Combined Arginine Vasopressin Research Articles

Effect of maternal periconceptional undernutrition in sheep on cortisol regulation in offspring from mid-late gestation, through to adulthood.

Maternal periconceptional undernutrition (PCUN) alters fetal hypothalamic-pituitary-adrenal axis (HPAA) function and placental glucocorticoid metabolism in sheep. The effects of PCUN on HPAA function in adult life are not known. We investigated the effects of PCUN on fetal adrenal development across gestation and on cortisol regulation in adult offspring. Ewes were undernourished from 61 days before to 30 days after conception ('PCUN') or fed ad libitum ('N'). mRNA expression in the fetal adrenal gland of ACTH receptor (ACTHR), steroidogenic acute regulatory protein (STAR), cytochrome P450 17A1 (CYP17A1), 11beta-hydroxysteroid-dehydrogenase type 2 (11βHSD2), insulin-like growth factor-2 (IGF2), and in the fetal hippocampus of 11βHSD1, 11βHSD2, mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) was determined at 50 (adrenal only), 85, 120 and 131 days of gestation (term=148 days). In adult offspring (≥ 3 years, N; 10 female, 5 male, PCUN; 10 female, 10 male) a combined arginine vasopressin (AVP, 0.1 μg/kg) and corticotropin-releasing hormone (CRH, 0.5 μg/kg) challenge and a metyrapone (40 mg/kg) challenge were undertaken. mRNA expression of ACTHR, STAR and CYP17A1 were determined in adult adrenals. Fetal adrenal STAR, CYP17A1 and IGF2 mRNA expression were not different between groups in early gestation but were higher in PCUN than N at 131 days' gestation (all p<0.01). PCUN reduced fetal hippocampal MR and GR mRNA expression by 50% at 85 day, but not in later gestation. Adult offspring plasma cortisol responses to AVP+CRH or metyrapone were not different between groups. Plasma ACTH response to AVP+CRH was lower in PCUN males but ACTH response to metyrapone was not different between groups. Adult adrenal ACTHR, STAR, and CYP17A1 mRNA expression were not affected by PCUN. We conclude that the effects of PCUN on fetal HPAA function that became apparent in late gestation, are not reflected in adrenal cortisol secretion in mid-adulthood.

Arginine vasopressin modulates electrical activity and calcium homeostasis in pulmonary vein cardiomyocytes

BackgroundAtrial fibrillation (AF) frequently coexists with congestive heart failure (HF) and arginine vasopressin (AVP) V1 receptor antagonists are used to treat hyponatremia in HF. However, the role of AVP in HF-induced AF still remains unclear. Pulmonary veins (PVs) are central in the genesis of AF. The purpose of this study was to determine if AVP is directly involved in the regulation of PV electrophysiological properties and calcium (Ca2+) homeostasis as well as the identification of the underlying mechanisms.MethodsPatch clamp, confocal microscopy with Fluo-3 fluorescence, and Western blot analyses were used to evaluate the electrophysiological characteristics, Ca2+ homeostasis, and Ca2+ regulatory proteins in isolated rabbit single PV cardiomyocytes incubated with and without AVP (1 μM), OPC 21268 (0.1 μM, AVP V1 antagonist), or OPC 41061 (10 nM, AVP V2 antagonist) for 4–6 h.ResultsAVP (0.1 and 1 μM)-treated PV cardiomyocytes had a faster beating rate (108 to 152%) than the control cells. AVP (1 μM) treated PV cardiomyocytes had higher late sodium (Na+) and Na+/Ca2+ exchanger (NCX) currents than control PV cardiomyocytes. AVP (1 μM) treated PV cardiomyocytes had smaller Ca2+i transients, and sarcoplasmic reticulum (SR) Ca2+ content as well as higher Ca2+ leak. However, combined AVP (1 μM) and OPC 21268 (0.1 μM) treated PV cardiomyocytes had a slower PV beating rate, larger Ca2+i transients and SR Ca2+ content, smaller late Na+ and NCX currents than AVP (1 μM)-treated PV cardiomyocytes. Western blot experiments showed that AVP (1 μM) treated PV cardiomyocytes had higher expression of NCX and p-CaMKII, and a higher ratio of p-CaMKII/CaMKII.ConclusionsAVP increases PV arrhythmogenesis with dysregulated Ca2+ homeostasis through vasopressin V1 signaling.

Vasopressin receptors in islets enhance glucose tolerance, pancreatic beta-cell secretory function, proliferation and survival

Arginine vasopressin (AVP), a peptide secreted from the posterior pituitary, is chiefly regarded as a hormone involved in the regulation of body fluid balance and osmolality. However, recent evidence has revealed that posterior pituitary hormones can exert important actions on endocrine pancreatic function. In the present study, the presence of AVP receptors, namely Avpr1a (V1a), Avpr1b (V1b) and Avpr2 (V2) was demonstrated in murine islets as well as rodent BRIN BD11 and human 1.1B4 beta-cells. Further to this, AVP was shown to induce significant concentration-dependent (10−12 – 10−6 M) increases of insulin release from both rodent and human beta-cells, as well as mouse islets. Insulinotropic actions of AVP were completely annulled by specific V1a or V1b receptor antagonists, and partially abolished by an oxytocin receptor antagonist. In addition, beta-cell insulin secretory actions of AVP were augmented by both IBMX (200 μM) and KCl (30 mM) and linked to significantly increased cAMP production and [Ca2+]i. AVP substantially increased proliferation of rodent and human beta-cells. Moreover, AVP fully protected against cytokine-induced beta-cell apoptosis. AVP had no effect on glucagon secretion. Immunohistochemical examination of beta- and alpha-cells revealed co-expression of AVP with glucagon, and particularly insulin. Finally, administration of AVP in combination with glucose to mice significantly reduced blood glucose, which was associated with increased plasma insulin. These data indicate that AVP possesses novel and potentially important effects on pancreatic endocrine function. Understanding disturbances in islet AVP receptor signalling could reveal insight into the beta-cell defects associated with diabetes.

Combined Evaluation of the Plasma Arginine Vasopressin and Noradrenaline Levels May be a Useful Predictor of the Prognosis of Patients with Acute Decompensated Heart Failure.

Few data exist regarding the association of plasma arginine vasopressin (AVP) and noradrenaline (NA) levels with subsequent cardiac events in acute decompensated heart failure (ADHF) patients. We measured plasma AVP and NA levels in ADHF patients on admission. In the follow-up (median: 487 days) of 291 patients, 41 cardiac events (cardiac death or re-hospitalization due to HF) were documented. The plasma AVP (26.4 versus 15.5 pg/mL, P = 0.014) and plasma NA (2347 versus 1524 pg/mL, P = 0.007) levels in the cardiac events group were significantly higher than those in the non-cardiac events group. The multivariable hazard ratios (HR) (95% confidence intervals [CI]) in the first tertile (1T) versus the third tertile (3T) of plasma AVP and NA levels were 2.97 (1.06-8.32) and 3.34 (1.21-9.26) for cardiac events, respectively. Group High (3T of combined AVP and NA) had a significantly higher incidence of cardiac events than Group Low (1T of combined groups) (HR: 3.50, 95% CI: 1.17-10.42, P = 0.017). Similarly, the relative risk ratio of cardiac events according to this stratification was more than that of plasma AVP or NA level alone (3.51, 2.65, and 2.95). Higher levels of plasma AVP and NA measured on admission may be associated with the incidence of cardiac events. Combined evaluation of these two parameters may be useful for assessing the prognosis of ADHF survivors.

Small Doses of Arginine Vasopressin in Combination With Norepinephrine “Buy” Time for Definitive Treatment for Uncontrolled Hemorrhagic Shock in Rats

Implementation of fluid resuscitation and blood transfusion are greatly limited in prehospital or evacuation settings after severe trauma or war wounds. With uncontrolled hemorrhagic shock rats, we investigated if arginine vasopressin (AVP) in combination with norepinephrine (NE) is independent (or slightly dependent) of fluid resuscitation and can "buy" time for the subsequently definitive treatment of traumatic hemorrhagic shock in the present study. The results showed that AVP (0.4 U/kg) alone or with NE (3 μg/kg) with one-eighth and one-fourth volumes of total blood volume of lactated Ringer's infusion significantly increased and maintained the mean arterial pressure. Among all groups, 0.4 U/kg of AVP + NE (3 μg/kg) with one-eighth volume of lactated Ringer's infusion had the best effect: it significantly increased and maintained hemodynamics and prolonged the survival time. This early treatment strategy significantly improved the effects of subsequently definitive treatments (after bleeding controlled): it increased the subsequent survival, improved the hemodynamic parameters, improved the cardiac function, and increased the tissue blood flow and oxygen delivery. These results suggested that early application of small doses of AVP (0.4 U/kg) + NE before bleeding control can "buy" time for the definitive treatment of uncontrolled hemorrhagic shock, which may be an effective measure for the early treatment of traumatic hemorrhagic shock.

Arginine vasopressin in combination with norepinephrine for uncontrolled hemorrhagic shock in rats

Objective To investigate the effects of arginine vasopressin (AVP) combined with norepinephrine (NE) in treatment of uncontrolled hemorrhagic shock (UHS) in rats.Methods UHS models were produced in rats and divided into three groups according to the random number table,which were resuscitated with LR equivalent to 1/2 (17.5 ml/kg) of shed blood,LR equivalent to 1/4 (8.75 mL/kg) of shed blood and without LR respectively.Each group was subdivided into six groups:AVP1 (0.04 U/kg) group,AVP2 (0.4 U/kg) group,NE (3 μg/kg) group,AVP1 + NE group,AVP2 + NE group and LR control group,with 10 rats per group.Effects of single AVP or NE infusion or combined infusion respectively grouped with different doses of LR on survival time and hemodynamics of UHS rats were observed.Results Compared with AVP,NE and AVP + NE groups without LR or with LR equivalent to 1/2 of shed blood respectively,AVP2 + NE group with LR equivalent to 1/4 of shed blood provided better main artery pressure (MAP),prolonged survival time and enhanced 4-hour survival rate in treatment of UHS rats.Moreover,survival time and 24-hour survival rate were increased significantly and hemodynamic parameters like MAP,left intraventricular systolic pressure (LVSP) and maximal change rate of left intraventricular pressure (± dp/dt max) were improved after hemostasis.Conclusion AVP (0.04 U/kg) + NE (3 μg/kg) infusion with LR equivalent to 1/4 of shed blood prior to hematosis can win the time for definitive treatment and improve the treatment outcome. Key words: Shock, hemorrhagic ; Resuscitation ; Arginine vasopressin; Norepinephrine

A Small Dose of Arginine Vasopressin in Combination with Norepinephrine is a Good Early Treatment for Uncontrolled Hemorrhagic Shock After Hemostasis

A Small Dose of Arginine Vasopressin in Combination with Norepinephrine is a Good Early Treatment for Uncontrolled Hemorrhagic Shock After Hemostasis

Combined arginine vasopressin and levosimendan: A promising therapy for septic shock

Combined arginine vasopressin and levosimendan: A promising therapy for septic shock

Combined arginine vasopressin and levosimendan: A promising therapy for septic shock

Combined arginine vasopressin and levosimendan: A promising therapy for septic shock

Effects of combined arginine vasopressin and levosimendan on organ function in ovine septic shock*

To compare the effects of a first-line therapy of combined arginine vasopressin, levosimendan, and norepinephrine with arginine vasopressin + norepinephrine or norepinephrine alone in ovine septic shock. Prospective, randomized, controlled laboratory experiment. University animal research facility. Twenty-one chronically instrumented sheep. After the onset of fecal peritonitis-induced septic shock (mean arterial pressure <60 mm Hg), sheep were randomly assigned to receive first-line treatment with arginine vasopressin (0.5 mU·kg·min), combined arginine vasopressin (0.5 mU·kg·min) and levosimendan (0.2 μg·kg·min), or normal saline (each n = 7) for 24 hrs. In all groups, open-label norepinephrine was additionally titrated to maintain mean arterial pressure at 70 ± 5 mm Hg, if necessary. Arginine vasopressin + levosimendan + norepinephrine improved left ventricular contractility (higher stroke work indices at similar or lower preload) and pulmonary function (Pao2/Fio2 ratio) when compared with the other groups (p < .05 each). Both nonadrenergic treatment strategies reduced open-label norepinephrine doses. However, only arginine vasopressin + levosimendan + norepinephrine limited fluid requirements and positive fluid balance vs. both other groups (p < .05 each). In addition, arginine vasopressin + levosimendan + norepinephrine increased mixed venous oxygen saturation as compared with arginine vasopressin + norepinephrine. Histologic tissue analyses and pulmonary hemeoxygenase-1 activity revealed no differences among groups. Notably, arginine vasopressin + levosimendan + norepinephrine therapy reduced pulmonary 3-nitrotyrosine levels (p = .028 vs. control animals) as well as urinary protein/creatinine ratio (p < .05 each) and slightly prolonged survival when compared with both other groups (4 hrs vs. arginine vasopressin + norepinephrine: p = .013; 7 hrs vs. norepinephrine alone: p = .003). First-line cardiovascular support with combined arginine vasopressin and levosimendan supplemented with norepinephrine improves myocardial, vascular, pulmonary, and renal function as compared with arginine vasopressin + norepinephrine in septic shock.

A Small Dose of Arginine Vasopressin in Combination with Norepinephrine is a Good Early Treatment for Uncontrolled Hemorrhagic Shock After Hemostasis

Limited fluid resuscitation has been proven to have a good effect on uncontrolled hemorrhagic shock. Arginine vasopressin (AVP) and norepinephrine (NE) were used to treat vasodilatory or septic shock, and were used to reduce the fluid requirement for uncontrolled hemorrhagic shock. Based on their pressor and hemodynamic stabilization effects, it is speculated that AVP and NE may be a good treatment for uncontrolled hemorrhagic shock at early stage after hemostasis. Experiments were conducted in two parts. Each part had control, lactated Ringer's solution (LR), whole blood, NE, arginine vasopressin (AVP), NE+AVP, and AVP+NE+whole blood. Rats (n = 8-10/group), respectively, received LR, whole blood, NE (1 μg/kg) and AVP (0.1 U/kg) infusion alone, or in combination after 60 min hypotensive resuscitation (50 mmHg). The volume in each group was two times the volume of shed blood. Whole blood improved all observed parameters, particularly the tissue blood flow and mitochondrial function of liver and kidney, and the 12-h survival (50%). NE only increased the hemodynamics. 0.1 U/kg of AVP had a similar effect with whole blood on hemodynamics, tissue blood flow, mitochondrial function, and the 12-h survival. AVP+NE significantly improved all observed variables (P < 0.05 or 0.01), the 12-h survival was 70%. Whole blood further potentiated the beneficial effect of AVP+NE, and 12-h animal survival rate in this group was 80%. AVP+NE is a good treatment for uncontrolled hemorrhagic shock at the early stage after hemostasis if blood is unavailable. Whole blood transfusion can potentiate this beneficial effect of AVP+NE.

Arginine vasopressin as a rescue vasopressor agent in the operating room

This review gives an overview of the current knowledge and research on the use of arginine vasopressin in cardiac arrest and severe shock states. Animal models have revealed the effectiveness of arginine vasopressin in increasing vital organ perfusion during cardiopulmonary resuscitation. A multicentre trial compared arginine vasopressin and epinephrine in out-of-hospital cardiac arrest, and documented a significant improvement in hospital discharge rates in arginine vasopressin-treated (up to 2 x 40 IU) patients with asystole, and a significant benefit of the combined administration of arginine vasopressin and epinephrine on hospital discharge, irrespective of the underlying electrocardiographic rhythm. The stabilization of advanced shock states unresponsive to conventional therapy can be achieved by supplementary arginine vasopressin (1-4 IU/h). A randomized, controlled trial found that the combined infusion of arginine vasopressin and norepinephrine was superior to norepinephrine alone in reversing advanced vasodilatory shock. Furthermore, the successful employment of arginine vasopressin in uncontrolled haemorrhagic shock and other shock states, such as anaphylaxis, hypotension during spinal/epidural anaesthesia, postcardiotomy shock, acute brain injury, brain-dead organ donors, perioperative hypotension in patients chronically treated with angiotensin-converting enzyme inhibitors, shock after pheochromocytoma surgery, and carcinoid crisis have been reported. Whereas arginine vasopressin in combination with epinephrine can significantly increase hospital discharge in cardiac arrest, arginine vasopressin combined with catecholamines improved haemodynamics in vasodilatory and haemorrhagic shock, but effects on outcome remain unknown. Nonetheless, in the perioperative setting, arginine vasopressin may already be considered as a potent adjunct vasopressor agent in advanced shock states unresponsive to conventional therapy.

Serotonin regulation of aggressive behavior in male golden hamsters (Mesocricetus auratus).

These studies examined the neurochemistry and neuroanatomy of the serotonin (5-HT) system innervating the anterior hypothalamus (AH) and the interaction of 5-HT receptor agonists with arginine vasopressin (AVP) in the regulation of offensive aggression in golden hamsters. Because specific 5-HT 1A , 5-HT 1B , and AVP V 1A binding sites were observed within the AH by in vitro autoradiography, the hamsters were tested for offensive aggression after microinjections of AVP in combination with either the 5-HT 1A agonist 8-hydroxy-2-(di-n-propylamino) tetraline (DPAT) or the 5-HT 1B agonist CGS-12066A (CGS) directly within the AH. Though treatment with DPAT resulted in a dose-dependent inhibition of AVP-facilitated offensive aggression, CGS was ineffective. In addition, a retrograde tracer was injected within the AH to localize the distribution of 5-HT neurons projecting to the area. Retrogradely labeled 5-HT neurons were found within the dorsal, median, and caudal linear raphe nuclei and are suspected to inhibit AVP-facilitated offensive aggression by an activation of 5-HT 1A receptors in the AH.

Serotonin regulation of aggressive behavior in male golden hamsters (Mesocricetus auratus).

These studies examined the neurochemistry and neuroanatomy of the serotonin (5-HT) system innervating the anterior hypothalamus (AH) and the interaction of 5-HT receptor agonists with arginine vasopressin (AVP) in the regulation of offensive aggression in golden hamsters. Because specific 5-HT1A, 5-HT1B, and AVP V1A binding sites were observed within the AH by in vitro autoradiography, the hamsters were tested for offensive aggression after microinjections of AVP in combination with either the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetraline (DPAT) or the 5-HT1B agonist CGS-12066A (CGS) directly within the AH. Though treatment with DPAT resulted in a dose-dependent inhibition of AVP-facilitated offensive aggression, CGS was ineffective. In addition, a retrograde tracer was injected within the AH to localize the distribution of 5-HT neurons projecting to the area. Retrogradely labeled 5-HT neurons were found within the dorsal, median, and caudal linear raphe nuclei and are suspected to inhibit AVP-facilitated offensive aggression by an activation of 5-HT1A receptors in the AH.

Separate receptors mediate oxytocin and vasopressin stimulation of cAMP in rat inner medullary collecting duct cells.

The two neurohypophysial hormones arginine vasopressin (AVP) and oxytocin have actions in the inner medullary collecting duct (IMCD) where both peptides induce an increase in cAMP accumulation. The present study has employed a novel IMCD cell line to determine whether these two hormones induce cAMP accumulation via common or separate receptors, and to characterize the potential receptors responsible. Equal volumes of vehicle (150 mM NaCl) or hormone/antagonist solutions were added to aliquots of 10(4) IMCD cells in the presence of 10(-3) M 3-isobutylmethylxanthine (IBMX) and incubated at 37 degrees C for 4 min. cAMP levels were determined by radioimmunoassay and protein concentration by Bradford assay. Both AVP and oxytocin elicited dose-dependent increases in cAMP generation, though oxytocin was less potent than AVP (EC50 = 1.6 x 10(-8) M vs. 7.4 x 10(-10) M). AVP at 10(-8) M and oxytocin at 10(-8) M, concentrations sufficient to elicit near-maximal cAMP accumulation, resulted in cAMP levels of 73.4 +/- 1.7 and 69.0 +/- 3.3 pmol (mg protein)-1 (4 min)-1, respectively (n = 10), compared with the vehicle-treated basal value of 37.7 +/- 2.2 pmol (mg protein)-1 (4 min)-1 (P < 0.001, n = 10). Combined AVP (10(-8) M) and oxytocin 10(-6) M) resulted in cAMP accumulation of 63.8 +/- 3.1 pmol (mg protein)-1 (4 min)-1 (n = 10), which was not significantly different from the effect of oxytocin alone, but slightly less than that for AVP alone (P < 0.05). A submaximal concentration of AVP (10(-10) M) induced cAMP accumulation of 48.6 +/- 2.5 pmol (mg protein)-1 (4 min)-1 (P < 0.01 compared with basal level of 34.9 +/- 2.4 pmol (mg protein)-1 (4 min)-1, n = 10), which was blocked in the presence of a vasopressin V2 receptor antagonist (10(-7) M OPC-31260) but not by the oxytocin receptor antagonist (10(-6) M [Pen1,pMePhe2, Thr4,Orn8]oxytocin) (36.3 +/- 6.1 and 45.1 +/- 1.3 pmol (mg protein)-1 (4 min)-1 respectively, P < 0.05, n = 10). A submaximal concentration of oxytocin (10(-7) M) induced a cAMP accumulation of 45.8 +/- 1.8 pmol (mg protein)-1 (4 min)-1 (n = 10), which was reduced by addition of 10(-6) M oxytocin antagonist (36.3 +/- 2.1 pmol (mg protein)-1 (4 min)-1, P < 0.05, n = 10), whereas co-incubation with 10(-6) M of the V2 receptor antagonist had no effect (43.2 +/- 1.3 pmol (mg protein)-1 (4 min)-1, n = 10). These results indicate that AVP and oxytocin induce cAMP accumulation from a common ATP pool in IMCD cells, and that separate vasopressin V2 and oxytocin receptor systems are involved, perhaps coupled to a common adenylate cyclase system.

Exploration of the conformational space of oxytocin and arginine-vasopressin using the electrostatically driven Monte Carlo and molecular dynamics methods.

Conformational analysis of the neurohypophyseal hormones oxytocin (OT) and arginine-vasopressin (AVP) has been carried out using two different computational approaches and three force fields, namely by the Electrostatically Driven Monte Carlo (EDMC) method, with the Empirical Conformational Energy Program for Peptides (ECEPP/3) force field or with the ECEPP/3 force field plus a hydration-shell model, and by simulated-annealing molecular dynamics with the Consistent Valence Force Field (CVFF). The low-energy conformations obtained for both hormones were classified using the minimal-tree clustering algorithm and characterized according to the locations of beta-turns in the cyclic moieties. Calculations with the CVFF force field located conformations with a beta-turn at residues 3 and 4 as the lowest energy ones both for OT and for AVP. In the ECEPP/3 force field the lowest energy conformation of OT contained a beta-turn at residues 2 and 3, conformations with this location of the turn being higher in energy for AVP. The latter difference can be attributed to the difference in the size of the side chain in position 3 of the sequences: the bulkier phenylalanine residue of AVP in combination with the bulky Tyr2 residue hinders the formation of a turn at residues 2 and 3. Conformations of OT and AVP with a turn at residues 3,4 were in the best agreement with the x-ray structures of deaminooxytocin and pressinoic acid (the cyclic moiety of vasopressin), respectively, and with the nmr-derived distance constraints. Generally, the low-energy conformations obtained with the hydration-shell model were in a better agreement with the experimental data than the conformations calculated in vacuo. It was found, however, that the obtained low-energy conformations do not satisfy all of the nmr-derived distance constraints and the nuclear Overhauser effect pattern observed in nmr studies can be fully explained only by assuming a dynamic equilibrium between conformations with beta-turns at residues 2,3, 3,4, and 4,5. The low-energy structures of OT with a beta-turn at residues 2,3 have the disulfide ring conformations close to the model proposed recently for a potent bicyclic antagonist of OT [M. D. Shenderovich et al. (1994) Polish Journal of Chemistry, Vol. 25, pp. 921-927], although the native hormone differs from the bicyclic analogue by the conformation of the C-terminal tripeptide. This finding confirms the hypothesis of different receptor-bound conformations of agonists and antagonists of OT.

Secretion of Adrenomedullin by Renal Tubular Cell Lines

Adrenomedullin (AM) is a novel and potent vasodilator peptide originally isolated from human pheochromocytoma. The present study was designed to study whether AM is produced by and secreted from renal tubular cell lines and whether arginine vasopressin (AVP) affects AM secretion from these cell lines. Three renal tubular cell lines derived from different species (LLCPK1, MDCK, and MDBK) secrete AM-like immunoreactivity (AM-LI) into culture medium, the immunological and physicochemical properties of which are similar to that of synthetic human AM as evaluated by reverse-phase high-performance liquid chromatography. Among the three cell lines, AVP in combination with a phosphodiesterase inhibitor (isobutylmethylxanthine) stimulated AM-LI secretion most potently from MDCK cells in a time- and dose-dependent manner. In MDCK cells, a V₂ receptor agonist (deamino-D-Arg⁸-vasopressin) dose-dependently stimulated AM-LI secretion in the same manner as AVP. Furthermore, the AVP-induced AM-LI secretion was blocked by a V₂ receptor antagonist (OPC31260), but not by a V₁ receptor antagonist (OPC21268). These data indicate that AM is secreted from renal tubular cell lines and that AVP stimulates AM secretion via V₂ receptors, suggesting its autocrine/paracrine role in renal function.

Arginine Vasopressin Increases Renal Sodium Excretion in the Anesthetized Rat Through V1 Receptors

We have previously suggested that the increase in renal Na+ excretion in response to physiological doses of arginine vasopressin (AVP) is not directly linked to the V2-mediated antidiuretic effect. In the present study we investigated the possible involvement of AVP V1 receptors in this natriuresis using a specific AVP V1 antagonist [I-(β-mercapto-β,β-cyclopentamethylenepropionic acid), 2-O-methyltyrosine arginine vasopressin, d(CH2)5(Me)2]AVP, infused at a rate of 15 ng·min-1. Male anesthetized Sprague-Dawley rats were placed on a continuous jugular infusion of 0.077 M NaCl at 150 μL·min-1. After a 3-h equilibration period, samples were collected at 20-min intervals for 4 h for the determination of urine flow, and Na+ and K+ excretion rates. In those animals in which the effects of AVP were studied, a 1-h control period was allowed following which AVP was infused at 0.02–0.08 pmol·min-1 for 1 h 20 min in separate groups of animals and then returned to the infusate alone for the last part of the experiment. In other groups the AVP V1 antagonist d(CH2)5[Tyr(Me)2]AVP (15 ng · min-1) alone or in combination with AVP (at various dose rates) was also administered for 1 h 20 min. All dose rates of AVP produced an antidiuresis which was associated significantly to increased Na+ excretion rate. However, AVP administration at the median dose rate (0.04 pmol · min-1) significantly (p < 0.01) decreased the amount of urine voided by comparison with control animals (6.34 ± 1.05 mL vs. 11.892 ± 0.03 mL, n = 7) although the urinary Na+ was elevated (967 ± 18 μmol vs. 742 ± 81 μmol, n = 7). This AVP-induced increase in urinary Na+ loss was abolished in animals receiving combined AVP (0.04 pmol · min-1) and AVP V1 antagonist (674 ± 47 μmol, n = 7) although the antidiuretic effect persisted. Urine flow and Na+ excretion rates remained unchanged in groups of animals administered AVP V1 antagonist alone. In all groups, the K+ excretion rates did not significantly differ. It is concluded that the V1 receptor mediates the natriuretic effect of AVP.

Reduced glucocorticoid response to corticotropin secretagogues in the aged Sprague-Dawley rat.

Aging, as well as some frequently associated pathological conditions (depression, dementia, Alzheimer's disease, etc.), has been shown to have a profound impact on the normal functioning of the hippocampus-hypothalamo-pituitary-adrenocortical axis system. The hypothalamo-pituitary-adrenocortical axis in the aged rat is characterized by an increase in the basal level of circulating corticosterone, an impaired ability to recover from the adrenocortical stress response, and a reduced sensitivity to the dexamethasone suppression test. All these alterations may arise from a reduced hippocampal negative feedback control of the axis, as suggested by the age-dependent loss of hippocampal adrenocorticoid receptors. Among the hypothalamic corticotropin secretagogues, corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP) are considered the main physiological mediators of hypothalamic control of ACTH release. Thus, we have investigated the dynamic and the temporal course of the adrenocortical response to CRH and AVP in the aged rat. Freely moving jugular-catheterized male Sprague-Dawley rats (3- and 24-month-old) were injected with CRH (0.5, 0.05 and 0.01 microgram/kg i.v.), or AVP (1.0, 0.1 and 0.05 microgram/kg i.v.), or CRH and AVP in combination. In addition, adrenocortical sensitivity to corticotropin has been studied by injecting ACTH (10 ng/kg i.v.). Our study has (1) indicated that the response to ACTH secretagogues is dampened with aging, and (2) shown in the aged rat a slower recovery. Moreover, the results had confirmed the age-dependent increase in the basal level of corticosterone in the rat, and shown no age-related differences in the glucocorticoid response to ACTH.

Effects of corticotrophin-releasing factor and arginine-vasopressin on proopiomelanocortin (POMC) mRNA levels, release and storage of adrenocorticotrophin from mouse anterior pituitary cells

1. 1. The present studies were undertaken to determine the effects of arginine vasopressin (AVP), corticotrophin-releasing factor (CRF) and AVP in combination with CRF on proopiomelanocortin (POMC) gene expression, and in the release and biosythesis of POMC products (i.e. ACTH). 2. 2. After a 3hr treatment, AVP (10 −7M), CRF (10 −7M) and AVP (10 −7M) in combination with CRF (10 −7 M) stimulated ACTH release by 291 ± 19.2%, 377.4 ± 25.6% and 462.1 ± 38.4% ( P < 0.01), respectively, with respect to basal secretion; while ACTH content diminished by 84.0 ± 4.6%, 81.3 ± 2.1% and 71.0 ± 1.5% ( P < 0.01), respectively, with respect to basal. Total POMC mRNA levels were not affected after a 3 hr treatment. 3. 3. When cells were treated with a wide range of AVP concentrations (10 −11−10 −7 M) to which we added different concentrations of CRF, modulation of AVP-induced ACTH release was most effective at CRF concentrations of < 10 −10M. 4. 4. Prolonged (3–6 hr) exposure to as low as 10 −10M CRF or 10 −9M AVP resulted in homologous desensitization of ACTH secretion. However, these pretreated cells were able to respond to a further challenge of CRF and AVP. This paper provides new information on the dose ranges over which desensitization and cross-sensitization between CRF and AVP secretory effects take place in mouse anterior pituitary cells.