright 2012 Physicians Postgraduate Press, Inc.

P2Y12 Receptor Localizes in the Renal Collecting Duct and Its Blockade Augments Arginine Vasopressin Action and Alleviates Nephrogenic Diabetes Insipidus.

PubMed

Zhang, Yue; Peti-Peterdi, Janos; Müller, Christa E; Carlson, Noel G; Baqi, Younis; Strasburg, David L; Heiney, Kristina M; Villanueva, Karie; Kohan, Donald E; Kishore, Bellamkonda K

2015-12-01

P2Y12 receptor (P2Y12-R) signaling is mediated through Gi, ultimately reducing cellular cAMP levels. Because cAMP is a central modulator of arginine vasopressin (AVP)-induced water transport in the renal collecting duct (CD), we hypothesized that if expressed in the CD, P2Y12-R may play a role in renal handling of water in health and in nephrogenic diabetes insipidus. We found P2Y12-R mRNA expression in rat kidney, and immunolocalized its protein and aquaporin-2 (AQP2) in CD principal cells. Administration of clopidogrel bisulfate, an irreversible inhibitor of P2Y12-R, significantly increased urine concentration and AQP2 protein in the kidneys of Sprague-Dawley rats. Notably, clopidogrel did not alter urine concentration in Brattleboro rats that lack AVP. Clopidogrel administration also significantly ameliorated lithium-induced polyuria, improved urine concentrating ability and AQP2 protein abundance, and reversed the lithium-induced increase in free-water excretion, without decreasing blood or kidney tissue lithium levels. Clopidogrel administration also augmented the lithium-induced increase in urinary AVP excretion and suppressed the lithium-induced increase in urinary nitrates/nitrites (nitric oxide production) and 8-isoprostane (oxidative stress). Furthermore, selective blockade of P2Y12-R by the reversible antagonist PSB-0739 in primary cultures of rat inner medullary CD cells potentiated the expression of AQP2 and AQP3 mRNA, and cAMP production induced by dDAVP (desmopressin). In conclusion, pharmacologic blockade of renal P2Y12-R increases urinary concentrating ability by augmenting the effect of AVP on the kidney and ameliorates lithium-induced NDI by potentiating the action of AVP on the CD. This strategy may offer a novel and effective therapy for lithium-induced NDI. Copyright © 2015 by the American Society of Nephrology.

Vasopressin responses to unloading arterial baroreceptors during cardiac nerve blockade in conscious dogs

NASA Technical Reports Server (NTRS)

O'Donnell, C. P.; Keil, L. C.; Thrasher, T. N.

1992-01-01

We examined the relative contributions of afferent input from the heart and from arterial baroreceptors in the stimulation of arginine vasopressin (AVP) secretion in response to hypotension caused by thoracic inferior vena caval constriction (TIVCC). Afferent input from cardiac receptors was reversibly blocked by infusing 2% procaine into the pericardial space to anesthetize the cardiac nerves. Acute cardiac nerve blockade (CNB) alone caused a rise in mean arterial pressure (MAP) of 24 +/- 3 mmHg but no change in plasma AVP. If the rise in MAP was prevented by TIVCC, plasma AVP increased by 39 +/- 15 pg/ml, and if MAP was allowed to increase and then was forced back to control by TIVCC, plasma AVP increased by 34 +/- 15 pg/ml. Thus the rise in MAP during CNB stimulated arterial baroreceptors, which in turn compensated for the loss of inhibitory input from cardiac receptors on AVP secretion. These results indicate that the maximum secretory response resulting from complete unloading of cardiac receptors at a normal MAP results in a mean increase in plasma AVP of 39 pg/ml in this group of dogs. When MAP was reduced 25% below control levels (from 95 +/- 5 to 69 +/- 3 mmHg) by TIVCC during pericardial saline infusion, plasma AVP increased by 79 +/- 42 pg/ml. However, the same degree of hypotension during CNB (MAP was reduced from 120 +/- 5 to 71 +/- 3 mmHg) led to a greater (P less than 0.05) increase in plasma AVP of 130 +/- 33 pg/ml. Because completely unloading cardiac receptors can account for an increase of only 39 pg/ml on average in this group of dogs, the remainder of the increase in plasma AVP must be due to other sources of stimulation. We suggest that the principal stimulus to AVP secretion after acute CNB in these studies arises from unloading the arterial baroreceptors.

Efficacy of vasopressin-epinephrine compared to epinephrine alone for out of hospital cardiac arrest patients: A systematic review and meta-analysis.

PubMed

Zhang, Qiang; Liu, Bo; Zhao, Lianxing; Qi, Zhijiang; Shao, Huan; An, Le; Li, Chunsheng

2017-10-01

The aim of this study was to conduct a meta-analysis to evaluate the efficacy of vasopressin-epinephrine compared to epinephrine alone in patients who suffered out-of-hospital cardiac arrest (OHCA). Relevant studies up to February 2017 were identified by searching in PubMed, EMBASE, the Cochrane Library, Wanfang for randomized controlled trials(RCTs) assigning adults with cardiac arrest to treatment with vasopressin-epinephrine (VEgroup) vs adrenaline (epinephrine) alone (E group). The outcome point was return of spontaneous circulation (ROSC) for patients suffering from OHCA. Heterogeneity, subgroup analysis, sensitivity analysis and publication bias were explored. Individual patient data were obtained from 5047 participants who experienced OHCA in nine studies. Odds ratios (ORs) were calculated using a random-effects model and results suggested that vasopressin-epinephrine was associated with higher rate of ROSC (OR=1.67, 95% CI=1.13-2.49, P<0.00001, and total I 2 =83%). Subgroup showed that vasopressin-epinephrine has a significant association with improvements in ROSC for patients from Asia (OR=3.30, 95% CI=1.30-7.88); but for patients from other regions, there was no difference between vasopressin-epinephrine and epinephrine alone (OR=1.07, 95% CI=0.72-1.61). According to the pooled results of the subgroup, combination of vasopressin and adrenaline can improve ROSC of OHCA from Asia, but patients from other regions who suffered from OHCA cannot benefit from combination of vasopressin and epinephrine. Copyright © 2017 Elsevier Inc. All rights reserved.

PGE2 receptor EP3 inhibits water reabsorption and contributes to polyuria and kidney injury in a streptozotocin-induced mouse model of diabetes.

PubMed

Hassouneh, Ramzi; Nasrallah, Rania; Zimpelmann, Joe; Gutsol, Alex; Eckert, David; Ghossein, Jamie; Burns, Kevin D; Hébert, Richard L

2016-06-01

The first clinical manifestation of diabetes is polyuria. The prostaglandin E2 (PGE2) receptor EP3 antagonises arginine vasopressin (AVP)-mediated water reabsorption and its expression is increased in the diabetic kidney. The purpose of this work was to study the contribution of EP3 to diabetic polyuria and renal injury. Male Ep 3 (-/-) (also known as Ptger3 (-/-)) mice were treated with streptozotocin (STZ) to generate a mouse model of diabetes and renal function was evaluated after 12 weeks. Isolated collecting ducts (CDs) were microperfused to study the contribution of EP3 to AVP-mediated fluid reabsorption. Ep 3 (-/-)-STZ mice exhibited attenuated polyuria and increased urine osmolality compared with wild-type STZ (WT-STZ) mice, suggesting enhanced water reabsorption. Compared with WT-STZ mice, Ep 3 (-/-)-STZ mice also had increased protein expression of aquaporin-1, aquaporin-2, and urea transporter A1, and reduced urinary AVP excretion, but increased medullary V2 receptors. In vitro microperfusion studies indicated that Ep 3 (-/-) and WT-STZ CDs responded to AVP stimulation similarly to those of wild-type mice, with a 60% increase in fluid reabsorption. In WT non-injected and WT-STZ mice, EP3 activation with sulprostone (PGE2 analogue) abrogated AVP-mediated water reabsorption; this effect was absent in mice lacking EP3. A major finding of this work is that Ep 3 (-/-)-STZ mice showed blunted renal cyclooxygenase-2 protein expression, reduced renal hypertrophy, reduced hyperfiltration and reduced albuminuria, as well as diminished tubular dilation and nuclear cysts. Taken together, the data suggest that EP3 contributes to diabetic polyuria by inhibiting expression of aquaporins and that it promotes renal injury during diabetes. EP3 may prove to be a promising target for more selective management of diabetic kidney disease.

In vivo somatostatin, vasopressin, and oxytocin synthesis in diabetic rat hypothalamus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fernstrom, J.D.; Fernstrom, M.H.; Kwok, R.P.

1990-04-01

The in vivo labeling of somatostatin-14, somatostatin-28, arginine vasopressin, and oxytocin was studied in rat hypothalamus after third ventricular administration of (35S)cysteine to streptozotocin-diabetic and normal rats. Immunoreactive somatostatin levels in hypothalamus were unaffected by diabetes, as was the incorporation of (35S)cysteine into hypothalamic somatostatin-14 and somatostatin-28. In contrast, immunoreactive vasopressin levels in hypothalamus and posterior pituitary (and oxytocin levels in posterior pituitary) were below normal in diabetic rats. Moreover, (35S)cysteine incorporation into hypothalamic vasopressin and oxytocin (probably mainly in the paraventricular nucleus because of its proximity to the third ventricular site of label injection) was significantly above normal. Themore » increments in vasopressin and oxytocin labeling were reversed by insulin administration. In vivo cysteine specific activity and the labeling of acid-precipitable protein did not differ between normal and diabetic animals; effects of diabetes on vasopressin and oxytocin labeling were therefore not caused by simple differences in cysteine specific activity. These results suggest that diabetes (1) does not influence the production of somatostatin peptides in hypothalamus but (2) stimulates the synthesis of vasopressin and oxytocin. For vasopressin at least, the increase in synthesis may be a compensatory response to the known increase in its secretion that occurs in uncontrolled diabetes.« less

Evolutionary Genetics of Hypoxia Tolerance in Cetaceans during Diving

PubMed Central

Tian, Ran; Wang, Zhengfei; Niu, Xu; Zhou, Kaiya; Xu, Shixia; Yang, Guang

2016-01-01

Hypoxia was a major challenge faced by cetaceans during the course of secondary aquatic adaptation. Although physiological traits of hypoxia tolerance in cetaceans have been well characterized, the underlying molecular mechanisms remain unknown. We investigated the sequences of 17 hypoxia-tolerance-related genes in representative cetaceans to provide a comprehensive insight into the genetic basis of hypoxia tolerance in these animals. Genes involved in carrying and transporting oxygen in the blood and muscle (hemoglobin-α and β, myoglobin), and genes involved in the regulation of vasoconstriction (endothelin-1, -2, and -3; endothelin receptor type A and B; adrenergic receptor α-1D; and arginine vasopressin) appear to have undergone adaptive evolution, evidence for positive selection on their particular sites, and radical physiochemical property changes of selected condons. Interestingly, “long-diving” cetaceans had relatively higher ω (dN/dS) values than “short-diving” cetaceans for the hemoglobin β gene, indicating divergent selective pressure presented in cetacean lineages with different diving abilities. Additionally, parallel positive selection or amino acid changes (ADRA1D: P50A, A53G, AVPR1B: I/V270T) among animals exposed to different hypoxia habitats reflect functional convergence or similar genetic mechanisms of hypoxia tolerance. In summary, positive selection, divergent selective pressures, and parallel evolution at the molecular level provided some new insights into the genetic adaptation of hypoxia tolerance. PMID:26912402

Exploiting cancer’s phenotypic guise against itself: targeting ectopically expressed peptide G-protein coupled receptors for lung cancer therapy

PubMed Central

Khan, Mahjabin; Huang, Tao; Lin, Cheng-Yuan; Wu, Jiang; Fan, Bao-Min; Bian, Zhao-Xiang

2017-01-01

Lung cancer, claiming millions of lives annually, has the highest mortality rate worldwide. This advocates the development of novel cancer therapies that are highly toxic for cancer cells but negligibly toxic for healthy cells. One of the effective treatments is targeting overexpressed surface receptors of cancer cells with receptor-specific drugs. The receptors-in-focus in the current review are the G-protein coupled receptors (GPCRs), which are often overexpressed in various types of tumors. The peptide subfamily of GPCRs is the pivot of the current article owing to the high affinity and specificity to and of their cognate peptide ligands, and the proven efficacy of peptide-based therapeutics. The article summarizes various ectopically expressed peptide GPCRs in lung cancer, namely, Cholecystokinin-B/Gastrin receptor, the Bombesin receptor family, Bradykinin B1 and B2 receptors, Arginine vasopressin receptors 1a, 1b and 2, and the Somatostatin receptor type 2. The autocrine growth and pro-proliferative pathways they mediate, and the distinct tumor-inhibitory effects of somatostatin receptors are then discussed. The next section covers how these pathways may be influenced or ‘corrected’ through therapeutics (involving agonists and antagonists) targeting the overexpressed peptide GPCRs. The review proceeds on to Nano-scaled delivery platforms, which enclose chemotherapeutic agents and are decorated with peptide ligands on their external surface, as an effective means of targeting cancer cells. We conclude that targeting these overexpressed peptide GPCRs is potentially evolving as a highly promising form of lung cancer therapy. PMID:29262666

Chimpanzee sociability is associated with vasopressin (Avpr1a) but not oxytocin receptor gene (OXTR) variation.

PubMed

Staes, Nicky; Koski, Sonja E; Helsen, Philippe; Fransen, Erik; Eens, Marcel; Stevens, Jeroen M G

2015-09-01

The importance of genes in regulating phenotypic variation of personality traits in humans and animals is becoming increasingly apparent in recent studies. Here we focus on variation in the vasopressin receptor gene 1a (Avpr1a) and oxytocin receptor gene (OXTR) and their effects on social personality traits in chimpanzees. We combine newly available genetic data on Avpr1a and OXTR allelic variation of 62 captive chimpanzees with individual variation in personality, based on behavioral assessments. Our study provides support for the positive association of the Avpr1a promoter region, in particular the presence of DupB, and sociability in chimpanzees. This complements findings of previous studies on adolescent chimpanzees and studies that assessed personality using questionnaire data. In contrast, no significant associations were found for the single nucleotide polymorphism (SNP) ss1388116472 of the OXTR and any of the personality components. Most importantly, our study provides additional evidence for the regulatory function of the 5' promoter region of Avpr1a on social behavior and its evolutionary stable effect across species, including rodents, chimpanzees and humans. Although it is generally accepted that complex social behavior is regulated by a combination of genes, the environment and their interaction, our findings highlight the importance of candidate genes with large effects on behavioral variation. Copyright © 2015 Elsevier Inc. All rights reserved.

Urinary concentration does not exclusively rely on plasma vasopressin. A study between genders. Gender and diurnal urine regulation.

PubMed

Graugaard-Jensen, C; Hvistendahl, G M; Frøkiaer, J; Bie, P; Djurhuus, J C

2014-09-01

We investigated the influence of gender on the diurnal regulation of urine production with special focus on vasopressin, oxytocin and prostaglandin E2. Fifteen young women in mid-follicular phase and 22 young men (20-33 years) were included. All participants underwent a 24-h circadian inpatient study under standardized conditions for measurements of plasma vasopressin, oxytocin, sodium and osmolality. Urine was fractionally collected for measurements of electrolytes, aquaporin-2 and prostaglandin E2. Plasma vasopressin expressed a diurnal rhythm with a night-time increase in both genders (P < 0.001). The ratio between mean daytime and mean night-time was 1.57 [95% CI: 1.33-1.84] P < 0.001 in men and 1.35 [95% CI: 1.11-1.64] P = 0.002 in women. P-vasopressin was higher in males during the night (P < 0.05). There was no difference in diuresis (P = 0.43), urine osmolality (P = 0.12) or aquaporin-2 excretion (P = 0.80) between genders. We found a trend towards a higher reabsorption of free water in males (P = 0.07). The excretion of prostaglandin E2 was higher in males (P < 0.001). There was no diurnal rhythm in p-oxytocin (P = 0.37) and no correlation to diuresis, urine osmolality or aquaporin-2 excretions. Similar urinary flows and osmolalities are associated with levels of plasma vasopressin and renal PGE2, which are higher in males than in females. Oxytocin does not seem to play a role in the diurnal urine formation, whereas prostaglandin E2 could represent a mediator of the gender difference, not only as a mediator of the vasopressin response, but also as an independent factor. These findings need further elucidation. © 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

Blockade of arginine vasotocin signaling reduces aggressive behavior and c-Fos expression in the preoptic area and periventricular nucleus of the posterior tuberculum in male Amphiprion ocellaris.

PubMed

Yaeger, C; Ros, A M; Cross, V; Deangelis, R S; Stobaugh, D J; Rhodes, J S

2014-05-16

Many marine fishes change sex in response to social cues when the dominance hierarchy is perturbed. Arginine-vasotocin (AVT) and the mammalian homolog arginine vasopressin are neuropeptides involved in social and reproductive behaviors across vertebrate taxa. The goal of this study was to determine whether AVT signaling influences aggression and expression of c-Fos, a marker of neuroplasticity, in key brain regions of the social decision circuit in Amphiprion ocellaris clownfish, a species where behavioral dominance precedes gonadal sex change from male to female. In experiment 1, juvenile clownfish (average mass 2.5g) were paired together in a tank (a total of 24 pairs), matched approximately for size with one fish randomly receiving either an intraperitoneal injection of the arginine vasopressin V1a receptor antagonist (Manning compound) or saline vehicle, and evaluated for aggressive and submissive behaviors over a 10-min period. The second experiment was a repeat of the first using five pairs of mature, reproductive males, except the animals interacted for 90-min immediately followed by euthanasia for immunohistochemical detection of c-Fos protein. Numbers of c-Fos-positive cells were quantified in the preoptic area of the hypothalamus (POA), the anterior tuberal nucleus (aTn), and periventricular nucleus of the posterior tuberculum (TPp). Manning compound significantly reduced aggression and the probability of winning the contest relative to saline (vehicle) controls. In experiment 2, saline-treated fish displayed approximately twice as many c-Fos-positive cells in the POA and 25% more in the TPp than the Manning-treated fish, no differences were observed in the aTn. Taken together, results suggest AVT signaling is necessary for aggressive behavior and expression of neuroplasticity in the POA and TPp that likely contributes to behavioral dominance and hence, sex change in A. ocellaris. Published by Elsevier Ltd.

Systemic PPARγ deletion causes severe disturbance in fluid homeostasis in mice

PubMed Central

Zhou, Li; Panasiuk, Alexandra; Downton, Maicy; Zhao, Daqiang; Yang, Baoxue; Jia, Zhanjun

2015-01-01

The pharmacological action of peroxisome proliferator-activated receptor (PPAR)γ in promoting sodium and water retention is well documented as highlighted by the major side-effect of body weight gain and edema associated with thiazolidinedione use. However, a possible physiological role of PPARγ in regulation of fluid metabolism has not been reported by previous studies. Here we analyzed fluid metabolism in inducible whole-body PPARγ knockout mice. The null mice developed severe polydipsia and polyuria, reduced urine osmolality, and modest hyperphagia. The phenomenon persisted during 3 days of pair feeding and pair drinking, accompanied by progressive weight loss. After 24 h water deprivation, the null mice had a lower urine osmolality, a higher urine volume, a greater weight loss, and a greater rise in hematocrit than the floxed control. Urinary vasopressin (AVP) excretion was not different between the genotypes under basal condition or after WD. The response of urine osmolality to acute and chronic 1-desamino-8-d-arginine vasopressin treatment was attenuated in the null mice, but the total abundance or phosphorylation of aquaporin 2 (AQP2) in the kidney or AVP-induced cAMP production in inner medullary collecting duct suspensions was unaffected. Overall, PPARγ participates in physiological control of fluid homeostasis through an unknown mechanism involving cAMP/AQP2-independent enhancement of AVP response. PMID:26330489

Effects of vasopressin administration on diuresis of water immersion in normal humans

NASA Technical Reports Server (NTRS)

Epstein, M.; Denunzio, A. G.; Loutzenhiser, R. D.

1981-01-01

The influence of vasopressin suppression on the diuresis encountered during water immersion is investigated in studies on normal humans immersed to the neck. Six hydrated male subjects were studied on two occasions while undergoing 6 h of immersion without or during the administration of aqueous vasopressin for the initial 4 h. Neck immersion is found to result in a significant increase in urinary flow rate beginning in the first hour and persisting throughout the immersion. The administration of vasopressin markedly attenuated the diuretic response throughout the period of infusion, while cessation of vasopressin administration during the final 2 h of immersion resulted in a marked offset of the antidiuresis. Results thus support the view that the suppression of antidiuretic hormone contributes to the immersion diuresis of hydrated subjects.

Oxytocin and vasopressin flatten dominance hierarchy and enhance behavioral synchrony in part via anterior cingulate cortex.

PubMed

Jiang, Yaoguang; Platt, Michael L

2018-05-29

The neuropeptides oxytocin (OT) and arginine vasopressin (AVP) influence social functions in many mammals. In humans and rhesus macaques, OT delivered intranasally can promote prosocial behavior in certain contexts. Yet the precise neural mechanisms mediating these behavioral effects remain unclear. Here we show that treating a group of male macaque monkeys intranasally with aerosolized OT relaxes their spontaneous social interactions with other monkeys. OT reduces differences in social behavior between dominant and subordinate monkeys, thereby flattening the status hierarchy. OT also increases behavioral synchrony within a pair. Intranasal delivery of aerosolized AVP reproduces the effects of OT with greater efficacy. Remarkably, all behavioral effects are replicated when OT or AVP is injected focally into the anterior cingulate gyrus (ACCg), a brain area linked to empathy and other-regarding behavior. ACCg lacks OT receptors but is rich in AVP receptors, suggesting exogenous OT may shape social behavior, in part, via nonspecific binding. Notably, OT and AVP alter behaviors of both the treated monkey and his untreated partner, consistent with enhanced feedback through reciprocal social interactions. These findings bear important implications for use of OT in both basic research and as a therapy for social impairments in neurodevelopmental disorders.

Involvement of Prolactin-Releasing Peptide in the Activation of Oxytocin Neurones in Response to Food Intake

PubMed Central

Yamashita, M; Takayanagi, Y; Yoshida, M; Nishimori, K; Kusama, M; Onaka, T

2013-01-01

Food intake activates neurones expressing prolactin-releasing peptide (PrRP) in the medulla oblongata and oxytocin neurones in the hypothalamus. Both PrRP and oxytocin have been shown to have an anorexic action. In the present study, we investigated whether the activation of oxytocin neurones following food intake is mediated by PrRP. We first examined the expression of PrRP receptors (also known as GPR10) in rats. Immunoreactivity of PrRP receptors was observed in oxytocin neurones and in vasopressin neurones in the paraventricular and supraoptic nuclei of the hypothalamus and in the bed nucleus of the stria terminalis. Application of PrRP to isolated supraoptic nuclei facilitated the release of oxytocin and vasopressin. In mice, re-feeding increased the expression of Fos protein in oxytocin neurones of the hypothalamus and bed nucleus of the stria terminalis. The increased expression of Fos protein in oxytocin neurones following re-feeding or i.p. administration of cholecystokinin octapeptide (CCK), a peripheral satiety factor, was impaired in PrRP-deficient mice. CCK-induced oxytocin increase in plasma was also impaired in PrRP-deficient mice. Furthermore, oxytocin receptor-deficient mice showed an increased meal size, as reported in PrRP-deficient mice and in CCKA receptor-deficient mice. These findings suggest that PrRP mediates, at least in part, the activation of oxytocin neurones in response to food intake, and that the CCK–PrRP–oxytocin pathway plays an important role in the control of the termination of each meal. PMID:23363338

Changes in social functioning and circulating oxytocin and vasopressin following the migration to a new country.

PubMed

Gouin, Jean-Philippe; Pournajafi-Nazarloo, Hossein; Carter, C Sue

2015-02-01

Prior studies have reported associations between plasma oxytocin and vasopressin and markers of social functioning. However, because most human studies have used cross-sectional designs, it is unclear whether plasma oxytocin and vasopressin influences social functioning or whether social functioning modulates the production and peripheral release of these peptides. In order to address this question, we followed individuals who experienced major changes in social functioning subsequent to the migration to a new country. In this study, 59 new international students were recruited shortly after arrival in the host country and reassessed 2 and 5 months later. At each assessment participants provided information on their current social functioning and blood samples for oxytocin and vasopressin analysis. Results indicated that changes in social functioning were not related to changes in plasma oxytocin. Instead, baseline oxytocin predicted changes in social relationship satisfaction, social support, and loneliness over time. In contrast, plasma vasopressin changed as a function of social integration. Baseline vasopressin was not related to changes in social functioning over time. These results emphasize the different roles of plasma oxytocin and vasopressin in responses to changes in social functioning in humans. Copyright © 2014 Elsevier Inc. All rights reserved.

Theoretical studies of the mechanism of the action of the neurohypophyseal hormones. I. Molecular electrostatic potential (MEP) and molecular electrostatic field (MEF) maps of some vasopressin analogues

NASA Astrophysics Data System (ADS)

Liwo, Adam; Tempczyk, Anna; Grzonka, Zbigniew

1989-09-01

Continuing our theoretical studies of the oxytocin and vasopressin analogues, we have analysed the molecular electrostatic potential (MEP) and the norm of the molecular electrostatic field (MEF) of [1- β-mercaptopropionic acid]-arginine-vasopressin ([Mpa1]-AVP), [1-( β-mercapto- β,β-cyclopentamethylene)propionic acid]-arginine-vasopressin ([Cpp']-AVP), and [1-thiosalicylic acid]-arginine-vasopressin ([Ths']-AVP) whose low-energy conformations were calculated in our previous work. These compounds are known from experiment to exhibit different biological activity. The scalar fields mentioned determine the energy of interaction with either charged (MEP) or polar (MEF) species, the energy being in the second case either optimal or Boltzmann-averaged over all the possible orientations of the dipole moment versus the electrostatic field. The electrostatic interactions slowly vanish with distance and can therefore be considered to be the factor determining the molecular shape at greater distances, which can help in both predicting the interactions with the receptor at the stage of remote recognition and in finding the preferred directions of solvation by a polar solvent. In the analysis of the fields three techniques have been used: (i) the construction of maps in certain planes; (ii) the construction of maps on spheres centered in the charge center of the molecule under study and of poles chosen according to the main axes of the quadrupole moment; and (iii) the construction of surfaces corresponding to a given value of potential. The results obtained show that the shapes of both MEP and MEF are similar in the case of [Mpa1]-AVP and [Cpp1-AVP (biologically active), while some differences emerge when comparing these compounds with [Ths1]-AVP (inactive). It has also been found that both MEP and MEF depend even more strongly on conformation.

Protein Kinase C-dependent Phosphorylation of Transient Receptor Potential Canonical 6 (TRPC6) on Serine 448 Causes Channel Inhibition*

PubMed Central

Bousquet, Simon M.; Monet, Michaël; Boulay, Guylain

2010-01-01

TRPC6 is a cation channel in the plasma membrane that plays a role in Ca2+ entry following the stimulation of a Gq-protein coupled or tyrosine kinase receptor. A dysregulation of TRPC6 activity causes abnormal proliferation of smooth muscle cells and glomerulosclerosis. In the present study, we investigated the regulation of TRPC6 activity by protein kinase C (PKC). We showed that inhibiting PKC with GF1 or activating it with phorbol 12-myristate 13-acetate potentiated and inhibited agonist-induced Ca2+ entry, respectively, into cells expressing TRPC6. Similar results were obtained when TRPC6 was directly activated with 1-oleyl-2-acetyl-sn-glycerol. Activation of the cells with carbachol increased the phosphorylation of TRPC6, an effect that was prevented by the inhibition of PKC. The target residue of PKC was identified by an alanine screen of all canonical PKC sites on TRPC6. Unexpectedly, all the mutants, including TRPC6S768A (a residue previously proposed to be a target for PKC), displayed PKC-dependent inhibition of channel activity. Phosphorylation prediction software suggested that Ser448, in a non-canonical PKC consensus sequence, was a potential target for PKCδ. Ba2+ and Ca2+ entry experiments revealed that GF1 did not potentiate TRPC6S448A activity. Moreover, activation of PKC did not enhance the phosphorylation state of TRPC6S448A. Using A7r5 vascular smooth muscle cells, which endogenously express TRPC6, we observed that a novel PKC isoform is involved in the inhibition of the vasopressin-induced Ca2+ entry. Furthermore, knocking down PKCδ in A7r5 cells potentiated vasopressin-induced Ca2+ entry. In summary, we provide evidence that PKCδ exerts a negative feedback effect on TRPC6 through the phosphorylation of Ser448. PMID:20961851

Protein kinase C-dependent phosphorylation of transient receptor potential canonical 6 (TRPC6) on serine 448 causes channel inhibition.

PubMed

Bousquet, Simon M; Monet, Michaël; Boulay, Guylain

2010-12-24

TRPC6 is a cation channel in the plasma membrane that plays a role in Ca(2+) entry following the stimulation of a G(q)-protein coupled or tyrosine kinase receptor. A dysregulation of TRPC6 activity causes abnormal proliferation of smooth muscle cells and glomerulosclerosis. In the present study, we investigated the regulation of TRPC6 activity by protein kinase C (PKC). We showed that inhibiting PKC with GF1 or activating it with phorbol 12-myristate 13-acetate potentiated and inhibited agonist-induced Ca(2+) entry, respectively, into cells expressing TRPC6. Similar results were obtained when TRPC6 was directly activated with 1-oleyl-2-acetyl-sn-glycerol. Activation of the cells with carbachol increased the phosphorylation of TRPC6, an effect that was prevented by the inhibition of PKC. The target residue of PKC was identified by an alanine screen of all canonical PKC sites on TRPC6. Unexpectedly, all the mutants, including TRPC6(S768A) (a residue previously proposed to be a target for PKC), displayed PKC-dependent inhibition of channel activity. Phosphorylation prediction software suggested that Ser(448), in a non-canonical PKC consensus sequence, was a potential target for PKCδ. Ba(2+) and Ca(2+) entry experiments revealed that GF1 did not potentiate TRPC6(S448A) activity. Moreover, activation of PKC did not enhance the phosphorylation state of TRPC6(S448A). Using A7r5 vascular smooth muscle cells, which endogenously express TRPC6, we observed that a novel PKC isoform is involved in the inhibition of the vasopressin-induced Ca(2+) entry. Furthermore, knocking down PKCδ in A7r5 cells potentiated vasopressin-induced Ca(2+) entry. In summary, we provide evidence that PKCδ exerts a negative feedback effect on TRPC6 through the phosphorylation of Ser(448).

Insulin-regulated aminopeptidase immunoreactivity is abundantly present in human hypothalamus and posterior pituitary gland, with reduced expression in paraventricular and suprachiasmatic neurons in chronic schizophrenia.

PubMed

Bernstein, Hans-Gert; Müller, Susan; Dobrowolny, Hendrik; Wolke, Carmen; Lendeckel, Uwe; Bukowska, Alicja; Keilhoff, Gerburg; Becker, Axel; Trübner, Kurt; Steiner, Johann; Bogerts, Bernhard

2017-08-01

The vasopressin- and oxytocin-degrading enzyme insulin-regulated aminopeptidase (IRAP) is expressed in various organs including the brain. However, knowledge about its presence in human hypothalamus is fragmentary. Functionally, for a number of reasons (genetic linkage, hydrolysis of oxytocin and vasopressin, its role as angiotensin IV receptor in learning and memory and others) IRAP might play a role in schizophrenia. We studied the regional and cellular localization of IRAP in normal human brain with special emphasis on the hypothalamus and determined numerical densities of IRAP-expressing cells in the paraventricular, supraoptic and suprachiasmatic nuclei in schizophrenia patients and controls. By using immunohistochemistry and Western blot analysis, IRAP was immunolocalized in postmortem human brains. Cell countings were performed to estimate numbers and numerical densities of IRAP immunoreactive hypothalamic neurons in schizophrenia patients and control cases. Shape, size and regional distribution of IRAP-expressing cells, as well the lack of co-localization with the glia marker glutamine synthetase, show that IRAP is expressed in neurons. IRAP immunoreactive cells were observed in the hippocampal formation, cerebral cortex, thalamus, amygdala and, abundantly, hypothalamus. Double labeling experiments (IRAP and oxytocin/neurophysin 1, IRAP with vasopressin/neurophysin 2) revealed that IRAP is present in oxytocinergic and in vasopressinergic neurons. In schizophrenia patients, the numerical density of IRAP-expressing neurons in the paraventricular and the suprachiasmatic nuclei is significantly reduced, which might be associated with the reduction in neurophysin-containing neurons in these nuclei in schizophrenia. The pathophysiological role of lowered hypothalamic IRAP expression in schizophrenia remains to be established.

Copeptin Associates with Cause-Specific Mortality in Patients with Impaired Renal Function: Results from the LURIC and the 4D Study.

PubMed

Krane, Vera; Genser, Bernd; Kleber, Marcus E; Drechsler, Christiane; März, Winfried; Delgado, Graciela; Allolio, Bruno; Wanner, Christoph; Fenske, Wiebke

2017-05-01

In chronic kidney disease (CKD) arginine vasopressin (AVP) cannot efficiently act via renal V2-receptors. AVP is upregulated leading to augmented activation of V1a- and V1b-receptors, which might contribute to the increase in cardiovascular and infectious complications in CKD. Here, we evaluate copeptin, a surrogate of AVP, and its association with cause specific mortality among patients within the whole spectrum of renal function. Copeptin was measured in baseline samples from the LURIC (n = 3131 patients with coronary angiograms) and the 4D-Study (n = 1241 type 2 diabetic hemodialysis patients). Patients were stratified into 4 groups: estimated glomerular filtration rate (eGFR) ≥90 mL/min/1.73 m 2 , 60-89 mL/min/1.73 m 2 , <60 mL/min/1.73 m 2 , and hemodialysis. The association of copeptin with mortality was assessed by Cox proportional hazards regression during 9.9 years of median follow-up in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study and 4 years of median follow-up in the German Diabetes Dialysis Study (4D-Study). Median copeptin increased with decreasing eGFR: 5.6 [interquartile range (IQR), 3.1-8.1] pmol/L (eGFR ≥90 mL/min/1.73 m 2 ), 6.7 (2.9-10.5) pmol/L (eGFR 60-89 mL/min/1.73 m 2 ), 15.3 (6.7-23.9) pmol/L (eGFR <60 mL/min/1.73 m 2 ), and 80.8 (51.2-122) pmol/L (hemodialysis), respectively. Per SD increase in copeptin, the risk of coronary, infectious, and all-cause mortality increased by 25, 30, and 15% [hazard ratios (HR), 1.25; 95% CI, 1.13-1.39; HR, 1.30; 95% CI, 0.98-1.71; and HR, 1.15; 95% CI, 1.05-1.25], respectively, in patients with eGFR 60-89 mL/min/1.73 m 2 . Except for coronary death, results were similar among patients with more advanced renal disease. No significant association was found in patients with normal renal function. Copeptin concentrations were independently associated with coronary, infectious, and all-cause mortality in patients with renal impairment. In patients with normal renal function no significant association was found. © 2017 American Association for Clinical Chemistry.

Aquaporin-2 Regulation in Health and Disease

PubMed Central

Radin, M. Judith; Yu, Ming-Jiun; Stoedkilde, Lene; Miller, R. Lance; Hoffert, Jason D.; Frokiaer, Jorgen; Pisitkun, Trairak; Knepper, Mark A.

2012-01-01

Aquaporin-2 (AQP2), the vasopressin-regulated water channel of the renal collecting duct, is dysregulated in numerous water balance disorders in humans and animals including those associated with polyuria (e.g. urinary tract obstruction, hypokalemia, inflammation, and lithium toxicity) and dilutional hyponatremia (e.g. SIADH). Normal regulation of AQP2 by vasopressin involves two independent regulatory mechanisms: 1) short-term regulation of AQP2 trafficking to and from the apical plasma membrane, and 2) long term regulation of the total abundance of the AQP2 protein in the cells. Most water balance disorders are the result of dysregulation of processes that regulate the total abundance of AQP2 in collecting duct cells. In general, the level of AQP2 in a collecting duct cell is determined by a balance between production via translation of AQP2 mRNA and removal via degradation and/or secretion into the urine in exosomes. AQP2 abundance increases in response to vasopressin chiefly due to increased translation subsequent to increases in AQP2 mRNA. Vasopressin-mediated regulation AQP2 gene transcription is poorly understood, although several transcription factor binding elements in the 5’ flanking region of the AQP2 gene have been identified and candidate transcription factors corresponding to these element have been discovered in proteomics studies. Here we review progress in this area and discuss elements of vasopressin signaling in the collecting duct that may impinge on regulation of AQP2 in health and in the context of examples of polyuric diseases. PMID:23130944

Agonist activation of cytosolic Ca2+ in subfornical organ cells projecting to the supraoptic nucleus

NASA Technical Reports Server (NTRS)

Johnson, R. F.; Beltz, T. G.; Sharma, R. V.; Xu, Z.; Bhatty, R. A.; Johnson, A. K.

2001-01-01

The subfornical organ (SFO) is sensitive to both ANG II and ACh, and local application of these agents produces dipsogenic responses and vasopressin release. The present study examined the effects of cholinergic drugs, ANG II, and increased extracellular osmolarity on dissociated, cultured cells of the SFO that were retrogradely labeled from the supraoptic nucleus. The effects were measured as changes in cytosolic calcium in fura 2-loaded cells by using a calcium imaging system. Both ACh and carbachol increased intracellular ionic calcium concentration ([Ca2+]i). However, in contrast to the effects of muscarinic receptor agonists on SFO neurons, manipulation of the extracellular osmolality produced no effects, and application of ANG II produced only moderate effects on [Ca2+]i in a few retrogradely labeled cells. The cholinergic effects on [Ca2+]i could be blocked with the muscarinic receptor antagonist atropine and with the more selective muscarinic receptor antagonists pirenzepine and 4-diphenylacetoxy-N-methylpiperdine methiodide (4-DAMP). In addition, the calcium in the extracellular fluid was required for the cholinergic-induced increase in [Ca2+]i. These findings indicate that ACh acts to induce a functional cellular response in SFO neurons through action on a muscarinic receptor, probably of the M1 subtype and that the increase of [Ca2+]i, at least initially, requires the entry of extracellular Ca2+. Also, consistent with a functional role of M1 receptors in the SFO are the results of immunohistochemical preparations demonstrating M1 muscarinic receptor-like protein present within this forebrain circumventricular organ.

GPCR-I-TASSER: A hybrid approach to G protein-coupled receptor structure modeling and the application to the human genome

PubMed Central

Zhang, Jian; Yang, Jianyi; Jang, Richard; Zhang, Yang

2015-01-01

SUMMARY Experimental structure determination remains very difficult for G protein-coupled receptors (GPCRs). We propose a new hybrid protocol to construct GPCR structure models that integrates experimental mutagenesis data with ab initio transmembrane (TM) helix assembly simulations. The method was tested on 24 known GPCRs where the ab initio TM-helix assembly procedure constructed the correct fold for 20 cases. When combined with weak-homology and sparse mutagenesis restraints, the method generated correct folds for all the tested cases with an average C-alpha RMSD 2.4 Å in the TM-regions. The new hybrid protocol was applied to model all 1026 GPCRs in the human genome, where 923 have a high confidence score that are expected to have correct folds; these contain many pharmaceutically important families with no previously solved structures, including Trace amine, Prostanoids, Releasing hormones, Melanocortins, Vasopressin and Neuropeptide Y receptors. The results demonstrate new progress on genome-wide structure modeling of transmembrane proteins. PMID:26190572

Estrogen receptor β and Liver X receptor β: biology and therapeutic potential in CNS diseases.

PubMed

Warner, M; Gustafsson, J-A

2015-02-01

In the last decade of the twentieth century, two nuclear receptors were discovered in our laboratory and, very surprisingly, were found to have key roles in the central nervous system. These receptors have provided some novel insights into the etiology and progression of neurodegenerative diseases and anxiety disorders. The two receptors are estrogen receptor beta (ERβ) and liver X receptor beta (LXRβ). Both ERβ and LXRβ have potent anti-inflammatory activities and, in addition, LXRβ is involved in the genesis of dopaminergic neurons during development and protection of these neurons against neurodegeneration in adult life. ERβ is involved in migration of cortical neurons and calretinin-positive GABAergic interneurons during development and maintenance of serotonergic neurons in adults. Both receptors are present in magnocellular neurons of the hypothalamic preoptic area including those expressing vasopressin and oxytocin. As both ERβ and LXRβ are ligand-activated transcription factors, their ligands hold great potential in the treatment of diseases of the CNS.

Vasopressin attenuates TNF-mediated inflammation in the rat cremaster microcirculation.

PubMed

McMahon, Paul J; Proctor, Kenneth G

2009-09-01

Our previous study in a swine polytrauma model suggested that equieffective systemic pressor doses of arginine vasopressin (AVP) versus phenylephrine (PE) have differential effects on the systemic and cerebral microcirculation. The purpose of this study was to directly observe the effects of AVP versus PE on inflammatory changes evoked by tumor necrosis factor alpha (TNF) in the skeletal muscle microcirculation. Seventy-five male rats (180-250 g) were anesthetized with isoforane, intubated and mechanically ventilated with 100% oxygen. The cremaster muscle microcirculation was prepared for intravital video microscopy while being suffused with a heated hetastarch-electrolyte solution. Fluorescein isothiocyanate-labeled albumin (100 mg/kg) was administered intravenously (i.v.) before one of five protocols. In series 1 (n = 20), either AVP (0.2 U/mL) or its vehicle was added to the suffusate for 10 minutes, washed out for 30 minutes, then TNF was suffused (5 ng/mL) for 30 minutes. In series 2 (n = 16), the protocol was similar, except AVP (0.2 U/mL) or an equieffective dose of PE (0.04 mg/mL) was administered i.v. (4.5 mL/h) for 15 minutes before, during, and 45 minutes after TNF suffusion. In series 3 (n = 12), the protocol was similar to series 2, except venous hemorrhage preceded i.v. AVP or PE. In series 4 (n = 15), the protocol was similar to series 3, except an AVP antagonist (vaprisol, 1 mg/kg i.v.) or its vehicle was administered after hemorrhage. In the control series (n = 13), inflammation was evaluated either with a different suffusate (lactated Ringers instead of hetastarch solution), different antigen (histamine instead of TNF), or hemorrhage with no antigen. In series 1, the TNF-evoked increase in leukocyte infiltration (i.e., rolling), leukocyte activation (i.e., sticking), and macromolecular permeability (i.e., albumin extravasation) were attenuated with topical AVP versus vehicle (both p < 0.05), with no effect on venular blood flow (which determines sheer stress). In series 2, the TNF-evoked increase in infiltration, activation, and permeability were all attenuated, and arteriolar blood flow (which determines perfused capillary surface area and hydrostatic pressure) was reduced with i.v. AVP versus i.v. PE (all p < 0.05). In series 3, after hemorrhage to mean arterial pressure <50 mm Hg for 30 minutes, the TNF-evoked increase in infiltration and activation was attenuated, and arteriolar and venular blood flow were both reduced with i.v. AVP versus PE (all p < 0.05). In series 4, after hemorrhage, the TNF-evoked increase in leukocyte activation was potentiated with the vaprisol versus vehicle (p < 0.05) with no effect on arteriolar or venular blood flow. In series 5 (controls), suffusion with lactated Ringers' versus hetastarch solution more than doubled the TNF-evoked increase in activation (p < 0.05). (1) AVP can attenuate TNF-evoked leukocyte infiltration, activation or permeability changes in the skeletal muscle microcirculation. (2) The mechanism is probably receptor mediated and does not entirely depend on sheer stress in venules or Starling forces in capillaries. (3) The magnitude of this anti-inflammatory effect is influenced by several conditions, including volume status, the colloid or crystalloid suffusion fluid, and is possibly specific to the antigenic stimulus (TNF vs. histamine).

Molecular genetic studies of the arginine vasopressin 1a receptor (AVPR1a) and the oxytocin receptor (OXTR) in human behaviour: from autism to altruism with some notes in between.

PubMed

Israel, Salomon; Lerer, Elad; Shalev, Idan; Uzefovsky, Florina; Reibold, Mathias; Bachner-Melman, Rachel; Granot, Roni; Bornstein, Gary; Knafo, Ariel; Yirmiya, Nurit; Ebstein, Richard P

2008-01-01

Converging evidence from both human and animal studies has highlighted the pervasive role of two neuropeptides, oxytocin (OXT) and arginine vasopressin (AVP), in mammalian social behaviours. Recent molecular genetic studies of the human arginine vasopressin 1a (AVPR1a) and oxytocin (OXTR) receptors have strengthened the evidence regarding the role of these two neuropeptides in a range of normal and pathological behaviours. Significant association between both AVPR1a repeat regions and OXTR single nucleotide polymorphisms (SNPs) with risk for autism has been provisionally shown which was mediated by socialization skills in our study. AVPR1a has also been linked to eating behaviour in both clinical and non-clinical groups, perhaps reflecting the social and ritualistic side of eating behaviour. Evidence also suggests that repeat variations in AVPR1a are associated with two other social domains in Homo sapiens: music and altruism. AVPR1a was associated with dance and musical cognition which we theorize as reflecting the ancient role of this hormone in social interactions executed by vocalization, ritual movement and dyadic (mother-offspring) and group communication. Finally, we have shown that individual differences in allocation of funds in the dictator game, a laboratory game of pure altruism, is predicted by length of the AVPR1a RS3 promoter-region repeat echoing the mechanism of this hormone's action in the vole model of affiliative behaviours and facilitation of positive group interactions. While still in its infancy, the current outlook for molecular genetic investigations of AVP-OXT continues to be fascinating. Future studies should profitably focus on pharmacogenomic and genomic imaging strategies facilitated by the ease and efficacy of manipulating AVP-OXT neurotransmission by intranasal administration. Importantly, physiological measures, behavioural paradigms and brain activation can be informed by considering between-group and also within-group individual differences defined by common polymorphisms. Ultimately, investigators should strive to develop a cohesive model explaining how genomic variations are translated into individual and group differences in higher-order social behaviours.

Neuroanatomical distribution of oxytocin and vasopressin 1a receptors in the socially monogamous coppery titi monkey (Callicebus cupreus)

PubMed Central

Freeman, Sara M.; Walum, Hasse; Inoue, Kiyoshi; Smith, Aaron L.; Goodman, Mark M.; Bales, Karen L.; Young, Larry J.

2014-01-01

The coppery titi monkey (Callicebus cupreus) is a socially monogamous New World primate that has been studied in the field and the laboratory to investigate the behavioral neuroendocrinology of primate pair bonding and parental care. Arginine vasopressin has been shown to influence male titi monkey pair-bonding behavior, and studies are currently underway to examine the effects of oxytocin on titi monkey behavior and physiology. Here, we use receptor autoradiography to identify the distribution of arginine vasopressin 1a (AVPR1a) and oxytocin receptors (OXTR) in hemispheres of titi monkey brain (n=5). AVPR1a are diffuse and widespread throughout the brain, but the OXTR distribution is much more limited, with the densest binding being in the hippocampal formation (dentate gyrus, CA1 field) and the presubiculum (layers I and III). Moderate OXTR binding was detected in the nucleus basalis of Meynert, pulvinar, superior colliculus, layer 4C of primary visual cortex, periaqueductal gray, pontine gray, nucleus prepositus, and spinal trigeminal nucleus. OXTR mRNA overlapped with OXTR radioligand binding, confirming that the radioligand was detecting OXTR protein. AVPR1a binding is present throughout the cortex, especially in cingulate, insular, and occipital cortices, as well as in the caudate, putamen, nucleus accumbens, central amygdala, endopiriform nucleus, hippocampus (CA4 field), globus pallidus, lateral geniculate nucleus, infundibulum, habenula, periaqueductal gray, substantia nigra, olivary nucleus, hypoglossal nucleus, and cerebellum. Furthermore, we show that, in titi monkey brain, the OXTR antagonist ALS-II-69 is highly selective for OXTR and that the AVPR1a antagonist SR49059 is highly selective for AVPR1a. Based on these results and the fact that both ALS-II-69 and SR49059 are non-peptide, small-molecule antagonists that should be capable of crossing the blood brain barrier, these two compounds emerge as excellent candidates for the pharmacological manipulation of OXTR and AVPR1a in future behavioral experiments in titi monkeys and other primate species. PMID:24814726

Tolvaptan as an alternative treatment for refractory fluid retention associated with sinusoidal obstruction syndrome after allogeneic stem cell transplantation.

PubMed

Yakushijin, Kimikazu; Yamamoto, Katsuya; Kurata, Keiji; Miyata, Yoshiharu; Kakiuchi, Seiji; Tomioka, Hideo; Kawamori-Iwamoto, Yuriko; Inui, Yumiko; Sanada, Yukinari; Okamura, Atsuo; Murayama, Tohru; Matsuoka, Hiroshi; Minami, Hironobu

2013-02-01

Tolvaptan is an oral vasopressin V2-receptor antagonist recognized as effective for fluid retention associated with congestive heart failure and liver cirrhosis. However, there have been no reports concerning clinical experience with tolvaptan for sinusoidal obstruction syndrome (SOS). A 42-year-old male with primarily refractory T-lymphoblastic lymphoma underwent allogeneic peripheral blood stem cell transplantation from an HLA-matched sibling donor. The myeloablative conditioning regimen consisted of busulfan and cyclophosphamide. On day 20, the total bilirubin level was elevated to 2.0 mg/dL, and body weight increased from 76 to 85 kg, allowing a diagnosis of SOS to be made. Treatments with thrombomodulin, furosemide, carperitide, and low-dose dopamine were ineffective. By day 27, the patient's body weight had increased to 90 kg, and he subsequently developed cardiopulmonary failure. Therefore, we administered low-dose tolvaptan for 2 days (3.75 mg on day 27 and 7.5 mg on day 28). Consequently, his ascites and edema were significantly reduced, and body weight returned to 77 kg by day 34. However, he died of lymphoma progression on day 55. Tolvaptan may be an alternative and promising treatment for refractory fluid retention associated with SOS, although it is unclear whether tolvaptan administration leads to improvement in clinical outcome.

Interaction of Vasopressin and Splenda on Glucose Metabolism and Long-term Preferences under Ad-libitum and Food-restricted Conditions.

PubMed

Murphy, H M; Wideman, C H; Cleary, A M

1999-01-01

Previous research has demonstrated that vasopressin-containing rats are capable of adapting to the stress of food restriction; whereas, vasopressin-deficient rats cannot adapt to this stressor. In the present study, the value of using a low-calorie (Splenda) or no-calorie (Equal) artificial sweetener to reverse the deleterious effects of food restriction in vasopressin-deficient rats was examined. In association with this effect, the role of vasopressin in long-term preferences for the two artificial sweeteners was studied. Vasopressin-deficient, Brattleboro (DI) rats and vasopressin-containing, Long-Evans (LE) rats underwent an habituation phase during which they had ad-libitum access to food. This was followed by an experimental phase during which the rats were divided into four groups. (1) DI rats continued with ad-libitum feeding, (2) LE rats continued with ad-libitum feeding, (3) DI rats subjected to 23 h of food restriction, and (4) LE rats subjected to 23 h of food restriction. All rats had ad-libitum access to an 8% Splenda solution, a 1% Equal solution, and water throughout both phases of the experiment. The deleterious effects of food restriction were completely reversed in DI rats, including survival, no stomach pathology, and normal plasma levels of glucose and urea nitrogen.

Early life manipulations of vasopressin-family peptides alter vocal learning.

PubMed

Baran, Nicole M; Peck, Samantha C; Kim, Tabitha H; Goldstein, Michael H; Adkins-Regan, Elizabeth

2017-07-26

Vocal learning from social partners is crucial for the successful development of communication in a wide range of species. Social interactions organize attention and enhance motivation to learn species-typical behaviour. However, the neurobiological mechanisms connecting social motivation and vocal learning are unknown. Using zebra finches ( Taeniopygia guttata ), a ubiquitous model for vocal learning, we show that manipulations of nonapeptide hormones in the vasopressin family (arginine vasotocin, AVT) early in development can promote or disrupt both song and social motivation. Young male zebra finches, like human infants, are socially gregarious and require interactive feedback from adult tutors to learn mature vocal forms. To investigate the role of social motivational mechanisms in song learning, in two studies, we injected hatchling males with AVT or Manning compound (MC, a nonapeptide receptor antagonist) on days 2-8 post-hatching and recorded song at maturity. In both studies, MC males produced a worse match to tutor song than controls. In study 2, which experimentally controlled for tutor and genetic factors, AVT males also learned song significantly better compared with controls. Furthermore, song similarity correlated with several measures of social motivation throughout development. These findings provide the first evidence that nonapeptides are critical to the development of vocal learning. © 2017 The Author(s).

Regulation of bone remodeling by vasopressin explains the bone loss in hyponatremia

PubMed Central

Tamma, Roberto; Sun, Li; Cuscito, Concetta; Lu, Ping; Corcelli, Michelangelo; Li, Jianhua; Colaianni, Graziana; Moonga, Surinder S.; Di Benedetto, Adriana; Grano, Maria; Colucci, Silvia; Yuen, Tony; New, Maria I.; Zallone, Alberta; Zaidi, Mone

2013-01-01

Although hyponatremia is known to be associated with osteoporosis and a high fracture risk, the mechanism through which bone loss ensues has remained unclear. As hyponatremic patients have elevated circulating arginine-vasopressin (AVP) levels, we examined whether AVP can affect the skeleton directly as yet another component of the pituitary-bone axis. Here, we report that the two Avp receptors, Avpr1α and Avpr2, coupled to Erk activation, are expressed in osteoblasts and osteoclasts. AVP injected into wild-type mice enhanced and reduced, respectively, the formation of bone-resorbing osteoclasts and bone-forming osteoblasts. Conversely, the exposure of osteoblast precursors to Avpr1α or Avpr2 antagonists, namely SR49059 or ADAM, increased osteoblastogenesis, as did the genetic deletion of Avpr1α. In contrast, osteoclast formation and bone resorption were both reduced in Avpr1α−/− cultures. This process increased bone formation and reduced resorption resulted in a profound enhancement of bone mass in Avpr1α−/− mice and in wild-type mice injected with SR49059. Collectively, the data not only establish a primary role for Avp signaling in bone mass regulation, but also call for further studies on the skeletal actions of Avpr inhibitors used commonly in hyponatremic patients. PMID:24167258

Vasopressin Analogue DDAVP in Diabetes Insipidus: Clinical and Laboratory Studies

PubMed Central

Edwards, C. R. W.; Kitau, M. J.; Chard, T.; Besser, G. M.

1973-01-01

In seven patients with cranial diabetes insipidus an analogue of vasopressin, DDAVP, produced an antidiuresis lasting up to 20 hours after a single intranasal dose. Lysine vasopressin (LVP) in the same dose produced a less potent antidiuresis which lasted for only three to four hours. The plasma half life of DDAVP was 7·8 and 75·5 min for the fast and slow phases, compared with 2·5 and 14·5 min for LVP. Radioiodine-labelled DDAVP was not destroyed by incubation with late pregnancy plasma, which contains an enzyme that inactivates vasopressin. The slow metabolic clearance of DDAVP, its absorption through the nasal mucosa, and its lack of side effects make this the ideal drug for the treatment of vasopressin-sensitive diabetes insipidus. Patients usually require 10 to 20 μg DDAVP given intranasally twice daily for good clinical control of their diabetes insipidus. PMID:4581079

The comparison of humeral intraosseous and intravenous administration of vasopressin on return of spontaneous circulation and pharmacokinetics in a hypovolemic cardiac arrest swine model.

PubMed

Wimmer, Mark H; Heffner, Kenneth; Smithers, Michael; Culley, Richard; Coyner, Jennifer; Loughren, Michael; Johnson, Don

2016-01-01

The American Heart Association (AHA) recommends intravenous (IV) or intraosseous (IO) vasopressin in Advanced Cardiac Life Support (ACLS). Obtaining IV access in hypovolemic cardiac arrest patients can be difficult, and IO access is often obtained in these life threatening situations. No studies have been conducted to determine the effects of humeral IO (HIO) access with vasopressin in the return of spontaneous circulation (ROSC). Our study compared the kinetics of vasopressin and ROSC with HIO with IV access in the hypovolemic swine model. Twenty-two Yorkshire swine were divided into three groups: HIO (n = 7), IV (n = 8), and a control group (n = 7). The IV and HIO group received vasopressin and cardiopulmonary resuscitation (CPR), while the control group received only CPR. All subjects were exsanguinated 31 percent of their blood volume, placed in cardiac arrest, and resuscitated per ACLS. Subjects that achieved ROSC were then monitored for 20 minutes. Blood samples (10 mL) collected at 0.5, 1, 1.5, 2, 2.5, 3, and 4 minutes after vasopressin injection and analyzed for maximum concentration (Cmax) and time to maximum concentration (Tmax). Data were analyzed using a multivariate analysis of variance (MANOVA) and a Fisher's Exact Test. ROSC was achieved in every subject that received vasopressin via the HIO route. Data analysis using a MANOVA pairwise comparison revealed no difference between mean Cmax (p = 0.601) and Tmax (p = 0.771) of vasopressin administered IV versus HIO routes. Analysis of the mean serum concentrations at time intervals using a repeated measures analysis of variance found no difference (p > 0.05). A Fisher's Exact Test revealed no difference in rate of ROSC between HIO and IV groups (p > 0.05). Odds ratio determined that there was a 33 times higher chance of survival among HIO subjects versus control (CPR and Defibrillation; p = 0.03) and no difference in the survivability of the HIO or IV groups (p = 0.52). The data from this study strongly suggest that there is no significant difference in ROSC, time to ROSC, hemodynamics, or pharmacokinetics between HIO vasopressin and IV vasopressin. This research reinforces current AHA guidelines recommending the use of HIO route early over delaying care awaiting IV access.

Density of transient K+ current influences excitability in acutely isolated vasopressin and oxytocin neurones of rat hypothalamus

PubMed Central

Fisher, Thomas E; Voisin, Daniel L; Bourque, Charles W

1998-01-01

The transient outward K+ current (ITO) was studied using whole-cell recording in immunocytochemically identified oxytocin (OT; n = 23) and vasopressin (VP; n = 67) magnocellular neurosecretory cells (MNCs) acutely isolated from the supraoptic nucleus of adult rats. The peak density of ITO during steps to −10 mV was 26 % smaller in OT-MNCs (355 ± 23 pA pF−1; mean ± s.e.m.; n = 18) than in VP-MNCs (478 ± 17 pA pF−1; n = 52). No differences were observed in the voltage dependence of activation or inactivation. Kinetic analysis revealed two components of ITO inactivation in both OT-MNCs (τ1 = 9.2 ± 0.4 ms and τ2 = 41.2 ± 1.6 ms; n = 18) and VP-MNCs (τ1 = 12.4 ± 0.4 ms and τ2 = 37.1 ± 1.2 ms; n = 52). Although the density of the rapid component (τ1) was not different (275 ± 13 versus 265 ± 16 pA pF−1, respectively), the slow component (τ2) was markedly smaller in OT-MNCs (183 ± 19 versus 331 ± 16 pA pF−1 in VP-MNCs). In unidentified MNCs, 0.5 mM 4-aminopyridine reduced ITO amplitude by 29 % and decreased the latency to spike discharge by about 70 % during depolarization from −70 mV. Latency to discharge from potentials less negative than −60 mV, where ITO is inactivated, was unaffected. Comparison of latency to spike discharge in identified cells showed that OT-MNCs achieve spike threshold twice as fast as VP-MNCs when depolarized from −70 mV. The lower density of ITO in OT-MNCs, therefore, accelerates the rate at which excitation can occur in response to depolarizing stimuli and may facilitate the occurrence of higher frequency discharges in OT-MNCs during physiological activation. PMID:9706020

Role of fructose and fructokinase in acute dehydration-induced vasopressin gene expression and secretion in mice

PubMed Central

Roncal-Jimenez, Carlos A.; Lanaspa-Garcia, Miguel A.; Oppelt, Sarah A.; Kuwabara, Masanari; Jensen, Thomas; Milagres, Tamara; Andres-Hernando, Ana; Ishimoto, Takuji; Garcia, Gabriela E.; Johnson, Ginger; MacLean, Paul S.; Sanchez-Lozada, Laura-Gabriela; Tolan, Dean R.; Johnson, Richard J.

2016-01-01

Fructose stimulates vasopressin in humans and can be generated endogenously by activation of the polyol pathway with hyperosmolarity. We hypothesized that fructose metabolism in the hypothalamus might partly control vasopressin responses after acute dehydration. Wild-type and fructokinase-knockout mice were deprived of water for 24 h. The supraoptic nucleus was evaluated for vasopressin and markers of the aldose reductase-fructokinase pathway. The posterior pituitary vasopressin and serum copeptin levels were examined. Hypothalamic explants were evaluated for vasopressin secretion in response to exogenous fructose. Water restriction increased serum and urine osmolality and serum copeptin in both groups of mice, although the increase in copeptin in wild-type mice was larger than that in fructokinase-knockout mice. Water-restricted, wild-type mice showed an increase in vasopressin and aldose reductase mRNA, sorbitol, fructose and uric acid in the supraoptic nucleus. In contrast, fructokinase-knockout mice showed no change in vasopressin or aldose reductase mRNA, and no changes in sorbitol or uric acid, although fructose levels increased. With water restriction, vasopressin in the pituitary of wild-type mice was significantly less than that of fructokinase-knockout mice, indicating that fructokinase-driven vasopressin secretion overrode synthesis. Fructose increased vasopressin release in hypothalamic explants that was not observed in fructokinase-knockout mice. In situ hybridization documented fructokinase mRNA in the supraoptic nucleus, paraventricular nucleus and suprachiasmatic nucleus. Acute dehydration activates the aldose reductase-fructokinase pathway in the hypothalamus and partly drives the vasopressin response. Exogenous fructose increases vasopressin release in hypothalamic explants dependent on fructokinase. Nevertheless, circulating vasopressin is maintained and urinary concentrating is not impaired. NEW & NOTEWORTHY This study increases our understanding of the mechanisms leading to vasopressin release under conditions of water restriction (acute dehydration). Specifically, these studies suggest that the aldose reductase-fructokinase pathways may be involved in vasopressin synthesis in the hypothalamus and secretion by the pituitary in response to acute dehydration. Nevertheless, mice undergoing water restriction remain capable of maintaining sufficient vasopressin (copeptin) levels to allow normal urinary concentration. Further studies of the aldose reductase-fructokinase system in vasopressin regulation appear indicated. PMID:27852737

Role of fructose and fructokinase in acute dehydration-induced vasopressin gene expression and secretion in mice.

PubMed

Song 宋志林, Zhilin; Roncal-Jimenez, Carlos A; Lanaspa-Garcia, Miguel A; Oppelt, Sarah A; Kuwabara, Masanari; Jensen, Thomas; Milagres, Tamara; Andres-Hernando, Ana; Ishimoto, Takuji; Garcia, Gabriela E; Johnson, Ginger; MacLean, Paul S; Sanchez-Lozada, Laura-Gabriela; Tolan, Dean R; Johnson, Richard J

2017-02-01

Fructose stimulates vasopressin in humans and can be generated endogenously by activation of the polyol pathway with hyperosmolarity. We hypothesized that fructose metabolism in the hypothalamus might partly control vasopressin responses after acute dehydration. Wild-type and fructokinase-knockout mice were deprived of water for 24 h. The supraoptic nucleus was evaluated for vasopressin and markers of the aldose reductase-fructokinase pathway. The posterior pituitary vasopressin and serum copeptin levels were examined. Hypothalamic explants were evaluated for vasopressin secretion in response to exogenous fructose. Water restriction increased serum and urine osmolality and serum copeptin in both groups of mice, although the increase in copeptin in wild-type mice was larger than that in fructokinase-knockout mice. Water-restricted, wild-type mice showed an increase in vasopressin and aldose reductase mRNA, sorbitol, fructose and uric acid in the supraoptic nucleus. In contrast, fructokinase-knockout mice showed no change in vasopressin or aldose reductase mRNA, and no changes in sorbitol or uric acid, although fructose levels increased. With water restriction, vasopressin in the pituitary of wild-type mice was significantly less than that of fructokinase-knockout mice, indicating that fructokinase-driven vasopressin secretion overrode synthesis. Fructose increased vasopressin release in hypothalamic explants that was not observed in fructokinase-knockout mice. In situ hybridization documented fructokinase mRNA in the supraoptic nucleus, paraventricular nucleus and suprachiasmatic nucleus. Acute dehydration activates the aldose reductase-fructokinase pathway in the hypothalamus and partly drives the vasopressin response. Exogenous fructose increases vasopressin release in hypothalamic explants dependent on fructokinase. Nevertheless, circulating vasopressin is maintained and urinary concentrating is not impaired. This study increases our understanding of the mechanisms leading to vasopressin release under conditions of water restriction (acute dehydration). Specifically, these studies suggest that the aldose reductase-fructokinase pathways may be involved in vasopressin synthesis in the hypothalamus and secretion by the pituitary in response to acute dehydration. Nevertheless, mice undergoing water restriction remain capable of maintaining sufficient vasopressin (copeptin) levels to allow normal urinary concentration. Further studies of the aldose reductase-fructokinase system in vasopressin regulation appear indicated. Copyright © 2017 the American Physiological Society.

Targeting Renal Purinergic Signalling for the Treatment of Lithium-induced Nephrogenic Diabetes Insipidus

PubMed Central

Kishore, B. K.; Carlson, N. G.; Ecelbarger, C. M.; Kohan, D. E.; Müller, C. E.; Nelson, R. D.; Peti-Peterdi, J.; Zhang, Y.

2015-01-01

Lithium still retains its critical position in the treatment of bipolar disorder by virtue of its ability to prevent suicidal tendencies. However, chronic use of lithium is often limited by the development nephrogenic diabetes insipidus (NDI), a debilitating condition. Lithium-induced NDI is due to resistance of the kidney to arginine vasopressin (AVP), leading to polyuria, natriuresis and kaliuresis. Purinergic signalling mediated by extracellular nucleotides (ATP/UTP), acting via P2Y receptors, opposes the action of AVP on renal collecting duct (CD) by decreasing the cellular cAMP and thus AQP2 protein levels. Taking a cue from this phenomenon, we discovered the potential involvement of ATP/UTP-activated P2Y2 receptor in lithium-induced NDI in rats, and showed that P2Y2 receptor knockout mice are significantly resistant to Li-induced polyuria, natriuresis and kaliuresis. Extension of these studies revealed that ADP-activated P2Y12 receptor is expressed in the kidney, and its irreversible blockade by the administration of clopidogrel bisulfate (Plavix®) ameliorates Li-induced NDI in rodents. Parallel in vitro studies showed that P2Y12 receptor blockade by the reversible antagonist PSB-0739 sensitizes CD to the action of AVP. Thus, our studies unraveled the potential beneficial effects of targeting P2Y2 or P2Y12 receptors to counter AVP resistance in lithium-induced NDI. If established in further studies, our findings may pave the way for the development of better and safer methods for the treatment of NDI by bringing a paradigm shift in the approach from the current therapies that predominantly counter the anti-AVP effects to those that enhance the sensitivity of the kidney to AVP action. PMID:25877068

Weak effects of common genetic variation in oxytocin and vasopressin receptor genes on rhesus macaque social behavior.

PubMed

Madlon-Kay, Seth; Montague, Michael J; Brent, Lauren J N; Ellis, Samuel; Zhong, Brian; Snyder-Mackler, Noah; Horvath, Julie E; Skene, Jesse Haynes Pate; Platt, Michael L

2018-06-21

The neuropeptides oxytocin (OT) and arginine vasopressin (AVP) influence pair bonding, attachment, and sociality, as well as anxiety and stress responses in humans and other mammals. The effects of these peptides are mediated by genetic variability in their associated receptors, OXTR and the AVPR gene family. However, the role of these genes in regulating social behaviors in non-human primates is not well understood. To address this question, we examined whether genetic variation in the OT receptor gene OXTR and the AVP receptor genes AVPR1A and AVPR1B influence naturally-occurring social behavior in free-ranging rhesus macaques-gregarious primates that share many features of their biology and social behavior with humans. We assessed rates of social behavior across 3,250 hr of observational behavioral data from 201 free-ranging rhesus macaques on Cayo Santiago island in Puerto Rico, and used genetic sequence data to identify 25 OXTR, AVPR1A, and AVPR1B single-nucleotide variants (SNVs) in the population. We used an animal model to estimate the effects of 12 SNVs (n = 3 OXTR; n = 5 AVPR1A; n = 4 AVPR1B) on rates of grooming, approaches, passive contact, contact aggression, and non-contact aggression, given and received. Though we found evidence for modest heritability of these behaviors, estimates of effect sizes of the selected SNVs were close to zero, indicating that common OXTR and AVPR variation contributed little to social behavior in these animals. Our results are consistent with recent findings in human genetics that the effects of individual common genetic variants on complex phenotypes are generally small. © 2018 Wiley Periodicals, Inc.

ACTH-independent macronodular adrenocortical hyperplasia reveals prevalent aberrant in vivo and in vitro responses to hormonal stimuli and coupling of arginine-vasopressin type 1a receptor to 11β-hydroxylase

PubMed Central

2013-01-01

Background Adrenal Cushing’s syndrome caused by ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) can be accompanied by aberrant responses to hormonal stimuli. We investigated the prevalence of adrenocortical reactions to these stimuli in a large cohort of AIMAH patients, both in vivo and in vitro. Methods In vivo cortisol responses to hormonal stimuli were studied in 35 patients with ACTH-independent bilateral adrenal enlargement and (sub-)clinical hypercortisolism. In vitro, the effects of these stimuli on cortisol secretion and steroidogenic enzyme mRNA expression were evaluated in cultured AIMAH and other adrenocortical cells. Arginine-vasopressin (AVP) receptor mRNA levels were determined in the adrenal tissues. Results Positive serum cortisol responses to stimuli were detected in 27/35 AIMAH patients tested, with multiple responses within individual patients occurring for up to four stimuli. AVP and metoclopramide were the most prevalent hormonal stimuli triggering positive responses in vivo. Catecholamines induced short-term cortisol production more often in AIMAH cultures compared to other adrenal cells. Short- and long-term incubation with AVP increased cortisol secretion in cultures of AIMAH cells. AVP also increased steroidogenic enzyme mRNA expression, among which an aberrant induction of CYP11B1. AVP type 1a receptor was the only AVPR expressed and levels were high in the AIMAH tissues. AVPR1A expression was related to the AVP-induced stimulation of CYP11B1. Conclusions Multiple hormonal signals can simultaneously induce hypercortisolism in AIMAH. AVP is the most prevalent eutopic signal and expression of its type 1a receptor was aberrantly linked to CYP11B1 expression. PMID:24034279

Social instability stress in adolescent male rats reduces social interaction and social recognition performance and increases oxytocin receptor binding.

PubMed

Hodges, Travis E; Baumbach, Jennet L; Marcolin, Marina L; Bredewold, Remco; Veenema, Alexa H; McCormick, Cheryl M

2017-09-17

Social experiences in adolescence are essential for displaying context-appropriate social behaviors in adulthood. We previously found that adult male rats that underwent social instability stress (SS) in adolescence had reduced social interactions with unfamiliar peers compared with non-stressed controls (CTL). Here we determined whether SS altered social recognition and social reward and brain oxytocin and vasopressin receptor density in adolescence. We confirmed that SS rats spent less time interacting with unfamiliar peers than did CTL rats (p=0.006). Furthermore, CTL rats showed a preference for novel over familiar conspecifics in a social recognition test whereas SS rats did not, which may reflect reduced recognition, impaired memory, or reduced preference for novelty in SS rats. The reward value of social interactions was not affected by SS based on conditioned place preference tests and based on the greater time SS rats spent investigating stimulus rats than did CTL rats when the stimulus rat was behind wire mesh (p=0.03). Finally, oxytocin receptor binding density was higher in the dorsal lateral septum and nucleus accumbens shell in SS rats compared with CTL rats (p=0.02, p=0.01, respectively). No effect of SS was found for vasopressin 1a receptor binding density in any of the brain regions analyzed. We discuss the extent to which the differences in social behavior exhibited after social instability in adolescence involve changes in social salience and social competency, and the possibility that changes in oxytocin signaling in the brain underlie the differences in social behavior. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Clock-driven vasopressin neurotransmission mediates anticipatory thirst prior to sleep.

PubMed

Gizowski, C; Zaelzer, C; Bourque, C W

2016-09-29

Circadian rhythms have evolved to anticipate and adapt animals to the constraints of the earth's 24-hour light cycle. Although the molecular processes that establish periodicity in clock neurons of the suprachiasmatic nucleus (SCN) are well understood, the mechanisms by which axonal projections from the central clock drive behavioural rhythms are unknown. Here we show that the sleep period in mice (Zeitgeber time, ZT0-12) is preceded by an increase in water intake promoted entirely by the central clock, and not motivated by physiological need. Mice denied this surge experienced significant dehydration near the end of the sleep period, indicating that this water intake contributes to the maintenance of overnight hydromineral balance. Furthermore, this effect relies specifically on the activity of SCN vasopressin (VP) neurons that project to thirst neurons in the OVLT (organum vasculosum lamina terminalis), where VP is released as a neurotransmitter. SCN VP neurons become electrically active during the anticipatory period (ZT21.5-23.5), and depolarize and excite OVLT neurons through the activation of postsynaptic VP V1a receptors and downstream non-selective cation channels. Optogenetic induction of VP release before the anticipatory period (basal period; ZT19.5-21.5) excited OVLT neurons and prompted a surge in water intake. Conversely, optogenetic inhibition of VP release during the anticipatory period inhibited the firing of OVLT neurons and prevented the corresponding increase in water intake. Our findings reveal the existence of anticipatory thirst, and demonstrate this behaviour to be driven by excitatory peptidergic neurotransmission mediated by VP release from central clock neurons.

Social Enrichment during Postnatal Development Induces Transgenerational Effects on Emotional and Reproductive Behavior in Mice

PubMed Central

Curley, James P.; Davidson, Stephanie; Bateson, Patrick; Champagne, Frances A.

2009-01-01

Across species there is evidence that the quality of the early social environment can have a profound impact on neurobiology and behavior. In the present study we explore the effect of communal rearing conditions (three dams with three litters per cage) during the postnatal period on offspring (F1) and grand-offspring (F2) anxiety-like and maternal behavior in Balb/c mice. Females rearing pups in communal nests exhibited increased levels of postpartum maternal care and communal rearing was found to abolish sex-differences in weaning weights. In adulthood, communally reared offspring were observed to display reduced anxiety-like behavior when placed in a novel environment. When rearing their own offspring under standard conditions, communally reared females demonstrated higher levels of motivation to retrieve pups, built higher quality nests, and exhibited higher levels of postpartum care compared to standard reared females. When exposed to an intruder male, communally reared females were more subordinate and less aggressive. F2 offspring of communally reared females were observed to engage in reduced anxiety-like behavior, have larger litter sizes and an increased frequency of nursing on PND 1. Analysis of neuropeptide receptor levels suggest that a communal rearing environment may exert sustained effects on behavior through modification of oxytocin and vasopressin (V1a) receptor densities. Though Balb-C mice are often considered “socially-incompetent” and high in anxiety-like behavior, our findings suggest that through enrichment of the postnatal environment, these behavioral and neuroendocrine deficits may be attenuated both within and across generations. PMID:19826497

Substance-specific importance of EGFR for vascular smooth muscle cells motility in primary culture.

PubMed

Schreier, Barbara; Schwerdt, Gerald; Heise, Christian; Bethmann, Daniel; Rabe, Sindy; Mildenberger, Sigrid; Gekle, Michael

2016-07-01

Besides their importance for the vascular tone, vascular smooth muscle cells (VSMC) also contribute to pathophysiological vessel alterations. Various G-protein coupled receptor ligands involved in vascular dysfunction and remodeling can transactivate the epidermal growth factor receptor (EGFR) of VSMC, yet the importance of EGFR transactivation for the VSMC phenotype is incompletely understood. The aims of this study were (i) to characterize further the importance of the VSMC-EGFR for proliferation, migration and marker gene expression for inflammation, fibrosis and reactive oxygen species (ROS) homeostasis and (ii) to test the hypothesis that vasoactive substances (endothelin-1, phenylephrine, thrombin, vasopressin and ATP) rely differentially on the EGFR with respect to the abovementioned phenotypic alterations. In primary, aortic VSMC from mice without conditional deletion of the EGFR, proliferation, migration, marker gene expression (inflammation, fibrosis and ROS homeostasis) and cell signaling (ERK 1/2, intracellular calcium) were analyzed. VSMC-EGFR loss reduced collective cell migration and single cell migration probability, while no difference between the genotypes in single cell velocity, chemotaxis or marker gene expression could be observed under control conditions. EGF promoted proliferation, collective cell migration, chemokinesis and chemotaxis and leads to a proinflammatory gene expression profile in wildtype but not in knockout VSMC. Comparing the impact of five vasoactive substances (all reported to transactivate EGFR and all leading to an EGFR dependent increase in ERK1/2 phosphorylation), we demonstrate that the importance of EGFR for their action is substance-dependent and most apparent for crowd migration but plays a minor role for gene expression regulation. Copyright © 2016 Elsevier B.V. All rights reserved.

Acute diabetes insipidus mediated by vasopressinase after placental abruption.

PubMed

Wallia, Amisha; Bizhanova, Aigerim; Huang, Wenyu; Goldsmith, Susan L; Gossett, Dana R; Kopp, Peter

2013-03-01

Postpartum, diabetes insipidus (DI) can be part of Sheehan's syndrome or lymphocytic hypophysitis in combination with anterior pituitary hormone deficiencies. In contrast, acute onset of isolated DI in the postpartum period is unusual. This patient presented at 33 weeks gestation with placental abruption, prompting a cesarean delivery of twins. Immediately after delivery, she developed severe DI. The DI could be controlled with the vasopressinase-resistant 1-deamino-8-D-arginine vasopressin (DDAVP), but not with arginine vasopressin (AVP), and it resolved within a few weeks. The aim of this study was to demonstrate that the postpartum DI in this patient was caused by the release of placental vasopressinase into the maternal bloodstream. Cells were transiently transfected with the AVP receptor 2 (AVPR2) and treated with either AVP or DDAVP in the presence of the patient's serum collected postpartum or 10 weeks after delivery. The response to the different treatments was evaluated by measuring the activity of a cAMP-responsive firefly luciferase reporter construct. The in vitro studies demonstrate that the patient's postpartum serum disrupts activation of the AVPR2 by AVP, but not by the vasopressinase-resistant DDAVP. Placental abruption can rarely be associated with acute postpartum DI caused by release of placental vasopressinase into the bloodstream. This clinical entity must be considered in patients with placental abruption and when evaluating patients presenting with DI after delivery.

Retrieval of Water Channels by Endocytosis in Renal Epithelia.

DTIC Science & Technology

1998-07-01

1983) and conformational changes ( DiBona , 1983) during enhanced water flow. Following cessation of hormone actions or receptor down regulation...and DiBona , 1982; Pearl and Taylor, 1983; Hays et al., 1994). In our studies, we report the role of proteins associated with microfilaments that may...vasopressin-activated transport. Proc. Soc. Exptl. Biol. Med. Invited Review. (Accepted). DiBona , D.R. 1983. Cytoplasmic involvement in ADH-mediated osmosis

Impact of Childhood Adversity and Vasopressin receptor 1a Variation on Social Interaction in Adulthood: A Cross-Sectional Study.

PubMed

Liu, Jia Jia; Lou, Fenglan; Lavebratt, Catharina; Forsell, Yvonne

2015-01-01

Arginine vasopressin (AVP) plays a role in social behavior, through receptor AVPR1A. The promoter polymorphism AVPR1A RS3 has been associated with human social behaviors, and with acute response to stress. Here, the relationships between AVPR1A RS3, early-life stressors, and social interaction in adulthood were explored. Adult individuals from a Swedish population-based cohort (n = 1871) were assessed for self-reported availability of social integration and social attachment and for experience of childhood adversities. Their DNA samples were genotyped for the microsatellite AVPR1A RS3. Among males, particularly those homozygous for the long alleles of AVPR1A RS3 were vulnerable to childhood adversity for their social attachment in adulthood. A similar vulnerability to childhood adversity among long allele carriers was found on adulthood social integration, but here both males and females were influenced. Data were self-reported and childhood adversity data were retrospective. Early-life stress influenced the relationship between AVPR1A genetic variants and social interaction. For social attachment, AVPR1A was of importance in males only. The findings add to previous reports on higher acute vulnerability to stress in persons with long AVPR1A RS3 alleles and increased AVP levels.

The effect of vasopressin on hormone secretion and blood flow from the thyroid vein in sheep with exteriorized thyroids.

PubMed

Falconer, I R

1968-12-01

1. Vasopressin has been shown to activate the thyroid in some species, and also to be released into the bloodstream after emotional and other stresses.2. Emotional stimuli applied to sheep have previously been shown to increase thyroid secretion and the possible influence of vasopressin in this process has been investigated. Sheep bearing exteriorized thyroid glands were used, so that thyroid vein blood could be collected in undisturbed conscious animals.3. (125)I or (131)I (50 muc) was injected I.M. into the sheep; 4-7 days later, samples of thyroid vein blood were collected at 10 min intervals for 4 hr, and the concentration of total and protein bound (125)I or (131)I was measured. Intravenous infusions of 0.3, 3.0 or 31 m-u./min arginine or lysine vasopressin, or close arterial infusions of 3.0 or 31 m-u./min arginine vasopressin were administered 1.5 hr after commencement of blood sampling. Blood flow from the thyroid was measured by a plethysmographic technique during similar experiments.4. No significant changes in thyroid hormone secretion were observed as a result of vasopressin infusion, and it was concluded that vasopressin release does not play a part in the activation of the thyroid resulting from emotional stimulus in the sheep.

Novel targets for the treatment of autosomal dominant polycystic kidney disease

PubMed Central

Belibi, Franck A; Edelstein, Charles L

2010-01-01

Importance of the field Autosomal dominant (AD) polycystic kidney disease (PKD) is the most common life-threatening hereditary disorder. There is currently no therapy that slows or prevents cyst formation and kidney enlargement in humans. An increasing number of animal studies have advanced our understanding of molecular and cellular targets of PKD. Areas covered in the review The purpose of this review is to summarize the molecular and cellular targets involved in cystogenesis and to update on the promising therapies that are being developed and tested based on knowledge of these molecular and cellular targets. What the reader will gain Insight into the pathogenesis of PKD and how a better understanding of the pathogenesis of PKD has led to the development of potential therapies to inhibit cyst formation and/or growth and improve kidney function. Take home message The results of animal studies in PKD have led to the development of clinical trials testing potential new therapies to reduce cyst formation and/or growth. A vasopressin V2 receptor antagonist, mTOR inhibitors, blockade of the renin–angiotensin system and statins that reduce cyst formation and improve renal function in animal models of PKD are being tested in interventional studies in humans. PMID:20141351

Role of vaptans in the management of hydroelectrolytic imbalance in liver cirrhosis.

PubMed

Facciorusso, Antonio; Amoruso, Annabianca; Neve, Viviana; Antonino, Matteo; Prete, Valentina Del; Barone, Michele

2014-11-27

Ascites and hyponatremia are the most common complications in patients with liver cirrhosis and develop as a consequence of a severe impairment of liver function and portal hypertension. Increasing evidences support the central role of renal function alterations in the pathogenesis of hydroelectrolytic imbalances in cirrhotic patients, thus implying a dense cross-talk between liver and kidney in the systemic and splanchnic vascular homeostasis in such subjects. Since Arginin Vasopressin (AVP) hyperincretion occurs at late stage of cirrhosis and plays an important role in the development of refractory ascites, dilutional hyponatremia and finally hepato-renal syndrome, selective antagonists of AVP receptors V2 (vaptans) have been recently introduced in the therapeutic algorithm of advanced cirrhotic patients. Despite the promising results of earlier phase-two studies, randomized controlled trials failed to find significant results in terms of efficacy of such drugs both in refractory ascites and hyponatremia. Moreover, concerns on their safety profile arise, due to the number of potentially severe side effects of vaptans in the clinical setting, such as hypernatremia, dehydration, renal impairment, and osmotic demyelination syndrome. More robust data from randomized controlled trials are needed in order to confirm the potential role of vaptans in the management of advanced cirrhotic patients.

Structural characterization of arginine-vasopressin and lysine-vasopressin by Fourier- transform ion cyclotron resonance mass spectrometry and infrared multiphoton dissociation.

PubMed

Bianco, Giuliana; Battista, Fabio; Buchicchio, Alessandro; Amarena, Concetta G; Schmitt-Kopplin, Philippe; Guerrieri, Antonio

2015-01-01

Arginine-vasopressin (AVP) and lysine-vasopressin (LVP) were analyzed by reversed-phase liquid chromatography/mass spectrometry (LC-MS) using Fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometry (MS) electrospray ionization (ESI) in the positive ion mode. LVP and AVP exhibited the protonated adduct [M+H](+) as the predominant ion at m/z 1056.43965 and at m/z 1084.44561, respectively. Infrared multiphoton dissociation (IRMPD), using a CO(2) laser source at a wavelength of 10.6 μm, was applied to protonated vasopressin molecules. The IRMPD mass spectra presented abundant mass fragments essential for a complete structural information. Several fragment ions, shared between two target molecules, are discussed in detail. Some previously unpublished fragments were identified unambiguously utilizing the high resolution and accurate mass information provided by the FT-ICR mass spectrometer. The opening of the disulfide loop and the cleavage of the peptide bonds within the ring were observed even under low-energy fragmentation conditions. Coupling the high-performance FT-ICR mass spectrometer with IRMPD as a contemporary fragmentation technique proved to be very promising for the structural characterization of vasopressin.

Glycogen synthase kinase-3 regulation of urinary concentrating ability.

PubMed

Rao, Reena

2012-09-01

Glycogen synthase kinase-3 (GSK3) is an enzyme that is gaining prominence as a critical signaling molecule in the epithelial cells of renal tubules. This review will focus on recent findings exploring the role of GSK3 in renal collecting ducts, especially its role in urine concentration involving vasopressin signaling. Recent studies using inhibition or tissue-specific gene deletion of GSK3 revealed the mechanism by which GSK3 regulates aquaporin 2 water channels via adenylate cyclase or the prostaglandin-E2 pathway. In other studies, postnatal treatment with lithium, an inhibitor of GSK3, increased cell proliferation and led to microcyst formation in rat kidneys. These studies suggest that loss of GSK3 activity could interfere with renal water transport at two levels. In the short term, it could disrupt vasopressin signaling in collecting duct cells and in the long term it could alter the structure of the collecting ducts, making them less responsive to the hydro-osmotic effects of vasopressin. Ongoing studies reveal the crucial role played by GSK3 in the regulation of vasopressin action in the renal collecting ducts and suggest a possible use of GSK3 inhibitors in disease conditions associated with disrupted vasopressin signaling.

Involvement of phosphoinositide 3-kinase and PTEN protein in mechanism of activation of TRPC6 protein in vascular smooth muscle cells.

PubMed

Monet, Michaël; Francoeur, Nancy; Boulay, Guylain

2012-05-18

TRPC6 is a cation channel in the plasma membrane that plays a role in Ca(2+) entry after the stimulation of a G(q)-protein-coupled or tyrosine-kinase receptor. TRPC6 translocates to the plasma membrane upon stimulation and remains there as long as the stimulus is present. However, the mechanism that regulates the trafficking and activation of TRPC6 are unclear. In this study we showed phosphoinositide 3-kinase and its antagonistic phosphatase, PTEN, are involved in the activation of TRPC6. The inhibition of PI3K by PIK-93, LY294002, or wortmannin decreased carbachol-induced translocation of TRPC6 to the plasma membrane and carbachol-induced net Ca(2+) entry into T6.11 cells. Conversely, a reduction of PTEN expression did not affect carbachol-induced externalization of TRPC6 but increased Ca(2+) entry through TRPC6 in T6.11 cells. We also showed that the PI3K/PTEN pathway regulates vasopressin-induced translocation of TRPC6 to the plasma membrane and vasopressin-induced Ca(2+) entry into A7r5 cells, which endogenously express TRPC6. In summary, we provided evidence that the PI3K/PTEN pathway plays an important role in the translocation of TRPC6 to the plasma membrane and may thus have a significant impact on Ca(2+) signaling in cells that endogenously express TRPC6.

Involvement of Phosphoinositide 3-Kinase and PTEN Protein in Mechanism of Activation of TRPC6 Protein in Vascular Smooth Muscle Cells*

PubMed Central

Monet, Michaël; Francoeur, Nancy; Boulay, Guylain

2012-01-01

TRPC6 is a cation channel in the plasma membrane that plays a role in Ca2+ entry after the stimulation of a Gq-protein-coupled or tyrosine-kinase receptor. TRPC6 translocates to the plasma membrane upon stimulation and remains there as long as the stimulus is present. However, the mechanism that regulates the trafficking and activation of TRPC6 are unclear. In this study we showed phosphoinositide 3-kinase and its antagonistic phosphatase, PTEN, are involved in the activation of TRPC6. The inhibition of PI3K by PIK-93, LY294002, or wortmannin decreased carbachol-induced translocation of TRPC6 to the plasma membrane and carbachol-induced net Ca2+ entry into T6.11 cells. Conversely, a reduction of PTEN expression did not affect carbachol-induced externalization of TRPC6 but increased Ca2+ entry through TRPC6 in T6.11 cells. We also showed that the PI3K/PTEN pathway regulates vasopressin-induced translocation of TRPC6 to the plasma membrane and vasopressin-induced Ca2+ entry into A7r5 cells, which endogenously express TRPC6. In summary, we provided evidence that the PI3K/PTEN pathway plays an important role in the translocation of TRPC6 to the plasma membrane and may thus have a significant impact on Ca2+ signaling in cells that endogenously express TRPC6. PMID:22493444

Randomised controlled trial of high versus ad libitum water intake in patients with autosomal dominant polycystic kidney disease: rationale and design of the DRINK feasibility trial

PubMed Central

El-Damanawi, Ragada; Lee, Michael; Harris, Tess; Mader, Laura B; Bond, Simon; Pavey, Holly; Sandford, Richard N; Wilkinson, Ian B; Burrows, Alison; Woznowski, Przemyslaw; Ben-Shlomo, Yoav; Karet Frankl, Fiona E; Hiemstra, Thomas F

2018-01-01

Introduction Vasopressin stimulates cyst growth in autosomal dominant polycystic kidney disease (ADPKD) leading to enlarged kidneys, hypertension and renal failure. Vasopressin receptor blockade slows disease progression. Physiological suppression of vasopressin secretion through high water (HW) intake could achieve a similar effect, necessitating a definitive large-scale trial of HW intake in ADPKD. The objective of the DRINK trial is to answer the key design and feasibility questions required to deliver a successful definitive water intake trial. Methods and analysis We describe the design of a single-centre, open-label, prospective, randomised controlled trial. The "Determining feasibility of R andomisation to high vs. ad libitum water In take in Polycystic K idney Disease" (DRINK) trial aims to enrol 50 patients with ADPKD, over the age of 16 years with an estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m2. Participants will be randomised 1:1 to HW intake based on an individualised water intake prescription, or to ad libitum (AW) water intake. The HW group will aim for a dilute urine (urine osmolality ≤270 mOsm/kg) as a surrogate marker of vasopressin suppression, and those in the AW group will target more concentrated urine. Participants will have an 8-week treatment period, and will be seen at weeks 0, 2, 4 and 8, undergoing assessments of fluid status, renal function and serum and urine osmolalities. They will receive dietary advice, and self-monitor urine specific gravity and fluid intake. The trial employs smartphone technology to permit home monitoring and remote direct data capture. The primary feasibility end points are recruitment rate and separation between arms in measured urinary osmolality. Key secondary assessments include acceptability, adherence, health-related quality of life, acute effects of HW intake on measured (51Cr-EDTA) and eGFR and ADPKD-related pain. Ethics and dissemination Ethical approval was awarded by the East of England Essex Research Ethics Committee (16/EE/0026). The results of DRINK will be submitted to peer-reviewed journals, and presented to patients via the PKD Charity. Trial registration number NCT02933268 and ISCRTN16794957 PMID:29743334

Association and Promoter Analysis of AVPR1A in Finnish Autism Families.

PubMed

Kantojärvi, Katri; Oikkonen, Jaana; Kotala, Ilona; Kallela, Jenni; Vanhala, Raija; Onkamo, Päivi; Järvelä, Irma

2015-10-01

The arginine vasopressin receptor 1A gene (AVPR1A) is known to affect social communication and has been reported to associate with autism in several studies. Given that the microsatellite RS1 and a few SNPs in the promoter region of the AVPR1A have repeatedly associated with several traits, including autism it is rather surprising that the molecular explanation for these associations has remained unknown, although it has been reported that the allele length of the AVPR1A microsatellites might affect disease risk. Here we carried out an extended association analysis of three microsatellites and 12 tag single nucleotide polymorphisms (SNPs) in and around the AVPR1A gene in 205 Finnish families followed by promoter analysis. FBAT version v2.0.3 was used for family-based genetic association analyses of AVPR1A microsatellites and SNPs. The nearby microsatellite RS1 was found to harbor the best association. Interestingly, there are two potentially relevant transcription factor (TF) binding sites at RS1: for MEF2C and PBX, predicted with the Match algorithm in the TRANSFAC database. Sequence variations changing the affinity of these TFs might partly explain the AVPR1A promoter region associations shown in autism. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Insidious adrenocortical insufficiency underlies neuroendocrine dysregulation in TIF-2 deficient mice.

PubMed

Patchev, Alexandre V; Fischer, Dieter; Wolf, Siegmund S; Herkenham, Miles; Götz, Franziska; Gehin, Martine; Chambon, Pierre; Patchev, Vladimir K; Almeida, Osborne F X

2007-01-01

The transcription-intermediary-factor-2 (TIF-2) is a coactivator of the glucocorticoid receptor (GR), and its disruption would be expected to influence glucocorticoid-mediated control of the hypothalamo-pituitary-adrenal (HPA) axis. Here, we show that its targeted deletion in mice is associated with altered expression of several glucocorticoid-dependent components of HPA regulation (e.g., corticotropin-releasing hormone, vasopressin, ACTH, glucocorticoid receptors), suggestive of hyperactivity under basal conditions. At the same time, TIF-2(-/-) mice display significantly lower basal corticosterone levels and a sluggish and blunted initial secretory response to brief emotional and prolonged physical stress. Subsequent analysis revealed this discrepancy to result from pronounced aberrations in the structure and function of the adrenal gland, including the cytoarchitectural organization of the zona fasciculata and basal and stress-induced expression of key elements of steroid hormone synthesis, such as the steroidogenic acute regulatory (StAR) protein and 3beta-hydroxysteroid dehydrogenase (3beta-HSD). In addition, altered expression levels of two nuclear receptors, DAX-1 and steroidogenic factor 1 (SF-1), in the adrenal cortex strengthen the view that TIF-2 deletion disrupts adrenocortical development and steroid biosynthesis. Thus, hyperactivity of the hypothalamo-pituitary unit is ascribed to insidious adrenal insufficiency and impaired glucocorticoid feedback.

Neurohypophyseal hormones as evolutionary tracers: identification of oxytocin, lysine vasopressin, and arginine vasopressin in two South American opossums (Didelphis marsupialis and Philander opossum).

PubMed

Chauvet, J; Hurpet, D; Colne, T; Michel, G; Chauvet, M T; Acher, R

1985-02-01

The neurohypophyseal hormones of two South American opossums (Didelphis marsupialis and Philander opossum) were isolated by molecular sieving and preparative high-pressure liquid chromatography (HPLC). One oxytocin-like and two vasopressin-like peptides were found in each species. These peptides have been identified by their amino acid composition and by their retention time in HPLC. Oxytocin, lysine vasopressin, and arginine vasopressin have been characterized in both species. Lysine vasopressin is roughly as abundant as arginine vasopressin. Comparison is made with Australian marsupials Macropodidae and Phalangeridae, and possible evolutionary mechanisms are discussed.

Variation in the oxytocin receptor gene (OXTR) is associated with differences in moral judgment

PubMed Central

Chaponis, Jonathan; Siburian, Richie; Gallagher, Patience; Ransohoff, Katherine; Wikler, Daniel; Perlis, Roy H.; Greene, Joshua D.

2016-01-01

Moral judgments are produced through the coordinated interaction of multiple neural systems, each of which relies on a characteristic set of neurotransmitters. Genes that produce or regulate these neurotransmitters may have distinctive influences on moral judgment. Two studies examined potential genetic influences on moral judgment using dilemmas that reliably elicit competing automatic and controlled responses, generated by dissociable neural systems. Study 1 (N = 228) examined 49 common variants (SNPs) within 10 candidate genes and identified a nominal association between a polymorphism (rs237889) of the oxytocin receptor gene (OXTR) and variation in deontological vs utilitarian moral judgment (that is, judgments favoring individual rights vs the greater good). An association was likewise observed for rs1042615 of the arginine vasopressin receptor gene (AVPR1A). Study 2 (N = 322) aimed to replicate these findings using the aforementioned dilemmas as well as a new set of structurally similar medical dilemmas. Study 2 failed to replicate the association with AVPR1A, but replicated the OXTR finding using both the original and new dilemmas. Together, these findings suggest that moral judgment is influenced by variation in the oxytocin receptor gene and, more generally, that single genetic polymorphisms can have a detectable effect on complex decision processes. PMID:27497314

Variation in the oxytocin receptor gene (OXTR) is associated with differences in moral judgment.

PubMed

Bernhard, Regan M; Chaponis, Jonathan; Siburian, Richie; Gallagher, Patience; Ransohoff, Katherine; Wikler, Daniel; Perlis, Roy H; Greene, Joshua D

2016-12-01

Moral judgments are produced through the coordinated interaction of multiple neural systems, each of which relies on a characteristic set of neurotransmitters. Genes that produce or regulate these neurotransmitters may have distinctive influences on moral judgment. Two studies examined potential genetic influences on moral judgment using dilemmas that reliably elicit competing automatic and controlled responses, generated by dissociable neural systems. Study 1 (N = 228) examined 49 common variants (SNPs) within 10 candidate genes and identified a nominal association between a polymorphism (rs237889) of the oxytocin receptor gene (OXTR) and variation in deontological vs utilitarian moral judgment (that is, judgments favoring individual rights vs the greater good). An association was likewise observed for rs1042615 of the arginine vasopressin receptor gene (AVPR1A). Study 2 (N = 322) aimed to replicate these findings using the aforementioned dilemmas as well as a new set of structurally similar medical dilemmas. Study 2 failed to replicate the association with AVPR1A, but replicated the OXTR finding using both the original and new dilemmas. Together, these findings suggest that moral judgment is influenced by variation in the oxytocin receptor gene and, more generally, that single genetic polymorphisms can have a detectable effect on complex decision processes. © The Author (2016). Published by Oxford University Press.

Physiopathology and diagnosis of nephrogenic diabetes insipidus.

PubMed

Devuyst, Olivier

2012-04-01

Nephrogenic diabetes insipidus (NDI) is caused by an improper response of the kidney to the antidiuretic hormone arginine vasopressin (AVP), leading to a decreased ability to concentrate urine which results in polyuria and polydipsia. The clinical diagnosis of NDI relies on demonstration of subnormal ability to concentrate urine despite the presence of AVP. NDI is most commonly acquired, secondary to kidney disorders, electrolyte imbalance and various drugs. Congenital forms of NDI are rare, and most commonly inherited in a X-linked manner with mutations of the AVP receptor type 2 (AVPR2). Mutations of the water channel aquaporin-2 (AQP2) can be detected in autosomal recessive or dominant forms of NDI. Management of NDI should focus on free access to drinking water and reduction of polyuria. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

The role of renal aquaporin 2 in the alleviation of dehydration associated with diabetic polyuria in KKAy mice.

PubMed

Satake, Masako; Ikarashi, Nobutomo; Ichikawa, Yuhei; Maniwa, Ayaka; Toda, Takahiro; Ito, Kiyomi; Ochiai, Wataru; Sugiyama, Kiyoshi

2010-10-09

Polyuria is a symptom that appears in association with diabetes mellitus. Because sustained polyuria causes serious dehydration, it is believed that the body has a compensating mechanism to alleviate dehydration. In the present study, the role of renal aquaporin 2 (AQP2) in the compensating mechanism was investigated in KKAy mice, a type 2 diabetes model. The renal AQP2 expression levels in KKAy mice aged between 5 and 24 weeks were determined using Western blotting. The hypothalamic vasopressin mRNA expression levels also were measured by real-time RT-PCR. Insulin was subcutaneously administered to 11-week-old KKAy mice twice a day for 7 days. After insulin treatment, the renal AQP2 protein expression and the hypothalamic vasopressin mRNA expression were measured. The urinary volumes of 5- and 12-week-old KKAy mice were 1.5 ± 0.3 mL and 9.5 ± 1.2 mL, respectively. The inner medullary AQP2 protein expression of 12-week-old KKAy mice was approximately 2.5-fold higher than that of 5-week-old KKAy mice. The hypothalamic vasopressin mRNA expression of 12-week-old KKAy mice was approximately twice that of 5-week-old KKAy mice. Insulin treatment in KKAy mice resulted in a significant reduction in the plasma glucose level, urinary volume, and inner medullary AQP2 protein and hypothalamic vasopressin mRNA expression. The present study demonstrated that AQP2 is a renal functional molecule of vasopressin that controls urinary volume and that AQP2 in the kidney increases to alleviate dehydration due to type 2 diabetes with polyuria. Copyright © 2010 Elsevier Inc. All rights reserved.

Experimental cardiac arrest treatment with adrenaline, vasopressin, or placebo.

PubMed

Palácio, Manoel Ângelo Gomes; Paiva, Edison Ferreira de; Azevedo, Luciano Cesar Pontes de; Timerman, Ari

2013-12-01

The effect of vasoconstrictors in prolonged cardiopulmonary resuscitation (CPR) has not been fully clarified. To evaluate adrenaline and vasopressin pressure effect, and observe the return of spontaneous circulation (ROSC). A prospective, randomized, blinded, and placebo-controlled study. After seven minutes of untreated ventricular fibrillation, pigs received two minutes cycles of CPR. Defibrillation was attempted (4 J/kg) once at 9 minutes, and after every cycle if a shockable rhythm was present, after what CPR was immediately resumed. At 9 minutes and every five minutes intervals, 0.02 mg/kg (n = 12 pigs) adrenaline, or 0.4 U/kg (n = 12) vasopressin, or 0.2 mL/kg (n = 8) 0.9% saline solution was administered. CPR continued for 30 minutes or until the ROSC. Coronary perfusion pressure increased to about 20 mmHg in the three groups. Following vasoconstrictors doses, pressure level reached 35 mmHg versus 15 mmHg with placebo (p < 0.001). Vasopressin effect remained at 15-20 mmHg after three doses versus zero with adrenaline or placebo. ROSC rate differed (p = 0.031) among adrenaline (10/12), vasopressin (6/12), and placebo (2/8). Time-to-ROSC did not differ (16 minutes), nor the number of doses previously received (one or two). There was no difference between vasoconstrictors, but against placebo, only adrenaline significantly increased the ROSC rate (p = 0.019). The vasoconstrictors initial pressure effect was equivalent and vasopressin maintained a late effect at prolonged resuscitation. Nevertheless, when compared with placebo, only adrenaline significantly increased the ROSC rate.

Differential routes of Ca2+ influx in Swiss 3T3 fibroblasts in response to receptor stimulation.

PubMed Central

Miyakawa, T; Kojima, M; Ui, M

1998-01-01

Ca2+ influx into cells in response to stimulation of various receptors was studied with Swiss 3T3 fibroblasts. The mechanisms involved were found to be so diverse that they were classified into four groups, Type I to IV. Type-I influx occurred, via pertussis toxin-susceptible G-proteins, immediately after internal Ca2+ mobilization by bradykinin, thrombin, endothelin, vasopressin or angiotensin II. Type-II influx induced by bombesin differed from Type I in its insusceptibility to pertussis toxin treatment. Ca2+ influx induced by prostaglandin E1, referred to as Type-III influx, was unique in that phospholipase C was apparently not activated without extracellular Ca2+, strongly suggesting that the Ca2+ influx preceded and was responsible for InsP3 generation and internal Ca2+ mobilization. More Ca2+ entered the cells more slowly via the Type-IV route opened by platelet-derived and other growth factors. These types of Ca2+ influx could be differentiated by their different susceptibilities to protein kinase C maximally activated by 1 h of exposure of cells to PMA, which inhibited phospholipase Cbeta coupled to receptors involved in Type-I and -II influx but did not inhibit growth-factor-receptor-coupled phospholipase Cgamma. Type-I and -II Ca2+ influxes, together with store-operated influx induced by thapsigargin, were not directly inhibited by exposure of cells to PMA, but Type-III and -IV influxes were completely inhibited. In addition, stimulation of receptors involved in Type-I and -IV Ca2+ influx, but not Type-II and -III influx, led to phospholipase A2 activation in the presence of extracellular Ca2+. Inhibition of Type-I and -IV Ca2+ influxes by their respective inhibitors, diltiazem and nifedipine, resulted in abolition of phospholipase A2 activation induced by the respective receptor agonists, in agreement with the notion that Ca2+ influx via these routes is responsible for receptor-mediated phospholipase A2 activation. PMID:9405282

Differential routes of Ca2+ influx in Swiss 3T3 fibroblasts in response to receptor stimulation.

PubMed

Miyakawa, T; Kojima, M; Ui, M

1998-01-01

Ca2+ influx into cells in response to stimulation of various receptors was studied with Swiss 3T3 fibroblasts. The mechanisms involved were found to be so diverse that they were classified into four groups, Type I to IV. Type-I influx occurred, via pertussis toxin-susceptible G-proteins, immediately after internal Ca2+ mobilization by bradykinin, thrombin, endothelin, vasopressin or angiotensin II. Type-II influx induced by bombesin differed from Type I in its insusceptibility to pertussis toxin treatment. Ca2+ influx induced by prostaglandin E1, referred to as Type-III influx, was unique in that phospholipase C was apparently not activated without extracellular Ca2+, strongly suggesting that the Ca2+ influx preceded and was responsible for InsP3 generation and internal Ca2+ mobilization. More Ca2+ entered the cells more slowly via the Type-IV route opened by platelet-derived and other growth factors. These types of Ca2+ influx could be differentiated by their different susceptibilities to protein kinase C maximally activated by 1 h of exposure of cells to PMA, which inhibited phospholipase Cbeta coupled to receptors involved in Type-I and -II influx but did not inhibit growth-factor-receptor-coupled phospholipase Cgamma. Type-I and -II Ca2+ influxes, together with store-operated influx induced by thapsigargin, were not directly inhibited by exposure of cells to PMA, but Type-III and -IV influxes were completely inhibited. In addition, stimulation of receptors involved in Type-I and -IV Ca2+ influx, but not Type-II and -III influx, led to phospholipase A2 activation in the presence of extracellular Ca2+. Inhibition of Type-I and -IV Ca2+ influxes by their respective inhibitors, diltiazem and nifedipine, resulted in abolition of phospholipase A2 activation induced by the respective receptor agonists, in agreement with the notion that Ca2+ influx via these routes is responsible for receptor-mediated phospholipase A2 activation.

Discrete expression of TRPV2 within the hypothalamo-neurohypophysial system: Implications for regulatory activity within the hypothalamic-pituitary-adrenal axis.

PubMed

Wainwright, Anna; Rutter, A Richard; Seabrook, Guy R; Reilly, Kathryn; Oliver, Kevin R

2004-06-14

Transient receptor potential channel proteins (TRPs) constitute a steadily growing family of ion channels with a range of purported functions. It has been demonstrated that TRPV2 is activated by moderate thermal stimuli and, in the rat, is expressed in medium to large diameter dorsal root ganglion neurons. In this study, antisera specific for the human TRPV2 homologue were raised and characterized for immunohistochemical use. Subsequently, thorough investigation was made of the localization of this cation channel in the macaque primate brain. TRPV2-immunoreactive material was highly restrictively localized to hypothalamic paraventricular, suprachiasmatic, and supraoptic nuclei. Confocal double- and triple-labeling studies demonstrated that TRPV2 immunoreactivity is preferentially localized to oxytocinergic and vasopressinergic neurons. Few, if any, cells in these regions expressed TRPV2 immunoreactivity in the absence of oxytocin immunoreactivity or vasopressin immunoreactivity. Expression in the paraventricular and supraoptic nuclei suggests that TRPV2 is likely to play a fundamental role in mediating cation transport in neurohypophysial neurons. TRPV2 has been shown to be translocated upon cell activation and neurons expressing TRPV2 immunoreactivity in vivo are among those known to engage in sporadic, intense activity. Taken together, these data suggest that this channel may play a vital role in mediating physiological activities associated with oxytocin and vasopressin release such as parturition, lactation, and diuresis. These data may also implicate the involvement of TRPV2 in disorders of the hypothalamic-pituitary-adrenal axis, including anxiety, depression, hypertension, and preterm labor. Copyright 2004 Wiley-Liss, Inc.

The vertebrate ancestral repertoire of visual opsins, transducin alpha subunits and oxytocin/vasopressin receptors was established by duplication of their shared genomic region in the two rounds of early vertebrate genome duplications.

PubMed

Lagman, David; Ocampo Daza, Daniel; Widmark, Jenny; Abalo, Xesús M; Sundström, Görel; Larhammar, Dan

2013-11-02

Vertebrate color vision is dependent on four major color opsin subtypes: RH2 (green opsin), SWS1 (ultraviolet opsin), SWS2 (blue opsin), and LWS (red opsin). Together with the dim-light receptor rhodopsin (RH1), these form the family of vertebrate visual opsins. Vertebrate genomes contain many multi-membered gene families that can largely be explained by the two rounds of whole genome duplication (WGD) in the vertebrate ancestor (2R) followed by a third round in the teleost ancestor (3R). Related chromosome regions resulting from WGD or block duplications are said to form a paralogon. We describe here a paralogon containing the genes for visual opsins, the G-protein alpha subunit families for transducin (GNAT) and adenylyl cyclase inhibition (GNAI), the oxytocin and vasopressin receptors (OT/VP-R), and the L-type voltage-gated calcium channels (CACNA1-L). Sequence-based phylogenies and analyses of conserved synteny show that the above-mentioned gene families, and many neighboring gene families, expanded in the early vertebrate WGDs. This allows us to deduce the following evolutionary scenario: The vertebrate ancestor had a chromosome containing the genes for two visual opsins, one GNAT, one GNAI, two OT/VP-Rs and one CACNA1-L gene. This chromosome was quadrupled in 2R. Subsequent gene losses resulted in a set of five visual opsin genes, three GNAT and GNAI genes, six OT/VP-R genes and four CACNA1-L genes. These regions were duplicated again in 3R resulting in additional teleost genes for some of the families. Major chromosomal rearrangements have taken place in the teleost genomes. By comparison with the corresponding chromosomal regions in the spotted gar, which diverged prior to 3R, we could time these rearrangements to post-3R. We present an extensive analysis of the paralogon housing the visual opsin, GNAT and GNAI, OT/VP-R, and CACNA1-L gene families. The combined data imply that the early vertebrate WGD events contributed to the evolution of vision and the other neuronal and neuroendocrine functions exerted by the proteins encoded by these gene families. In pouched lamprey all five visual opsin genes have previously been identified, suggesting that lampreys diverged from the jawed vertebrates after 2R.

Coordinated Regulation of Vasopressin Inactivation and Glucose Uptake by Action of TUG Protein in Muscle.

PubMed

Habtemichael, Estifanos N; Alcázar-Román, Abel; Rubin, Bradley R; Grossi, Laura R; Belman, Jonathan P; Julca, Omar; Löffler, Michael G; Li, Hongjie; Chi, Nai-Wen; Samuel, Varman T; Bogan, Jonathan S

2015-06-05

In adipose and muscle cells, insulin stimulates the exocytic translocation of vesicles containing GLUT4, a glucose transporter, and insulin-regulated aminopeptidase (IRAP), a transmembrane aminopeptidase. A substrate of IRAP is vasopressin, which controls water homeostasis. The physiological importance of IRAP translocation to inactivate vasopressin remains uncertain. We previously showed that in skeletal muscle, insulin stimulates proteolytic processing of the GLUT4 retention protein, TUG, to promote GLUT4 translocation and glucose uptake. Here we show that TUG proteolysis also controls IRAP targeting and regulates vasopressin action in vivo. Transgenic mice with constitutive TUG proteolysis in muscle consumed much more water than wild-type control mice. The transgenic mice lost more body weight during water restriction, and the abundance of renal AQP2 water channels was reduced, implying that vasopressin activity is decreased. To compensate for accelerated vasopressin degradation, vasopressin secretion was increased, as assessed by the cosecreted protein copeptin. IRAP abundance was increased in T-tubule fractions of fasting transgenic mice, when compared with controls. Recombinant IRAP bound to TUG, and this interaction was mapped to a short peptide in IRAP that was previously shown to be critical for GLUT4 intracellular retention. In cultured 3T3-L1 adipocytes, IRAP was present in TUG-bound membranes and was released by insulin stimulation. Together with previous results, these data support a model in which TUG controls vesicle translocation by interacting with IRAP as well as GLUT4. Furthermore, the effect of IRAP to reduce vasopressin activity is a physiologically important consequence of vesicle translocation, which is coordinated with the stimulation of glucose uptake. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Gastric electrical stimulation with short pulses reduces vomiting but not dysrhythmias in dogs.

PubMed

Chen, Jiande D Z; Qian, Liwei; Ouyang, Hui; Yin, Jieyun

2003-02-01

The aim of this study was to investigate the acute effects of 3 different methods of electrical stimulation in the prevention of vasopressin-induced emetic response and gastric dysrhythmias. Seven female hound dogs chronically implanted with 4 pairs of electrodes on gastric serosa were used in a 5-session study. Saline and vasopressin were infused in sessions 1 and 2, respectively. In the other 3 sessions with vasopressin infusion, 3 different methods of electrical stimulation (short-pulse stimulation, long-pulse stimulation, and electroacupuncture) were applied. Gastric slow waves and vomiting and behaviors suggestive of nausea were recorded in each session. In a separate study, additional experiments were performed in 5 vagotomized dogs to investigate vagally mediated mechanisms. Vasopressin induced gastric dysrhythmias, uncoupling of slow waves, and vomiting and behaviors suggestive of nausea (P < 0.02, analysis of variance). Long-pulse stimulation, but not short-pulse stimulation or electroacupuncture, was capable of preventing vasopressin-induced gastric dysrhythmias and gastric slow wave uncoupling. Short-pulse stimulation and electroacupuncture, but not long-pulse stimulation, prevented vomiting and significantly reduced the symptom scores, which was not noted in the dogs with truncal vagotomy. Long-pulse stimulation normalizes vasopressin-induced slow wave abnormalities with no improvement in vomiting and behaviors suggestive of nausea. Short-pulse stimulation and electroacupuncture prevent vomiting and behaviors suggestive of nausea induced by vasopressin but have no effects on slow waves, and their effects are vagally mediated.

Diabetes Insipidus—Difficulties in Diagnosis and Treatment; Use of Synthetic Lysine-8 Vasopressin in Patients Intolerant of Other Therapy

PubMed Central

Eisenberg, Eugene

1965-01-01

Frequent errors in the diagnosis of diabetes insipidus arise from (1) failure to produce an adequate stimulus for release of antidiuretic hormone, and (2) failure to appreciate acute or chronic changes in renal function that may obscure test results. Properly timed determination of body weight, urine volume and serum and urine osmolarity during the course of water deprivation, and comparison of these values with those obtained after administration of exogenous vasopressin, eliminates most diagnostic errors. In four patients who had experienced local and systemic reactions to other exogenous forms of vasopressin, diabetes insipidus was satisfactorily controlled by administration of synthetic lysine-8 vasopressin in nasal spray. A fifth patient was also treated satisfactorily with this preparation. PMID:14290932

A POC Clinical Trial for PTSD with a First-In-Class Vasopressin 1a Receptor Antagonist

DTIC Science & Technology

2016-10-01

benefit of SRX246 for the treatment of anger , irritability, and aggression; major depression ; disturbed sleep; and quality of life that frequently...treatment of major depression , anger , irritability, and aggression, disturbed sleep, and quality of life that frequently accompany PTSD. In this...BID) and ii) clinical benefit of SRX246 for the treatment of major depression ; anger , irritability, and aggression; disturbed sleep; and quality of

Impact of prosocial neuropeptides on human brain function.

PubMed

Meyer-Lindenberg, Andreas

2008-01-01

Oxytocin and vasopressin are key effectors of social behaviour (Insel, T. R. and Fernald, R. D. (2004). Annu. Rev. Neurosci., 27: 697-722). Oxytocin effects in humans were recently demonstrated by a behavioural study showing selectively increased trust after hormone administration (Kosfeld, M., et al. (2005). Nature, 435: 673-676). Since this suggested involvement of the amygdala, which is linked to trust (Winston, J. S., et al. (2002). Nat. Neurosci., 5: 277-283) - presumably because of its role in danger monitoring - and highly expresses oxytocin receptors (Huber, D., et al. (2005). Science, 308: 245-248), we studied amygdala circuitry after double-blind crossover intranasal application of placebo or oxytocin (Kirsch, P., et al. (2005). J. Neurosci., 25: 11489-11493). Oxytocin potently reduced amygdala activation and decreased coupling to brainstem regions implicated in autonomic and behavioural manifestations of fear, indicating a neural mechanism for the effects of oxytocin in social cognition in humans and providing a potential therapeutic approach to social anxiety currently being tested in social phobia and autism. Furthermore, these data suggested a translational genetic approach. Preliminary findings (data not presented) from our laboratory using imaging genetics indeed implicate genetic variants for both AVPR1A, encoding the primary receptor of vasopressin in brain, and the oxytocin receptor, OXTR, in amygdala regulation and activation. Taken together, our results indicate neural mechanisms for human social behaviour mediating genetic risk for autism through an impact on amygdala signalling and provide a rationale for exploring therapeutic strategies aimed at abnormal amygdala function in this disorder and in social dysfunction in general.

Development of Alopecia Areata Is Associated with Higher Central and Peripheral Hypothalamic–Pituitary–Adrenal Tone in the Skin Graft Induced C3H/HeJ Mouse Model

PubMed Central

Zhang, Xingqi; Yu, Mei; Yu, Wayne; Weinberg, Joanne; Shapiro, Jerry; McElwee, Kevin J.

2016-01-01

The relationship of the stress response to the pathogenesis of alopecia areata (AA) was investigated by subjecting normal and skin graft-induced, AA-affected C3H/HeJ mice to light ether anesthesia or restraint stress. Plasma corticosterone (CORT), adrenocorticotropic hormone (ACTH), and estradiol (E2) levels were determined by RIA, whereas gene expression in brains, lymphoid organs, and skin was measured by quantitative RT-PCR for corticotropin-releasing hormone (Crh), arginine vasopressin (Avp), proopiomelanocortin (Pomc), glucocorticoid receptor (Nr3c1), mineralo corticoid receptor (Nr3c2), corticotropin-releasing hormone receptor types 1 and 2 (Crhr1, Crhr2), interleukin-12 (Il12), tumor necrosis factor-α (Tnfα), and estrogen receptors type-1 (Esr1) and type-2 (Esr2). AA mice had a marked increase in hypothalamic–pituitary–adrenal (HPA) tone and activity centrally, and peripherally in the skin and lymph nodes. There was also altered interaction between the adrenal and gonadal axes compared with that in normal mice. Stress further exacerbated changes in AA mouse HPA activity both centrally and peripherally. AA mice had significantly blunted CORT and ACTH responses to acute ether stress (physiological stressor) and a deficit in habituation to repeated restraint stress (psychological stressor). The positive correlation of HPA hormone levels with skin Th1 cytokines suggests that altered HPA activity may occur as a consequence of the immune response associated with AA. PMID:19020552

Binding of Thyrotropin-Releasing Hormone to Plasma Membranes of Bovine Anterior Pituitary Gland

PubMed Central

Labrie, Fernand; Barden, Nicholas; Poirier, Guy; De Lean, Andre

1972-01-01

An assay for the binding of [3H]thyrotropin-releasing hormone ([3H]TRH) is described. Plasma membranes isolated from bovine anterior pituitary gland bind about 600 femtomoles of this hormone per mg of protein, as compared to 15 femtomoles per mg of protein in the total adenohypophyseal homogenate (40-fold purification). The equilibrium constant of membrane receptor-[3H]TRH binding at 0°C is 4.3 × 107 L·M-1, or a half-maximal binding of this hormone at 23 nM. The binding is time-dependent; addition of unlabeled hormone induces dissociation of the receptor-[3H]TRH complex with a half-life of 14 min. The binding of TRH is not altered by 10 μM melanocyte-stimulating hormone-release inhibiting hormone, lysine-vasopressin, adrenocorticotropin, growth hormone, prolactin, luteinizing hormone, insulin, glucagon, L-thyroxine, or L-triiodothyronine. K+ and Mg++ increase formation of the receptor-TRH complex at optimal concentrations of 5-25 mM and 0.5-2.5 mM, respectively, with inhibition at higher concentrations. Ca++ inhibits binding of TRH at all concentrations tested. PMID:4621548

GPCR-I-TASSER: A Hybrid Approach to G Protein-Coupled Receptor Structure Modeling and the Application to the Human Genome.

PubMed

Zhang, Jian; Yang, Jianyi; Jang, Richard; Zhang, Yang

2015-08-04

Experimental structure determination remains difficult for G protein-coupled receptors (GPCRs). We propose a new hybrid protocol to construct GPCR structure models that integrates experimental mutagenesis data with ab initio transmembrane (TM) helix assembly simulations. The method was tested on 24 known GPCRs where the ab initio TM-helix assembly procedure constructed the correct fold for 20 cases. When combined with weak homology and sparse mutagenesis restraints, the method generated correct folds for all the tested cases with an average Cα root-mean-square deviation 2.4 Å in the TM regions. The new hybrid protocol was applied to model all 1,026 GPCRs in the human genome, where 923 have a high confidence score and are expected to have correct folds; these contain many pharmaceutically important families with no previously solved structures, including Trace amine, Prostanoids, Releasing hormones, Melanocortins, Vasopressin, and Neuropeptide Y receptors. The results demonstrate new progress on genome-wide structure modeling of TM proteins. Copyright © 2015 Elsevier Ltd. All rights reserved.

Visualization of Oxytocin Release that Mediates Paired Pulse Facilitation in Hypothalamic Pathways to Brainstem Autonomic Neurons

PubMed Central

Piñol, Ramón A.; Jameson, Heather; Popratiloff, Anastas; Lee, Norman H.; Mendelowitz, David

2014-01-01

Recent work has shown that oxytocin is involved in more than lactation and uterine contraction. The paraventricular nucleus of the hypothalamus (PVN) contains neuroendocrine neurons that control the release of hormones, including vasopressin and oxytocin. Other populations of PVN neurons do not release hormones, but rather project to and release neurotransmitters onto other neurons in the CNS involved in fluid retention, thermoregulation, sexual behavior and responses to stress. Activation of oxytocin receptors can be cardioprotective and reduces the adverse cardiovascular consequences of anxiety and stress, yet how oxytocin can affect heart rate and cardiac function is unknown. While anatomical work has shown the presence of peptides, including oxytocin, in the projections from the PVN to parasympathetic nuclei, electrophysiological studies to date have only demonstrated release of glutamate and activation of fast ligand gated receptors in these pathways. In this study, using rats, we directly show, using sniffer CHO cells that express oxytocin receptors and the Ca2+ indicator R-GECO, that optogenetic activation of channelrhodopsin-2 (ChR2) expressing PVN fibers in the brainstem activates oxytocin receptors in the dorsomotor nucleus of the vagus (DMNV). We also demonstrate that while a single photoactivation of PVN terminals only activates glutamatergic receptors in brainstem cardiac vagal neurons (CVNs), neurons that dominate the neural control of heart rate, both the paired pulse facilitation, and sustained enhancement of glutamate release in this pathway is mediated by activation of oxytocin receptors. Our results provide direct evidence that a pathway from the PVN likely releases oxytocin and enhances short-term plasticity of this critical autonomic connection. PMID:25379676

Oxytocin induces penile erection and yawning when injected into the bed nucleus of the stria terminalis: Involvement of glutamic acid, dopamine, and nitric oxide.

PubMed

Sanna, Fabrizio; Bratzu, Jessica; Argiolas, Antonio; Melis, Maria Rosaria

2017-11-01

Oxytocin (5-100ng), but not Arg 8 -vasopressin (100ng), injected unilaterally into the bed nucleus of the stria terminalis (BNST) induces penile erection and yawning in a dose-dependent manner in male rats. The minimal effective dose was 20ng for penile erection and 5ng for yawning. Oxytocin responses were abolished not only by the oxytocin receptor antagonist d(CH 2 ) 5 Tyr(Me) 2 -Orn 8 -vasotocin (1μg), but also by (+) MK-801 (1μg), an excitatory amino acid receptor antagonist of the N-methyl-d-aspartic acid (NMDA) subtype, SCH 23390 (1μg), a D1 receptor antagonist, but not haloperidol (1μg), a D2 receptor antagonist, and SMTC (40μg), an inhibitor of neuronal nitric oxide synthase, injected into the BNST 15min before oxytocin. Oxytocin-induced penile erection, but not yawning, was also abolished by CNQX (1μg), an excitatory amino acid receptor antagonist of the AMPA subtype. In contrast, oxytocin responses were not reduced by bicuculline (20ng), a GABA A receptor antagonist, phaclofen (5μg), a GABA B receptor antagonist, CP 376395, a CRF receptor-1 antagonist (5μg), or astressin 2B, a CRF receptor-2 antagonist (150ng). Considering the ability of NMDA (100ng) to induce penile erection and yawning when injected into the BNST and the available evidence showing possible interaction among oxytocin, glutamic acid, and dopamine in the BNST, oxytocin possibly activates glutamatergic neurotransmission in the BNST. This in turn leads to the activation of neural pathways projecting back to the paraventricular nucleus, medial preoptic area, ventral tegmental area, and/or ventral subiculum/amygdala, thereby inducing penile erection and yawning. Copyright © 2017 Elsevier Inc. All rights reserved.

Glycogen synthase kinase-3 regulation of urinary concentrating ability

PubMed Central

Rao, Reena

2013-01-01

Purpose of review Glycogen synthase kinase-3 (GSK3) is an enzyme that is gaining prominence as a critical signaling molecule in the epithelial cells of renal tubules. This review will focus on recent findings exploring the role of GSK3 in renal collecting ducts, especially its role in urine concentration involving vasopressin signaling. Recent findings Recent studies using inhibition or tissue-specific gene deletion of GSK3 revealed the mechanism by which GSK3 regulates aquaporin 2 water channels via adenylate cyclase or the prostaglandin-E2 pathway. In other studies, postnatal treatment with lithium, an inhibitor of GSK3, increased cell proliferation and led to microcyst formation in rat kidneys. These studies suggest that loss of GSK3 activity could interfere with renal water transport at two levels. In the short term, it could disrupt vasopressin signaling in collecting duct cells and in the long term it could alter the structure of the collecting ducts, making them less responsive to the hydro-osmotic effects of vasopressin. Summary Ongoing studies reveal the crucial role played by GSK3 in the regulation of vasopressin action in the renal collecting ducts and suggest a possible use of GSK3 inhibitors in disease conditions associated with disrupted vasopressin signaling. PMID:22691876

Mice heterozygous for the oxytocin receptor gene (Oxtr(+/-)) show impaired social behaviour but not increased aggression or cognitive inflexibility: evidence of a selective haploinsufficiency gene effect.

PubMed

Sala, M; Braida, D; Donzelli, A; Martucci, R; Busnelli, M; Bulgheroni, E; Rubino, T; Parolaro, D; Nishimori, K; Chini, B

2013-02-01

We characterised the behavioural phenotype of mice heterozygous (Oxtr(+/-)) for the oxytocin receptor gene (Oxtr) and compared it with that of Oxtr null mice (Oxtr(-/-)), which display autistic-like behaviours, including impaired sociability and preference for social novelty, impaired cognitive flexibility, and increased aggression. Similar to Oxtr(-/-) mice, the Oxtr(+/-) showed impaired sociability and preference for social novelty but, unlike the null genotype, their cognitive flexibility and aggression were normal. By autoradiography, Oxtr(+/-) mice were found to have approximately 50% fewer oxytocin receptors (OXTRs) in all of the examined brain regions. Thus, because a partial reduction in Oxtr gene expression is sufficient to compromise social behaviour, the Oxtr acts as a haploinsufficient gene. Furthermore, the inactivation of the Oxtr gene affects specific behaviours in a dose-dependent manner: social behaviour is sensitive to even a partial reduction in Oxtr gene expression, whereas defects in aggression and cognitive flexibility require the complete inactivation of the Oxtr gene to emerge. We then investigated the rescue of the Oxtr(+/-) social deficits by oxytocin (OT) and Thr(4)Gly(7)OT (TGOT) administered i.c.v. at different doses. TGOT was more potent than OT in rescuing sociability and social novelty in both genotypes. Furthermore, the TGOT doses that reverted impaired sociability and preference for social novelty in Oxtr(+/-) were lower than those required in Oxtr(-/-), thus suggesting that the rescue effect is mediated by OXTR in Oxtr(+/-) and by other receptors (presumably vasopressin V1a receptors) in Oxtr(-/-). In line with this, a low dose of the selective oxytocin antagonist desGlyDTyrOVT blocks the rescue effect of TGOT only in the Oxtr(+/-) genotype, whereas the less selective antagonist SR49059 blocks rescue in both genotypes. In conclusion, the Oxtr(+/-) mouse is a unique animal model for investigating how partial loss of the Oxtr gene impair social interactions, and for designing pharmacological rescue strategies. © 2012 British Society for Neuroendocrinology.

Improvement of cationic albumin conjugated pegylated nanoparticles holding NC-1900, a vasopressin fragment analog, in memory deficits induced by scopolamine in mice.

PubMed

Xie, Yue-Ling; Lu, Wei; Jiang, Xin-Guo

2006-10-02

NC-1900, an active fragment analog of arginine vasopressin [arginine vasopressin-(4-9)], has proved to be capable of improving the spatial memory deficits and the impairments in passive avoidance test. In this study, a novel drug carrier for brain delivery, cationic bovine serum albumin conjugated pegylated nanoparticles (CBSA-NPs) holding NC-1900, was developed and its improvement on scopolamine-induced memory deficits was investigated in mice using the platform-jumping avoidance test. CBSA-NPs loaded with NC-1900 in spherical shape and uniform size below 100 nm were prepared by the double emulsion/solvent evaporation procedure, and the zeta potential of CBSA-NPs was about -8mV with the loading capacity of NC-1900 around 0.46%. The in vitro study showed that approximately 10% NC-1900 was released from CBSA-NPs in pH 7.4 phosphate buffer saline (PBS) during 56 h incubation with about 15% NC-1900 released in pH 4.0 PBS during 7 days, indicating the sustained release of this carrier. Furthermore, the half-life of NC-1900 loaded in CBSA-NPs in plasma was about 78 h, which was 4-fold longer than that of free NC-1900 (19 h). The active avoidance behavioral results showed that the s.c. administration of NC-1900 tended to improve memory deficits, but the difference did not present any statistical significance, whereas this peptide failed to produce any positive effects by i.v. administration. However, the i.v. injection of CBSA-NPs loaded with NC-1900 greatly improved memory impairments to a normal level, but the efficacy was slight if the loaded nanoparticles (NPs) were exclusive of the conjugation of CBSA, indicating that CBSA-NP was a promising brain delivery carrier for NC-1900 with CBSA as a potent brain targetor. It was concluded that CBSA-NP loaded with NC-1900 was potentially efficacious in the treatment of memory deficits via i.v. administration.

A century old renin-angiotensin system still grows with endless possibilities: AT1 receptor signaling cascades in cardiovascular physiopathology.

PubMed

Balakumar, Pitchai; Jagadeesh, Gowraganahalli

2014-10-01

Ang II, the primary effector pleiotropic hormone of the renin-angiotensin system (RAS) cascade, mediates physiological control of blood pressure and electrolyte balance through its action on vascular tone, aldosterone secretion, renal sodium absorption, water intake, sympathetic activity and vasopressin release. It affects the function of most of the organs far beyond blood pressure control including heart, blood vessels, kidney and brain, thus, causing both beneficial and deleterious effects. However, the protective axis of the RAS composed of ACE2, Ang (1-7), alamandine, and Mas and MargD receptors might oppose some harmful effects of Ang II and might promote beneficial cardiovascular effects. Newly identified RAS family peptides, Ang A and angioprotectin, further extend the complexities in understanding the cardiovascular physiopathology of RAS. Most of the diverse actions of Ang II are mediated by AT1 receptors, which couple to classical Gq/11 protein and activate multiple downstream signals, including PKC, ERK1/2, Raf, tyrosine kinases, receptor tyrosine kinases (EGFR, PDGF, insulin receptor), nuclear factor κB and reactive oxygen species (ROS). Receptor activation via G12/13 stimulates Rho-kinase, which causes vascular contraction and hypertrophy. The AT1 receptor activation also stimulates G protein-independent signaling pathways such as β-arrestin-mediated MAPK activation and Src-JAK/STAT. AT1 receptor-mediated activation of NADPH oxidase releases ROS, resulting in the activation of pro-inflammatory transcription factors and stimulation of small G proteins such as Ras, Rac and RhoA. The components of the RAS and the major Ang II-induced signaling cascades of AT1 receptors are reviewed. Copyright © 2014 Elsevier Inc. All rights reserved.

Effect of vasopressin blockade on blood pressure during water deprivation in intact and baroreceptor-denervated conscious dogs.

PubMed

Gregory, L C; Quillen, E W; Keil, L C; Chang, D; Reid, I A

1988-04-01

Previous studies have provided evidence that vasopressin plays an important role in blood pressure regulation during water deprivation. However, these investigations have been complicated by reflex compensatory increases in cardiac output and renin secretion. The aim of the present study was to investigate the effect of blockade of the vasoconstrictor action of vasopressin in conscious water-deprived dogs in which the low- and/or high-pressure baroreceptors were denervated to minimize reflex responses. Vasopressin blockade in sham-operated dogs (n = 7) did not change arterial pressure. Heart rate rose from 78 +/- 9 to 119 +/- 13 beats/min (P less than 0.01), and plasma renin activity increased from 10.9 +/- 2.1 to 21.6 +/- 4.6 ng.ml-1.3 h-1 (P less than 0.01). In carotid sinus-denervated dogs (n = 6), vasopressin blockade again failed to decrease arterial pressure. Heart rate increased from 105 +/- 10 to 132 +/- 10 beats/min (P less than 0.01), and plasma renin activity rose from 6.8 +/- 1.7 to 15.5 +/- 2.4 ng.ml-1.3 h-1 (P less than 0.01). The antagonist also failed to change blood pressure in cardiac-denervated dogs (n = 5). Heart rate increased from 111 +/- 9 to 119 +/- 1 beats/min (P less than 0.01), but plasma renin activity did not increase significantly. In marked contrast, vasopressin blockade in sinoaortic/cardiac-denervated dogs (n = 7) promptly decreased arterial pressure from 115 +/- 8 to 94 +/- 7 mmHg (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental Cardiac Arrest Treatment with Adrenaline, Vasopressin, or Placebo

PubMed Central

Palácio, Manoel Ângelo Gomes; de Paiva, Edison Ferreira; de Azevedo, Luciano Cesar Pontes; Timerman, Ari

2013-01-01

Background The effect of vasoconstrictors in prolonged cardiopulmonary resuscitation (CPR) has not been fully clarified. Objectives To evaluate adrenaline and vasopressin pressure effect, and observe the return of spontaneous circulation (ROSC). Methods A prospective, randomized, blinded, and placebo-controlled study. After seven minutes of untreated ventricular fibrillation, pigs received two minutes cycles of CPR. Defibrillation was attempted (4 J/kg) once at 9 minutes, and after every cycle if a shockable rhythm was present, after what CPR was immediately resumed. At 9 minutes and every five minutes intervals, 0.02 mg/kg (n = 12 pigs) adrenaline, or 0.4 U/kg (n = 12) vasopressin, or 0.2 mL/kg (n = 8) 0.9% saline solution was administered. CPR continued for 30 minutes or until the ROSC. Results Coronary perfusion pressure increased to about 20 mmHg in the three groups. Following vasoconstrictors doses, pressure level reached 35 mmHg versus 15 mmHg with placebo (p < 0.001). Vasopressin effect remained at 15-20 mmHg after three doses versus zero with adrenaline or placebo. ROSC rate differed (p = 0.031) among adrenaline (10/12), vasopressin (6/12), and placebo (2/8). Time-to-ROSC did not differ (16 minutes), nor the number of doses previously received (one or two). There was no difference between vasoconstrictors, but against placebo, only adrenaline significantly increased the ROSC rate (p = 0.019). Conclusion The vasoconstrictors initial pressure effect was equivalent and vasopressin maintained a late effect at prolonged resuscitation. Nevertheless, when compared with placebo, only adrenaline significantly increased the ROSC rate. PMID:24173134

Prevention of hypoxic brain oedema by the administration of vasopressin receptor antagonist OPC-31260.

PubMed

Molnár, Andor H; Varga, Csaba; Berkó, Anikó; Rojik, Imre; Párducz, Arpád; László, Ferenc; László, Ferenc A

2008-01-01

The numerous situations which can result in cerebral hypoxic damage occur in newborn infants and in the elderly. In research aimed at more effective therapeutic intervention in ischaemic disorders of the brain, the animal model used and the principles of the causal therapy should be better outlined. The effects of the non-peptide AVPR (V2) antagonist 5-dimethylamino-1-[4-(2-methylbenzoylamino) benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride (OPC-31260) on the cerebral oedema induced by general cerebral hypoxia were studied in rats. The general cerebral hypoxia was produced by bilateral common carotid ligation in Sprague-Dawley rats of the CFY strain. By 6h after the ligation, half of the rats had died, but the survival rate was significantly higher following OPC-31260 administration. Electron microscopic examinations revealed typical ischaemic changes after the carotid ligation, and OPC-31260 treatment did not significantly reduce the hypoxic signs in the brain cortex; only a certain decrease in the pericapillary oedema was observed. The carotid ligation increased the brain contents of water and Na(+) and enhanced the plasma AVP level. The increased brain water and Na(+) accumulation was prevented by OPC-31260 administration, but the plasma AVP level was further enhanced by OPC-31260. These results demonstrate the important role of AVP in the development of the disturbances in brain water and electrolyte balance in response to general cerebral hypoxia. The carotid ligation-induced cerebral oedema was significantly reduced following oral OPC-31260 administration. The protective mechanism exerted by OPC-31260 stems from its influence on the renal AVPR (V2). These observations might suggest an effective approach to the treatment of global hypoxia-induced cerebral oedema in humans.

Nature and Recurrence of AVPR2 Mutations in X-linked Nephrogenic Diabetes Insipidus

PubMed Central

Bichet, Daniel G.; Birnbaumer, Mariel; Lonergan, Michèle; Arthus, Marie-Françoise; Rosenthal, Walter; Goodyer, Paul; Nivet, Hubert; Benoit, Stéphane; Giampietro, Philip; Simonetti, Simonetta; Fish, Alfred; Whitley, Chester B.; Jaeger, Philippe; Gertner, Joseph; New, Maria; DiBona, Francis J.; Kaplan, Bernard S.; Robertson, Gary L.; Hendy, Geoffrey N.; Fujiwara, T. Mary; Morgan, Kenneth

1994-01-01

X-linked nephrogenic diabetes insipidus (NDI) is a rare disease with defective renal and extrarenal arginine-vasopressin V2 receptor responses due to mutations in the AVPR2 gene in Xq28. We analyzed 31 independent NDI families to determine the nature and recurrence of AVPR2 mutations. Twenty-one new putative disease-causing mutations were identified: 113delCT, 253del35, 255del9, 274insG, V88M, R106C, 402delCT, C112R, Y124X, S126F, W164S, S167L, 684delTA, 804insG, W284X, A285P, W293X, R337X, and three large deletions or gene rearrangements. Five other mutations—R113W, Y128S, R137H, R181C, and R202C—that previously had been reported in other families were detected. There was evidence for recurrent mutation for four mutations (R113W, R137H, S167L, and R337X). Eight de novo mutation events were detected (274insG, R106C, Y128S, 167L [twice], R202C, 684delTA, and R337X). The origins were maternal (one), grandmaternal (one), and grandpaternal (six). In the 31 NDI families and 6 families previously reported by us, there is evidence both for mutation hot spots for nucleotide substitutions and for small deletions and insertions. More than half (58%) of the nucleotide substitutions in 26 families could be a consequence of 5-methylcytosine deamination at a CpG dinucleotide. Most of the small deletions and insertions could be attributed to slipped mispairing during DNA replication. PMID:8037205

Genetics and diagnosis of central diabetes insipidus.

PubMed

Bichet, Daniel G

2012-04-01

Most of the central diabetes insipidus cases seen in general practice are acquired but the rare cases of hereditary autosomal dominant or recessive neurohypophyseal diabetes insipidus have provided further cellular understanding of the mechanisms responsible for pre-hormone folding, maturation and release. Autosomal dominant central diabetes insipidus is secondary to the toxic accumulation of vasopressin mutants as fibrillar aggregates in the endoplasmic reticulum of hypothalamic magnocellular neurons producing vasopressin. As well, Trpv1(-/-) and Trpv4(-/-) mice have shed new light on the perception of tonicity through the stretch receptors TRPVs expressed both in central and peripheral neurons. The genomic information provided by sequencing the AVP gene is key to the routine care of these patients and, as in other genetic diseases, reduces health costs and provides psychological benefits to patients and families. In addition, simple, inexpensive blood and urine measurements together with clinical characteristics and brain magnetic resonance imaging (MRI) could distinguish between central, nephrogenic and polydipsic cases. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Effects of 2G on Gene Expression of Stress-Related Hormones in Rat Placenta

NASA Technical Reports Server (NTRS)

Benson, S.; Talyansky, Y.; Moyer, E. L.; Lowe, M.; Baer, L. A.; Ronca, A. E.

2017-01-01

Understanding the effects of spaceflight on mammalian reproductive and developmental physiology is important to future human space exploration and permanent settlement beyond Earth orbit. Fetal developmental programming, including modulation of the HPA axis, is thought to originate at the placental-uterine interface, where both transfer of maternal hormones to the fetus and synthesis of endogenous hormones occurs. In healthy rats, fetal corticosterone levels are kept significantly lower by 11BetaHSD-2, which inactivates corticosterone by conversion into cortisone. Placental tissues express endogenous HPA axis-associated hormones including corticotropin-releasing hormone (CRH), pre-opiomelanocortin (POMC), and vasopressin, which may contribute to fetal programming alongside maternal hormones. DNA methylase 3A, 11BetaHSD-2, and 11BetaHSD-1, which are involved in the regulation of maternal cortisol transfer and modulation of the HPA axis, are also expressed in placental tissues along with glucocorticoid receptor and may be affected by differential gravity exposure during pregnancy. Fetuses may respond differently to maternal glucocorticoid exposure during gestation through sexually dimorphic expression of corticosterone-modulating hormones. To elucidate effects of altered gravity on placental gene expression, here we present a ground-based analogue study involving continuous centrifugation to produce 2g hypergravity. We hypothesized that exposure to 2g would induce a decrease in 11BetaHSD-2 expression through the downregulation of DNA methylase 3a and GC receptor, along with concurrent upregulation in endogenous CRH, POMC, and vasopressin expression. Timed pregnant female rats were exposed to 2G from Gestational day 6 to Gestational day 20, and comparisons made with Stationary Control (SC) and Vivarium Control (VC) dams at 1G. Dams were euthanized and placentas harvested on G20. We homogenized placental tissues, extracted and purified RNA, synthesized cDNA, and quantified the expression levels of the genes of interest relative to the GAPDH housekeeping gene, using RT-qPCR and gene-specific cDNA probes. Elucidation of glucocorticoid transfer and synthesis in the placenta can provide new insights into the unique dynamics of mammalian development in microgravity and guide future multi-generational studies in space.

Social preference and maternal defeat-induced social avoidance in virgin female rats: sex differences in involvement of brain oxytocin and vasopressin.

PubMed

Lukas, Michael; Neumann, Inga D

2014-08-30

Research concerning non-reproductive sociability in rodents is mainly restricted to assessing the effects of oxytocin (OXT) and arginine-vasopressin (AVP) in male rats and mice. Comparable studies on natural social preference and social avoidance in females are substantially lacking. Here, we adapted a behavioral paradigm for monitoring social preference of female rats consisting of two consecutive exposures to either non-social or social stimuli. Further, to induce stimulus-specific social avoidance, female rats were exposed to a single 10-min maternal defeat by a lactating dam. Social preference towards same-sex conspecifics in female rats was shown to be independent of the estrous cycle and even more pronounced than in male rats. Intracerebroventricular (icv) application of OXT, AVP, or their selective receptor antagonists or agonists, did not alter naturally-occurring social preference in female rats. Stimulus-specific social avoidance could be induced by prior exposure to a lactating rat: an effect that could not be reversed/overcome by icv OXT. The female social preference paradigm for rats established in this study detected subtle sex differences in social preference behavior of rats. Further, stimulus-specific social deficits could be induced in female rats using an acute exposure to social defeat - as previously observed in male rodents. Female rats show strong social preference behavior, which can be prevented by social defeat, but does not seem to be regulated by the OXT or AVP systems. Accordingly, icv application of synthetic OXT does not reverse maternal defeat-induced social avoidance in female rats. Copyright © 2014 Elsevier B.V. All rights reserved.

Dose-Dependent and Lasting Influences of Intranasal Vasopressin on Face Processing in Men

PubMed Central

Price, Daniel; Burris, Debra; Cloutier, Anna; Thompson, Carol B.; Rilling, James K.; Thompson, Richmond R.

2017-01-01

Arginine vasopressin (AVP) and related peptides have diverse effects on social behaviors in vertebrates, sometimes promoting affiliative interactions and sometimes aggressive or antisocial responses. The type of influence, in at least some species, depends on social contexts, including the sex of the individuals in the interaction and/or on the levels of peptide within brain circuits that control the behaviors. To determine if AVP promotes different responses to same- and other-sex faces in men, and if those effects are dose dependent, we measured the effects of two doses of AVP on subjective ratings of male and female faces. We also tested if any influences persist beyond the time of drug delivery. When AVP was administered intranasally on an initial test day, 20 IU was associated with decreased social assessments relative to placebo and 40 IU, and some of the effects persisted beyond the initial drug delivery and appeared to generalize to novel faces on subsequent test days. In single men, those influences were most pronounced, but not exclusive, for male faces, whereas in coupled men they were primarily associated with responses to female faces. Similar influences were not observed if AVP was delivered after placebo on a second test day. In a preliminary analysis, the differences in social assessments observed between men who received 20 and 40 IU, which we suggest primarily reflect lowered social assessments induced by the lower dose, appeared most pronounced in subjects who carry what has been identified as a risk allele for the V1a receptor gene. Together, these results suggest that AVP’s effects on face processing, and possibly other social responses, differ according to dose, depend on relationship status, and may be more prolonged than previously recognized. PMID:29018407

G protein-coupled receptor mutations and human genetic disease.

PubMed

Thompson, Miles D; Hendy, Geoffrey N; Percy, Maire E; Bichet, Daniel G; Cole, David E C

2014-01-01

Genetic variations in G protein-coupled receptor genes (GPCRs) disrupt GPCR function in a wide variety of human genetic diseases. In vitro strategies and animal models have been used to identify the molecular pathologies underlying naturally occurring GPCR mutations. Inactive, overactive, or constitutively active receptors have been identified that result in pathology. These receptor variants may alter ligand binding, G protein coupling, receptor desensitization and receptor recycling. Receptor systems discussed include rhodopsin, thyrotropin, parathyroid hormone, melanocortin, follicle-stimulating hormone (FSH), luteinizing hormone, gonadotropin-releasing hormone (GNRHR), adrenocorticotropic hormone, vasopressin, endothelin-β, purinergic, and the G protein associated with asthma (GPRA or neuropeptide S receptor 1 (NPSR1)). The role of activating and inactivating calcium-sensing receptor (CaSR) mutations is discussed in detail with respect to familial hypocalciuric hypercalcemia (FHH) and autosomal dominant hypocalemia (ADH). The CASR mutations have been associated with epilepsy. Diseases caused by the genetic disruption of GPCR functions are discussed in the context of their potential to be selectively targeted by drugs that rescue altered receptors. Examples of drugs developed as a result of targeting GPCRs mutated in disease include: calcimimetics and calcilytics, therapeutics targeting melanocortin receptors in obesity, interventions that alter GNRHR loss from the cell surface in idiopathic hypogonadotropic hypogonadism and novel drugs that might rescue the P2RY12 receptor congenital bleeding phenotype. De-orphanization projects have identified novel disease-associated receptors, such as NPSR1 and GPR35. The identification of variants in these receptors provides genetic reagents useful in drug screens. Discussion of the variety of GPCRs that are disrupted in monogenic Mendelian disorders provides the basis for examining the significance of common pharmacogenetic variants.

Congenital nephrogenic diabetes insipidus with a novel mutation in the aquaporin 2 gene.

PubMed

Park, Youn Jong; Baik, Haing Woon; Cheong, Hae Il; Kang, Ju Hyung

2014-07-01

Congenital nephrogenic diabetes insipidus (CNDI) is a rare disorder caused by mutations of the arginine vasopressin (AVP) V2 receptor or aquaporin 2 ( AQP2 ) genes. The current study presented the case of CNDI in a 1-month-old male with a novel mutation in the AQP2 gene. The patient was referred due to the occurrence of hypernatremia and mild-intermittent fever since birth. An AVP stimulation test was compatible with CNDI as there was no significant response to desmopressin. Molecular genetic analysis demonstrated two mutations in exon 1 of the AQP2 gene: C to T transition, which resulted in a missense mutation of 108 Thr (ACG) to Met (ATG); and a 127, 128 delCA, which resulted in a deletion mutation of glutamine in position 43 at codon CAG as the first affected amino acid, with the new reading frame endign in a termination codon at position 62. The molecular genetic analysis of the parents showed that the missense mutation was inherited maternally and the deletion mutation was inherited paternally. The parents showed no signs or symptoms of CNDI, indicating autosomal recessive inheritance. The 108 Thr (ACG) to Met (ATG) mutation was confirmed as a novel mutation. Therefore, the molecular identification of the AQP2 gene has clinical significance, as early recognition of CNDI in infants that show only non-specific symptoms, can be facilitated. Thus, repeated episodes of dehydration, which may cause physical and mental retardation can be avoided.

Congenital nephrogenic diabetes insipidus with a novel mutation in the aquaporin 2 gene

PubMed Central

PARK, YOUN JONG; BAIK, HAING WOON; CHEONG, HAE IL; KANG, JU HYUNG

2014-01-01

Congenital nephrogenic diabetes insipidus (CNDI) is a rare disorder caused by mutations of the arginine vasopressin (AVP) V2 receptor or aquaporin 2 (AQP2) genes. The current study presented the case of CNDI in a 1-month-old male with a novel mutation in the AQP2 gene. The patient was referred due to the occurrence of hypernatremia and mild-intermittent fever since birth. An AVP stimulation test was compatible with CNDI as there was no significant response to desmopressin. Molecular genetic analysis demonstrated two mutations in exon 1 of the AQP2 gene: C to T transition, which resulted in a missense mutation of 108Thr (ACG) to Met (ATG); and a 127, 128 delCA, which resulted in a deletion mutation of glutamine in position 43 at codon CAG as the first affected amino acid, with the new reading frame endign in a termination codon at position 62. The molecular genetic analysis of the parents showed that the missense mutation was inherited maternally and the deletion mutation was inherited paternally. The parents showed no signs or symptoms of CNDI, indicating autosomal recessive inheritance. The 108Thr (ACG) to Met (ATG) mutation was confirmed as a novel mutation. Therefore, the molecular identification of the AQP2 gene has clinical significance, as early recognition of CNDI in infants that show only non-specific symptoms, can be facilitated. Thus, repeated episodes of dehydration, which may cause physical and mental retardation can be avoided. PMID:24944815

Role of protein kinase C-α in hypertonicity-stimulated urea permeability in mouse inner medullary collecting ducts.

PubMed

Wang, Yanhua; Klein, Janet D; Froehlich, Otto; Sands, Jeff M

2013-01-15

The kidney's ability to concentrate urine is vitally important to our quality of life. In the hypertonic environment of the kidney, urea transporters must be regulated to optimize function. We previously showed that hypertonicity increases urea permeability and that the protein kinase C (PKC) blockers chelerythrine and rottlerin decreased hypertonicity-stimulated urea permeability in rat inner medullary collecting ducts (IMCDs). Because PKCα knockout (PKCα(-/-)) mice have a urine-concentrating defect, we tested the effect of hypertonicity on urea permeability in isolated perfused mouse IMCDs. Increasing the osmolality of perfusate and bath from 290 to 690 mosmol/kgH(2)O did not change urea permeability in PKCα(-/-) mice but significantly increased urea permeability in wild-type mice. To determine whether the response to protein kinase A was also missing in IMCDs of PKCα(-/-) mice, tubules were treated with vasopressin and subsequently with the PKC stimulator phorbol dibutyrate (PDBu). Vasopressin stimulated urea permeability in PKCα(-/-) mice. Like vasopressin, forskolin stimulated urea permeability in PKCα(-/-) mice. We previously showed that, in rats, vasopressin and PDBu have additive stimulatory effects on urea permeability. In contrast, in PKCα(-/-) mice, PDBu did not further increase vasopressin-stimulated urea permeability. Western blot analysis showed that expression of the UT-A1 urea transporter in IMCDs was increased in response to vasopressin in wild-type mice as well as PKCα(-/-) mice. Hypertonicity increased UT-A1 phosphorylation in wild-type mice but not in PKCα(-/-) mice. We conclude that PKCα mediates hypertonicity-stimulated urea transport but is not necessary for vasopressin stimulation of urea permeability in mouse IMCDs.

Vasopressin Receptor Signaling and Cycling of Water Channels in Renal Epithelia

DTIC Science & Technology

1992-08-22

as well as renal model epithelia, including amphibian urinary bladder tissue (Bentley, 1958; DiBona , 1981; Hays, 1983; Mia et al., 1987). The increase...propagation of numerous microvilli on the membrane surface (Davis et al., 1974; DiBona , 1981; Mia et al., 1983, 1988; Mills and Malik, 1978; Spinelli et...fusion events are dependent very likely on the presence of cytosolic microtubules and microfilaments (Taylor et al., 1973; Hardy and DiBona , 1982; Hays

Bonobo personality traits are heritable and associated with vasopressin receptor gene 1a variation

PubMed Central

Staes, Nicky; Weiss, Alexander; Helsen, Philippe; Korody, Marisa; Eens, Marcel; Stevens, Jeroen M.G.

2016-01-01

Despite being closely related, bonobos and chimpanzees show remarkable behavioral differences, the proximate origins of which remain unknown. This study examined the link between behavioral variation and variation in the vasopressin 1a receptor gene (Avpr1a) in bonobos. Chimpanzees are polymorphic for a ~360 bp deletion (DupB), which includes a microsatellite (RS3) in the 5′ promoter region of Avpr1a. In chimpanzees, the DupB deletion has been linked to lower sociability, lower social sensitivity, and higher anxiety. Chimpanzees and bonobos differ on these traits, leading some to believe that the absence of the DupB deletion in bonobos may be partly responsible for these differences, and to the prediction that similar associations between Avpr1a genotypes and personality traits should be present in bonobos. We identified bonobo personality dimensions using behavioral measures (SociabilityB, BoldnessB, OpennessB, ActivityB) and trait ratings (AssertivenessR, ConscientiousnessR, OpennessR, AgreeablenessR, AttentivenessR, ExtraversionR). In the present study we found that all 10 dimensions have nonzero heritabilities, indicating there is a genetic basis to personality, and that bonobos homozygous for shorter RS3 alleles were lower in AttentivenessR and higher in OpennessB. These results suggest that variations in Avpr1a genotypes explain both within and between species differences in personality traits of bonobos and chimpanzees. PMID:27910885

The (pro)renin receptor and body fluid homeostasis

PubMed Central

Cao, Theresa

2013-01-01

The renin-angiotensin system (RAS) has long been established as one of the major mechanisms of hypertension through the increased levels of angiotensin (ANG) II and its resulting effect on the sympathetic nerve activity, arterial vasoconstriction, water reabsorption, and retention, etc. In the central nervous system, RAS activation affects body fluid homeostasis through increases in sympathetic nerve activity, water intake, food intake, and arginine vasopressin secretion. Previous studies, however, have shown that ANG II can be made in the brain, and it could possibly be through a new component called the (pro)renin receptor. This review intends to summarize the central and peripheral effects of the PRR on body fluid homeostasis. PMID:23678024

Controlled long-term release of small peptide hormones using a new microporous polypropylene polymer: its application for vasopressin in the Brattleboro rat and potential perinatal use

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kruisbrink, J.; Boer, G.J.

1984-12-01

Based on drug release by microporous hollow fibers and the recent introduction of microporous polymers, a new technique was developed for controlled delivery of peptides. Small-diameter microporous polypropylene tubing, lumen-loaded with microgram quantities of vasopressin, and coated with collodion, releases vasopressin after in vitro immersion slowly (1-100 ng/d) and constantly for months. The mechanism of pseudo-zero-order delivery is based on high adsorption of vasopressin, keeping the void volume concentration of dissolved vasopressin constant, which is consequently a constant driving force of outward diffusion. The collodion coating prevents the entry of proteinaceous compounds which would result in rapid desorption of vasopressin.more » The present delivery module provides a lasting release for other peptides as well (lysine-vasopressin, oxytocin, alpha-melanocyte-stimulating hormone and, to a lesser extent, Met-enkephalin). The microporous polymer-collodion device is biocompatible and, loaded with vasopressin, successfully alleviates the diabetes insipidus of Brattleboro rats deficient for vasopressin. Subcutaneous implantation normalized diuresis for a period of 60 d and constant urine vasopressin excretion is observed. When the commercially available osmotic minipump is too large for implantation, the small size of the present controlled-delivery system allows peptide treatment of young and immature laboratory rats, even if located in utero.« less

A de novo novel missense mutation in AVPR2 with severe nephrogenic diabetes insipidus

PubMed Central

Kobayashi, Daisuke; Nagaraj, Shashi K.; Lin, Jen-Jar; Bichet, Daniel G.

2010-01-01

We describe a paediatric case of nephrogenic diabetes insipidus (NDI) with a novel mutation in the arginine vasopressin receptor 2 gene (AVPR2) in the absence of a family history of congenital polyuria. The patient, a 5-month-old Caucasian boy, had failure to thrive and hypernatraemia. On admission to hospital, he had a plasma sodium of 171 mEq/L with a concomittant urine osmolality of 131 mOsm/kg. Molecular genetic analysis demonstrated that the patient had an AVPR2 mutation (c.861C > G) resulting in a substitution of tryptophan for serine at amino acid position 167 (p.Ser167Trp). His mother was heterozygous for the same Ser167Trp mutation which was found to be de novo from the DNA analysis of the maternal grandparents. PMID:25949462

BG60S dissolution interferes with osteoblast calcium signals.

PubMed

Valério, P; Pereira, M M; Goes, A M; Leite, M F

2007-02-01

We investigated the influence of extracellular calcium concentration, caused by the dissolution of a bioactive glass with 60% of silicon (BG60S), on intracellular calcium (Ca(i) (2 +)) signals and expression of inositol 1, 4, 5-triphosphate receptors (InsP(3)R) in primary culture of osteoblasts. We found that BG60S caused an increase in Ca(i) (2 +) signals in this cell type. Additionally, osteoblasts pre-incubated in the presence of BG60S showed an increase in Ca(i) (2 +) when cells were stimulated with vasopressin. On the other hand, a decrease in Ca(i) (2 +) signals were observed in osteoblasts pre-treated with BG60S and stimulated with KCl. We furher found that in osteoblasts, the type I InsP(3)R is preferentially distributed in the nucleus while the type II InsP(3)R in the cytoplasm. Preincubation of osteoblasts with BG60S altered the receptor expression level, increasing the type I InsP(3)R in the nucleus and decreasing type II InsP(3)R in the cytosol. Together, our results showed that in osteoblasts, BG60S increased Ca(i) (2 +)signals and altered Ca(i) (2 +) machinery.

Diagnostic and Predictive Values of Thirst, Angiotensin II, and Vasopressin During Trauma Resuscitation

DTIC Science & Technology

2010-09-01

and plasma AVP and AT2 levels across a broader spectrum of hemorrhagic shock severity may be warranted. The authors wish to thank the medical, nursing ...301. 2. Olsson K. Central control of vasopressin release and thirst. Acta Paediatr Scand Suppl. 1983;305:36–9. Pr eh os p E m er g C ar e D ow nl oa

Norepinephrine content in discrete brain areas and neurohypophysial vasopressin in rats after a 9-d spaceflight (SLS-1)

NASA Technical Reports Server (NTRS)

Fareh, Jeannette; Cottet-Emard, Jean-Marie; Pequignot, Jean-Marc; Jahns, Gary; Meylor, John; Viso, Michel; Vassaux, Didier; Gauquelin, Guillemette; Gharib, Claude

1993-01-01

The norepinephrine (NE) content in discrete brain areas and the vasopressin content in the neurohypophysial system were assessed in rats after a 9-d spaceflight and after a recovery period. The NE content in the locus coeruleus decreased significantly in spaceflight rats, but showed no difference between control and flight animals after a 9-d recovery. These findings were probably due to an acute stress undergone during landing. The NE content was unchanged in the A2 and A5 cell groups. In rats flown aboard SLS-1, the vasopressin content was increased in the posterior pituitary, and was significantly decreased in the hypothalamus. We conclude that the NE depletion in the locus coeruleus and the alteration in vasopressin release were consistent with an acute stress, likely occurring during and/or after landing. These changes tend to mask the actual neuroendocrine modifications caused by microgravity.

Vasopressin and Oxytocin Reduce Food Sharing Behavior in Male, but Not Female Marmosets in Family Groups

PubMed Central

Taylor, Jack H.; Intorre, Allison A.; French, Jeffrey A.

2017-01-01

Oxytocin (OT) is critical for lactation and maternal care, but OT and the related nonapeptide vasopressin are important for caregiving behaviors in fathers and alloparents as well. This experiment tested the effects of vasopressin and OT on food sharing in marmoset families. We treated caregivers (parents, siblings) with intranasal vasopressin, OT, or saline, and then paired them with the youngest marmoset in the family. Caregivers were given preferred food, and then observed for food sharing and aggressive behavior with young marmosets. OT reduced food sharing from male alloparents to youngest siblings, and fathers that received vasopressin refused to share food with their youngest offspring more often than when treated with OT. Vasopressin increased aggressive vocalizations directed toward potential food recipients in all classes of caregivers. These results indicate that vasopressin and OT do not always enhance prosocial behavior: modulation of food sharing depends on both sex and parental status. PMID:28798724

Vasopressin and Oxytocin Reduce Food Sharing Behavior in Male, but Not Female Marmosets in Family Groups.

PubMed

Taylor, Jack H; Intorre, Allison A; French, Jeffrey A

2017-01-01

Oxytocin (OT) is critical for lactation and maternal care, but OT and the related nonapeptide vasopressin are important for caregiving behaviors in fathers and alloparents as well. This experiment tested the effects of vasopressin and OT on food sharing in marmoset families. We treated caregivers (parents, siblings) with intranasal vasopressin, OT, or saline, and then paired them with the youngest marmoset in the family. Caregivers were given preferred food, and then observed for food sharing and aggressive behavior with young marmosets. OT reduced food sharing from male alloparents to youngest siblings, and fathers that received vasopressin refused to share food with their youngest offspring more often than when treated with OT. Vasopressin increased aggressive vocalizations directed toward potential food recipients in all classes of caregivers. These results indicate that vasopressin and OT do not always enhance prosocial behavior: modulation of food sharing depends on both sex and parental status.

Suppression of HPA-axis activity by haloperidol after experimentally induced heat stress.

PubMed

Hennig, J; Rzepka, U; Mai, B; Netter, P

1995-07-01

1. Healthy male volunteers were exposed to either a heat condition (52 degrees C) or normal temperature (28 degrees C) receiving a single oral dose of 3 mg haloperidol or placebo in a double-blind design. 2. Ratings on aversiveness as well as on intensity of ambient temperature and saliva samples for determination of cortisol were sampled at defined intervals. Body core temperature and sweat loss were measured continuously throughout the three hour experiment. 3. Results indicate increased levels of cortisol after exposure to heat but not after a pretreatment with haloperidol. 4. The findings of this study suggest that D2-receptors of tuberoinfundibular neurons are blocked by haloperidol which suppresses the dopamine mediated release of vasopressin induced by dehydration and the subsequent stimulation of CRH.

A Two-Year Randomized Trial of Interventions to Decrease Stress Hormone Vasopressin Production in Patients with Meniere's Disease-A Pilot Study.

PubMed

Kitahara, Tadashi; Okamoto, Hidehiko; Fukushima, Munehisa; Sakagami, Masaharu; Ito, Taeko; Yamashita, Akinori; Ota, Ichiro; Yamanaka, Toshiaki

2016-01-01

Meniere's disease, a common inner ear condition, has an incidence of 15-50 per 100,000. Because mental/physical stress and subsequent increase in the stress hormone vasopressin supposedly trigger Meniere's disease, we set a pilot study to seek new therapeutic interventions, namely management of vasopressin secretion, to treat this disease. We enrolled 297 definite Meniere's patients from 2010 to 2012 in a randomized-controlled and open-label trial, assigning Group-I (control) traditional oral medication, Group-II abundant water intake, Group-III tympanic ventilation tubes and Group-IV sleeping in darkness. Two hundred sixty-three patients completed the planned 2-year-follow-up, which included assessment of vertigo, hearing, plasma vasopressin concentrations and changes in stress/psychological factors. At 2 years, vertigo was completely controlled in 54.3% of patients in Group-I, 81.4% in Group-II, 84.1% in Group-III, and 80.0% in Group-IV (statistically I < II = III = IV). Hearing was improved in 7.1% of patients in Group-I, 35.7% in Group-II, 34.9% in Group-III, and 31.7% in Group-IV (statistically I < II = III = IV). Plasma vasopressin concentrations decreased more in Groups-II, -III, and -IV than in Groups-I (statistically I < II = III = IV), although patients' stress/psychological factors had not changed. Physicians have focused on stress management for Meniere's disease. However, avoidance of stress is unrealistic for patients who live in demanding social environments. Our findings in this pilot study suggest that interventions to decrease vasopressin secretion by abundant water intake, tympanic ventilation tubes and sleeping in darkness is feasible in treating Meniere's disease, even though these therapies did not alter reported mental/physical stress levels. ClinicalTrials.gov NCT01099046.

Targeting renal purinergic signalling for the treatment of lithium-induced nephrogenic diabetes insipidus.

PubMed

Kishore, B K; Carlson, N G; Ecelbarger, C M; Kohan, D E; Müller, C E; Nelson, R D; Peti-Peterdi, J; Zhang, Y

2015-06-01

Lithium still retains its critical position in the treatment of bipolar disorder by virtue of its ability to prevent suicidal tendencies. However, chronic use of lithium is often limited by the development of nephrogenic diabetes insipidus (NDI), a debilitating condition. Lithium-induced NDI is due to resistance of the kidney to arginine vasopressin (AVP), leading to polyuria, natriuresis and kaliuresis. Purinergic signalling mediated by extracellular nucleotides (ATP/UTP), acting via P2Y receptors, opposes the action of AVP on renal collecting duct (CD) by decreasing the cellular cAMP and thus AQP2 protein levels. Taking a cue from this phenomenon, we discovered the potential involvement of ATP/UTP-activated P2Y2 receptor in lithium-induced NDI in rats and showed that P2Y2 receptor knockout mice are significantly resistant to Li-induced polyuria, natriuresis and kaliuresis. Extension of these studies revealed that ADP-activated P2Y12 receptor is expressed in the kidney, and its irreversible blockade by the administration of clopidogrel bisulphate (Plavix(®)) ameliorates Li-induced NDI in rodents. Parallel in vitro studies showed that P2Y12 receptor blockade by the reversible antagonist PSB-0739 sensitizes CD to the action of AVP. Thus, our studies unravelled the potential beneficial effects of targeting P2Y2 or P2Y12 receptors to counter AVP resistance in lithium-induced NDI. If established in further studies, our findings may pave the way for the development of better and safer methods for the treatment of NDI by bringing a paradigm shift in the approach from the current therapies that predominantly counter the anti-AVP effects to those that enhance the sensitivity of the kidney to AVP action. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

Neonatal capsaicin treatment impairs vasopressin-mediated blood pressure recovery following acute hypotension.

PubMed Central

Bennett, T.; Gardiner, S. M.

1984-01-01

Rats were treated with a single injection of either capsaicin (50 mg kg-1 s.c.) or vehicle on day 2 after birth. When the animals were adult, they were challenged with osmotic (water deprivation) and haemodynamic (acute hypotension) stimuli that normally evoke vasopressin release. Capsaicin-treated and vehicle-injected rats showed similar body weight losses and plasma osmolalities following 48 h of water deprivation. Thus it appears that neonatal treatment with capsaicin does not impair the antidiuretic response to plasma hyperosmolality. Following acute ganglion blockade in the presence of angiotensin converting enzyme inhibition, there was some recovery of blood pressure in the vehicle-injected rats, but recovery was significantly (P less than 0.001) less in the capsaicin-treated animals. The recovery may be attributed to vasopressin since it was abolished by an antagonist selective for the pressor action of the peptide (d(CH2)5DAVP). These results suggest that neonatal treatment with capsaicin impairs vasopressin-mediated recovery of blood pressure following acute hypotension. The possible involvement of baro- or chemoreceptor afferents is discussed. PMID:6704593