Vasopressin Response Research Articles

The Science Behind Hyponatremia and Its Clinical Manifestations

Body sodium, water, and extracellular fluid volume are tightly regulated by neural, humoral, and renal mechanisms to maintain osmolality in extracellular fluid and to maintain normal intravascular volume. This is accomplished by controlling sodium content in extracellular fluid. In the normal physiologic state, total body water (which accounts for ~60% of body weight) is distributed among three compartments: intracellular, interstitial, and intravascular spaces. About two thirds of total body water is intracellular fluid. Potassium is the major intracellular cation, and sodium is the major extracellular cation. Body water content and plasma osmolality are tightly regulated by the action of arginine vasopressin on renal tubules. A wide variety of disease states are associated with a nonosmotic response of arginine vasopressin, also known as the antidiuretic hormone. Determination of the serum sodium concentration is the most direct measure of hyponatremia. The vasopressin V(2)-receptor antagonists are effective aquaretic agents and correct hyponatremia in several hyponatremic disorders.

Vasopressin Pituitary Stores Acutely Released in Vasodilatory and Hypovolemic Shock Are Not Immediately Restored With Prolonged Hypotension

Insufficient release of vasopressin (VP) in maintaining elevated circulating VP levels in response to shock is not well understood. Thus, we compared VP responses in anesthetized 8 kg pig models of vasodilatory or hypovolemic shock in the first 4 hours after endotoxin (ETX n=8), hemorrhage (HEMO n=11), or partial cardiopulmonary bypass (ECMO n=9), with that of controls (CON n=9). Mean arterial pressures (MAP) were 88±6, 54±3, 48±8, and 82±4 mmHg, respectively for CON, ETX, HEMO, and ECMO. With ETX, plasma VP levels (pVP) increased with decreased pulmonary arterial and wedge pressures, indicating an intact baroreceptor unloading mechanism for VP stimulation. In hemorrhage, pVP negatively correlated (r=0.97, p<0.01) with decreased MAP indicating VP release in response to hypovolemia. During ECMO, pVP directly correlated (r=0.72, p<0.05) with MAP, unmasking VP influence on maintaining MAP, not normally seen under control conditions. Overall, pVP increased with increased hypothalamic VP mRNA expression. However, pituitary VP content after 4 hours of shock was significantly less (p<0.01) in ETX (257±43 mU) and HEMO (751±92 mU) compared to CON (2139±350 mU) or ECMO (1357±314 mU). Results suggest that while the body responds within the first minutes of a sudden drop in blood pressure with immediate release of VP stores, these stores become depleted, and sustained synthesis does not keep up with prolonged hypotension.

Quantitative Protein and mRNA Profiling Shows Selective Post-Transcriptional Control of Protein Expression by Vasopressin in Kidney Cells

Previous studies in yeast have supported the view that post-transcriptional regulation of protein abundances may be more important than previously believed. Here we ask the question: "In a physiological regulatory process (the response of mammalian kidney cells to the hormone vasopressin), what fraction of the expressed proteome undergoes a change in abundance and what fraction of the regulated proteins have corresponding changes in mRNA levels?" In humans and other mammals, vasopressin fulfills a vital homeostatic role (viz. regulation of renal water excretion) by regulating the water channel aquaporin-2 in collecting duct cells. To address the question posed, we utilized large-scale quantitative protein mass spectrometry (LC-MS/MS) employing stable isotopic labeling in cultured mpkCCD cells ('SILAC') coupled with transcriptomic profiling using oligonucleotide expression arrays (Affymetrix). Preliminary studies analyzing two nominally identical control samples by SILAC LC-MS/MS yielded a relative S.D. of 13% (for ratios), establishing the precision of the SILAC approach in our hands. We quantified nearly 3000 proteins with nontargeted SILAC LC-MS/MS, comparing vasopressin- versus vehicle-treated samples. Of these proteins 786 of them were quantified in each of 3 experiments, allowing statistical analysis and 188 of these showed significant vasopressin-induced changes in abundance, including aquaporin-2 (20-fold increase). Among the proteins with statistically significant abundance changes, a large fraction (at least one-third) was found to lack changes in the corresponding mRNA species (despite sufficient statistical power), indicating that post-transcriptional regulation of protein abundance plays an important role in the vasopressin response. Bioinformatic analysis of the regulated proteins (versus all transcripts) shows enrichment of glutathione S-transferase isoforms as well as proteins involved in organization of the actin cytoskeleton. The latter suggests that long-term regulatory processes may contribute to actomyosin-dependent trafficking of the water channel aquaporin-2. The results provide impetus for increased focus on translational regulation and regulation of protein degradation in physiological control in mammalian epithelial cells.

Clinical study on desmopressin acetate therapy in patients with adipsic hypernatremia: Five cases report

Objective Adipsic hypernatremia is very rare in clinical practice and only a few cases have been reported so far. Since the pathogenesis of adipsic hypernatremia is unclear, therapeutic method is very limited and uncertain. We previously found the existence of partial central diabetes insipidus in the patient with adipsic hypernatremia according to a series of clinical studies. In this clinical study, we observed the response of vasopressin in the treatment of adipsic hypernatremia as a routinely used agent in treating central diabetes insipidus.Methods Five patients with chronic sustained hypernatremia and hypodipsia were diagnosed as adipsic hypernatremia according to the criteria by Halter. After testing plasma electrolytes, urinary osmolality, plasma osmolality, and free water clearance (CH2O);with evaluating thirsty grade and anterior pituitary function, patients were forced to drink water 2 000-2 500 ml each day combined with prednisone and/or levethyroxin supplementation therapy if hypopituitarsm was revealed. One week later, since the hypernatremia was unrelieved, desmopressin acetate (0.05-0.2 mg/d)was administered to those 5 patients. About 5-7 days later, plasma electrolytes, urinary and plasma osmolality, and free water clearance ( CH2O ) were reevaluated. Osmolality was detected by the method of freezing point depression and thirst grade by the method of visual analogue scales. Results The plasma sodium was 160-190 mmol/L and plasma osmolality was 330-370 mmoL/L without thirsty perception during the hospitalization. Four of the five patients were revealed to be suffering from hypopituitarism, but the hypernatremia could not be corrected by intentional water intake combined with prednisone treatment. After administering vasopressin 0.05-0.2 mg/d to these patients, that hypernatremia was relieved, and hyperosmolality and hypodypsia were improved effectively. During this period of time, no side effects were detected in these patients. Conclusion We testified the existence of central partial diabetes insipidus in the patients with adipsic hypernatremia. Desmopressin acetate in the treatment of adipsic hypernatremia is proved to be effective, simple, and safe. Key words: Adipsic hypernatremia; Central diabetes insipidus; Therapy; Vasopressin

Angiotensin II-stimulated secretion of arginine vasopressin is inhibited by atrial natriuretic peptide in humans

We investigated the effect of the intravenous infusion of atrial natriuretic peptide (ANP) on the response of plasma arginine vasopressin (AVP) levels to intravenous infusion of angiotensin II (ANG II) in healthy individuals. Intravenous infusion of ANP (10 ng·kg(-1)·min(-1)) slightly but significantly decreased plasma AVP levels, while intravenous infusion of ANG II (10 ng·kg(-1)·min(-1)) resulted in slightly increased plasma AVP levels. ANG II infused significant elevations in arterial blood pressure and central venous pressure (CVP). Because the elevation in blood pressure could have potentially inhibited AVP secretion via baroreceptor reflexes, the effect of ANG II on blood pressure was attenuated by the simultaneous infusion of nitroprusside. ANG II alone produced a remarkable increase in plasma AVP levels when infused with nitroprusside, whereas the simultaneous ANP intravenous infusion (10 ng·kg(-1)·min(-1)) abolished the increase in plasma AVP levels induced by ANG II when blood pressure elevation was attenuated by nitroprusside. Thus, ANG II increased AVP secretion and ANP inhibited not only basal AVP secretion but also ANG II-stimulated AVP secretion in humans. These findings support the hypothesis that circulating ANP modulates AVP secretion, in part, by antagonizing the action of circulating ANG II.

Xenon/Remifentanil Anesthesia Protects Against Adverse Effects of Losartan on Hemodynamic Challenges Induced by Anesthesia and Acute Blood Loss

The authors aimed to test the hypothesis that xenon anesthesia limits adverse hypotensive effects of losartan during acute hemorrhage. In six conscious unsedated Beagle dogs, the systemic and pulmonary circulation were monitored invasively, and two subsequent 60-min hypotensive challenges were performed by (a) induction (propofol) and maintenance of anesthesia with isoflurane/remifentanil or xenon/remifentanil and by (b) subsequent hemorrhage (20 mL kg⁻¹ within 5 min) from a central vein. The same amount of blood was retransfused 1 h after hemorrhage. Experiments were performed with or without acute angiotensin II receptor subtype 1 blockade by i.v. losartan (100 μg·kg⁻¹·min⁻¹) starting 45 min before induction of anesthesia. Four experiments were performed in each individual dog. Xenon/remifentanil anesthesia provided higher baseline mean arterial blood pressure (85 ± 6 mmHg) than isoflurane/remifentanil anesthesia (67 ± 3 mmHg). In losartan-treated animals, isoflurane/remifentanil caused significant hypotension (42 ± 4 mmHg for isoflurane/remifentanil vs. 71 ± 6 mmHg for xenon/remifentanil). Independent of losartan, hemorrhage did not induce any further reduction of mean arterial blood pressure or cardiac output in either group. Spontaneous hemodynamic recovery was observed in all groups before retransfusion was started. Losartan did not alter the adrenaline, noradrenaline, and vasopressin response to acute hemorrhage. Losartan potentiates hypotension induced by isoflurane/remifentanil anesthesia but does not affect the hemodynamic stability during xenon/remifentanil anesthesia. Losartan does not deteriorate the hemodynamic adaptation to hemorrhage of 20 mL kg⁻¹ during xenon/remifentanil and isoflurane/remifentanil anesthesia. Therefore, xenon/remifentanil anesthesia protects against circulatory side effects of losartan pretreatment and thus may afford safer therapeutic use of losartan during acute hemorrhage.

Does prearrest adrenergic integrity affect pressor response? A comparison of epinephrine and vasopressin in a spontaneous ventricular fibrillation swine model

Objectives Coronary perfusion pressure (CPP) during resuscitation from cardiac arrest has been shown to correlate with return of spontaneous circulation. Adrenergic blockade of beta-1 and alpha-1 receptors is common in the long-term management of ischemic heart disease and congestive heart failure. We sought to compare the CPP response to vasopressin vs. epinephrine in a swine model of cardiac arrest following pre-arrest adrenergic blockade. Methods Eight anesthetized and instrumented swine were administered 0.1 mg epinephrine and arterial pressure and heart rate response were measured. An infusion of labetalol was then initiated and animals periodically challenged with epinephrine until adrenergic blockade was confirmed. The left anterior descending coronary artery was occluded to produce ventricular fibrillation (VF). After 7 min of untreated VF, mechanical chest compressions were initiated. After 1 min of compressions, 1 mg epinephrine was given while CPP was recorded. When CPP values had returned to pre-epinephrine levels, 40 U of bolus vasopressin was given. Differences in CPP (post-vasopressor–pre-vasopressor) were compared within animals for the epinephrine and vasopressin response and with eight, non-adrenergically blocked, historical controls using Bayesian statistics with a non-informative prior. Results The CPP response following epinephrine was 15.1 mmHg lower in adrenergically blocked animals compared to non-adrenergically blocked animals (95% Highest Posterior Density [HPD] 2.9–27.2 mmHg lower). CPP went up 18.4 mmHg more following vasopressin when compared to epinephrine (95% HPD 8.2–29.1 mmHg). The posterior probability of a higher CPP response from vasopressin (vs. epinephrine) in these animals was 0.999. Conclusions Pre-arrest adrenergic blockade blunts the CPP response to epinephrine. Superior augmentation of CPP is attained with vasopressin under these conditions.

Age related decreases in thermoregulation and cardiovascular function in horses

Older horses have an increased risk of hyperthermia due to impaired cardiovascular function. While many studies have investigated thermoregulation in horses during exercise, none have investigated the effects of ageing. To test the hypothesis that there is a difference in thermoregulation during exercise and plasma volume (PV) in young and old horses. Study 1: 6 young (Y, 7.7 ± 0.5 years) and 5 old (O, 26.0 ± 0.8 years) unfit Standardbred mares (507 ± 11 kg, mean ± s.e.) ran on a treadmill (6% grade, velocity calculated to generate a work rate of 1625 watts) until core temperature reached 40 °C. Core (CT), skin (ST), rectal temperature (RT) and heart rate (HR) were measured every min until 10 min post exertion. Packed cell volume (HCT), lactate (LA) and plasma protein (TP) were measured in blood samples collected before, at 40 °C and every 5 min until 10 min post exercise. Sweat loss was estimated using bodyweight. Study 2: Plasma volume was measured in 26 young (8.2 ± 0.7 years) and 8 old (26.6 ± 0.7 years) Standardbred mares (515 ± 12 kg) using Evans Blue dye. Pre-exercise blood (rBV) and red cell (rRCV) volumes were calculated using PV and HCT. Data analysis utilised repeated measures ANOVA and t tests and data are expressed as mean ± s.e. Old horses reached 40 °C faster (998 ± 113 vs. 1925 ± 259 s; P < 0.05) with a greater HR at 40 °C (184 ± 6 vs. 140 ± 5 beats/min; P < 0.05) and greater sweat losses (P < 0.05). Heart rate did not differ (P > 0.05) post exercise. Age did not alter (P > 0.05) CT, ST, RT, LA, HCT or TP. Plasma volume was greater in Y vs. O horses (P < 0.05, 28.5 ± 1.4 vs. 24.1 ± 1.6 l) as was rBV (41.3 ± 2.0 vs. 35.3 ± 2.3 l) and rRCV (13.3 ± 0.6 vs. 11.1 ± 0.8 l). Ageing compromises the ability to handle the combined demand of exercise and thermoregulation in part due to decreased absolute pre-exercise PV.

High plasma mid-regional pro-adrenomedullin levels in children with severe dengue virus infections

Background Dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) is characterized by hemorrhage, plasma leakage and shock. Adrenomedullin and vasopressin are vaso-active hormones that mediate endothelial permeability, vascular tone and water balance and may therefore play a role during DHF/DSS. Adrenomedullin reduces endothelial permeability and has vasodilatory properties, while vasopressin is a potent vasoconstrictor with anti-diuretic effects. Objectives To determine mid-regional pro-adrenomedullin (MR-proADM) and copeptin, which are reliable and stable markers for adrenomedullin and vasopressin response, respectively, and relate their plasma concentrations to outcome and markers of plasma leakage in Indonesian children with DHF and DSS. Study design In this observational cohort study Indonesian children with DHF/DSS were enrolled. On study days 0 and 2, plasma MR-proADM and copeptin concentrations as well as parameters of plasma leakage were determined. Plasma MR-proADM and copeptin concentrations were compared to values of healthy controls. Results MR-proADM was increased in both DHF ( n = 43) and DSS ( n = 28) vs. controls ( n = 17), with median (IQR) values of 0.47 (0.40–0.68), 0.56 (0.44–1.00) vs. 0.22 (0.19–0.29) nmol/L, respectively. Additionally, MR-proADM correlated with signs of increased vascular leakage such as low albumin and increased pleural effusion. Copeptin concentrations showed no significant changes as compared to controls. Conclusions MR-proADM concentrations are elevated in children with DHF and DSS and correlate with the severity of plasma leakage, in contrast to copeptin concentrations. We speculate that adrenomedullin has a functional role in limiting endothelial hyperpermeability during DHF/DSS. Finally, MR-proADM may be a candidate biomarker to predict development of DHF/DSS.

Simvastatin effects on portal‐systemic collaterals of portal hypertensive rats

Portal-systemic collateral vascular resistance and vasoconstrictor responsiveness are crucial in portal hypertension and variceal bleeding control. Statins enhance vasodilators production, but their influence on collaterals is unknown. This study aimed to survey the effect of simvastatin on collaterals. Partially portal vein-ligated rats received oral simvastatin (20 mg/kg/day) or distilled water from -2 to +7 day of ligation. After hemodynamic measurements on the eighth postoperative day, baseline perfusion pressure (i.e. an index of collateral vascular resistance) and arginine vasopressin (AVP, 0.1 nM-0.1 microM) responsiveness were evaluated with an in situ perfusion model for collateral vascular beds. RT-PCR of endothelial NO synthase (eNOS), inducible NOS (iNOS), cyclooxygenase-1 (COX-1), COX-2, thromboxane A(2) synthase (TXA(2)-S) and prostacyclin synthase genes was performed in parallel groups for splenorenal shunt (SRS), the most prominent intra-abdominal collateral vessel. To determine the acute effects of simvastatin, collateral AVP response was assessed with vehicle or simvastatin. SRS RT-PCR of eNOS, iNOS, COX-1, COX-2 and TXA(2)-S, and measurements of perfusate nitrite/nitrate, 6-keto-PGF1(alpha) and TXB(2) levels were performed in parallel groups without AVP. Acute simvastatin administration enhanced SRS eNOS expression and elevated perfusate nitrite/nitrate and 6-keto-PGF1(alpha) concentrations. Chronic simvastatin treatment reduced baseline collateral vascular resistance and portal pressure and enhanced SRS eNOS, COX-2 and TXA(2)-S mRNA expression. Neither acute nor chronic simvastatin administration influenced collateral AVP responsiveness. Simvastatin reduces portal-systemic collateral vascular resistance and portal pressure in portal hypertensive rats. This may be related to the enhanced portal-systemic collateral vascular NO and prostacyclin activities.

Mechanisms of impaired vasopressin response in acute alcohol‐intoxicated hemorrhaged rats

Acute alcohol intoxication (AAI) blunts the neuroendocrine (catecholamine and arginine vasopressin (AVP)) response to hemorrhagic shock (HS) resulting in impaired blood pressure recovery during fluid resuscitation. Central stimulation of cholinergic nicotinic receptors restores AVP responses in AAI+HS suggesting that AAI disrupts signaling mechanisms controlling AVP release. We hypothesize the AAI‐mediated inhibition of supraoptic (SON) and paraventricular (PVN) responsiveness is controlled by alterations in the balance between inhibitory nitric oxide (NO) and stimulatory angiotensin II (ANG II) signaling. Chronically‐catheterized, adult male Sprague‐Dawley rats (250–300g) received a primed‐constant (2.5g/kg + 0.3g/kg/h) 15h intragastric infusion of alcohol or isocaloric/isovolumic dextrose (DEX). AAI produced a significant (~30%) increase in NO levels in the PVN and SON and NO synthase activity in the SON as compared to DEX controls. AAI did not alter circulating ANG II, but showed significant attenuation of ANG II in response to HS. These results suggest that the mechanisms underlying the attenuation of AVP release during HS in AAI involve altered balance between NO and ANG II control of hypothalamic responses. We predict that central inhibition of NO or ANG II stimulation will restore AVP and will in turn improve hemodynamic recovery from HS in AAI. Supported by DOD PR‐054196 and NIAAA‐AA7577.

Influences of hypertonic and hypovolemic treatments on vasopressin response in propylthiouracil (PTU) induced hypothyroid rat and effect on supplementation with L-thyroxine

This study was performed to investigate the effects of L-thyroxine treatment on plasma vasopressin (AVP) levels in rats with hypothyroidism induced by propylthiouracil (PTU). Animals were separated into three groups each having 6 rats: control, PTU, PTU+L-thyroxine groups. Then, the groups were further divided into 3 sub-groups including 6 rats (a; basal, b; hypertonic stimulated and c; hypovolemic stimulated). At the end of the experiments all rats were decapitated in order to obtain plasma samples for analysis in terms of Hct, osmolality, TT 3 , TT 4 and vasopressin. Haematocrit (Hct) levels were the highest in hypovolemic stimulated sub-group (P < 0.001). Osmolality levels were higher in hypertonic stimulated sub-groups (P < 0.001). Total T 3 and T 4 values were the lowest in the PTU group and the highest in the L-thyroxine treated group (P < 0.001). Plasma AVP levels were reduced by hypothyroidism. However, L-thyroxine treatment after the hypothyroidism prevented this reduction (P < 0.001). Vasopressin responses to basal, hypovolemic and hypertonic stimulations were the lowest in the PTU group (P < 0.001). The results of the present study show that basal and stimulated plasma vasopressin levels are reduced in PTU-induced hypothyroidism. However, L-thyroxine treatment following hypothyroidism prevents this reduction.

Nax-deficient mice show normal vasopressin response to dehydration

In dehydrated animals, the antidiuretic hormone vasopressin (VP) is released from the nerve terminals of magnocellular neurons of the supraoptic nucleus (SON) and paraventricular nucleus (PVN) into the systemic circulation at the posterior pituitary. Increases in sodium (Na +)-level and osmolality in body fluids upon dehydration are reportedly sensed by a Na +-sensor and/or an osmosensor, respectively. However, it is still unknown whether both are involved in the regulation of production and/or release of VP. Na x is the cerebral Na +-level sensor and Na x -knockout mice do not stop ingesting salt even when dehydrated. Here we examined VP production/release in Na x -knockout mice, and found that they are normal in the VP response to dehydration or intraperitoneal-administration with hypertonic saline. In situ hybridization using an intron-specific probe showed that VP gene expression in the SON did not differ from wild-type mice when dehydrated. Also, there was no significant difference in the activity of subfornical organ neurons projecting to the SON between the two genotypes when stimulated by water deprivation. Furthermore, Na x -knockout mice showed a normal response in urine excretion to dehydration. All these results indicate that the information of Na +-level increase detected by Na x does not contribute to the control of VP production/release.

Sexually diergic, dose-dependent hypothalamic–pituitary–adrenal axis responses to nicotine in a dynamic in vitro perfusion system

Introduction The hypothalamic–pituitary–adrenal cortical (HPA) axis modulates physiological responses to stress. We previously reported sexually diergic, dose-dependent HPA responses in vivo following nicotine administration: Male rats had greater arginine vasopressin (AVP) responses than females, and female rats had greater adrenocorticotropic hormone (ACTH) and corticosterone (CORT) responses than males. The goal of the present study was to further investigate sexually diergic, dose-dependent HPA responses following nicotine addition to an in vitro model of the HPA axis, so that hormone output could be determined at each level of the axis. Methods Hypothalami, pituitaries, and adrenal glands were harvested from male and female rats. One-half hypothalamus, one-half pituitary, and one adrenal gland were placed individually into three jacketed tissue baths connected by tubing and perfused in series with physiological medium. Sampling ports between tissue baths were used to collect buffer before and after addition of various doses of nicotine, for measurement of AVP and corticotropin-releasing hormone (CRH) from the hypothalamus bath, ACTH from the pituitary bath, and CORT from the adrenal bath. Hormones were measured by highly specific immunoassays. Results Stable temperatures, flow rates, pH, and hormone baselines were achieved in the in vitro system. Consistent with our in vivo and earlier in vitro studies, nicotine added to the hypothalamus tissue bath significantly increased HPA responses in a sex- and dose-dependent manner: Males had greater AVP responses than did females, and females had greater CRH responses than did males. Sexually diergic ACTH and CORT responses were less apparent and were higher in females. Discussion Our in vitro system accurately models in vivo HPA responses to nicotine in both sexes and thus represents a reliable method for investigating the effects of nicotine on components of the HPA axis. These studies may be pertinent to understanding the biological differences to nicotine between men and women smokers.

Effect of melatonin supplementation on plasma vasopressin response to different conditions in rats with hyperthyroidism induced by l-thyroxine

The present study was performed to determine how basal, isotonic, hypertonic and hypovolemic conditions affect fluid–electrolyte balance and plasma arginine vasopressin (AVP) levels in rats with experimental hyperthyroidism supplemented with melatonin. The rats were divided into four groups of twenty-four subjects each kept under the following treatments during one month: (1) Controls; (2) treated with l-thyroxine; (3) treated with l-thyroxine and sham melatonin and (4) treated with l-thyroxine and melatonin. After this each group was further subdivided into subgroups that were subject to normal, isotonic, hypertonic and hypovolemic conditions. The plasma AVP, total triiodothyronine (TT 3), total thyroxine (TT 4) and melatonin levels were measured in plasma by means of a Phoenix Pharmaceutical RIA test kit. Hematocrit and osmolality levels were also determined. There were significant increases of total T3 and T4 levels in the l-thyroxine treated groups, p < 0.001. The AVP levels were also increased in groups 2 and 3, but not so in the rats treated with melatonin ( p < 0.001), which also showed increased plasma melatonin levels ( p < 0.001). These results indicate that treatment with l-thyroxine increases stimulated and non-stimulated AVP release that are inhibited by melatonin supplementation. It was also shown that AVP response to hypertonic and hypovolemic conditions was not affected by l-thyroxine treatment and/or l-thyroxine + melatonin treatment.

A possible relationship between brain-derived adrenomedullin and oxytocin in the regulation of sodium balance

Exaggerated thirst and salt appetite occurs when endogenous, brain-derived adrenomedullin (AM) production is compromised. In addition, the arginine vasopressin (AVP) response to hypovolemia is compromised. We hypothesized that AM acts in the hypothalamus to control oxytocin (OT) release and that the inhibitory action of AM on salt appetite is mediated via its effects on OT release in the rat. When plasma tonicity was elevated with sodium, ribozyme-induced compromise of central AM production significantly blunted the release of OT into plasma. OT responses to elevation of plasma osmolality without concomitant change in plasma sodium levels were not altered by compromise of AM production. Thus, brain-derived AM controls OT release in response to altered plasma sodium levels. Furthermore, central AM-induced inhibition of NaCl intake can be reversed by pretreatment with an OT antagonist, and the increase in NaCl appetite seen following ribozyme compromise of central AM can be attenuated with central OT administration. These data support the hypothesis that endogenous, brain-derived AM is an essential participant in the hypothalamic response to hypernatremia via its actions on OT-expressing neurons. Together with our previous reports of the effects of AM on AVP secretion and ingestive behaviors, our results suggest that endogenous AM is a physiologically relevant regulator of the endocrine and behavioral mechanisms that maintain fluid and electrolyte homeostasis.

POSTOPERATIVE VASOPRESSIN AND COPEPTIN LEVELS IN NONCARDIAC SURGERY PATIENTS

Further information on the endogenous arginine vasopressin (AVP) response in patients with postoperative systemic inflammatory response syndrome (SIRS) and vasodilatory shock would provide more insight into the pathophysiology of SIRS-associated cardiovascular failure and help indicate AVP therapy. Patients after uncomplicated abdominal surgery without SIRS (n = 10), critically ill patients after noncardiac surgery with SIRS (n = 9), and patients with SIRS plus vasodilatory shock (n = 22) were included in this prospective trial. Plasma AVP (radioimmunoassay) and copeptin (immunoluminometric assay) concentrations together with clinical parameters were documented daily during the first 7 days postoperative. The AVP response significantly differed between the three groups. Patients without SIRS had lower AVP concentrations than SIRS patients with (P = 0.001) or without shock (P = 0.003). Patients with SIRS and shock had higher AVP levels than patients with SIRS alone (P < 0.001). Arginine vasopressin decreased over time (P = 0.007) in all groups. At day 28, nonsurvivors had higher AVP levels than did survivors (P < 0.001). In SIRS patients without shock, serum osmolarity was indirectly associated with AVP levels, whereas mean arterial blood pressure and serum osmolarity were associated with AVP in SIRS patients with shock. Arginine vasopressin and copeptin correlated significantly with each other (P < 0.001; r = 0.76). In patients without hemofiltration, copeptin levels predicted 28-day mortality with high sensitivity and specificity. The postoperative AVP response in noncardiac surgery patients seems well maintained. The possibility that AVP plays a contributory role in the failure to restore vascular tone in patients with vasodilatory shock cannot be excluded but seems less important than in septic or postcardiotomy shock.

The V-ATPase B1-subunit promoter drives expression of Cre recombinase in intercalated cells of the kidney

The collecting duct of the kidney is composed of two morphologically and physiologically distinct cell types, principal and intercalated cells. To better understand intercalated cell function we generated a transgenic mouse expressing Cre recombinase under the control of a cell type- specific promoter. We used 7 kb of the ATP6V1B1 5' untranslated region (B1 promoter), a gene found in the intercalated cells of the kidney and the male reproductive tract. We first crossed these B1-Cre transgenic mice with the ROSA26-loxP-stop-loxP-yellow fluorescent protein reporter mice to assess the specificity of Cre expression. Immunohistochemistry and confocal fluorescence microscopy showed that Cre is selectively active in all intercalated cells (type A, type B, and non-A/B cells) within the collecting duct and most cells of the connecting segment. About half of the principal cells of the connecting segment also expressed Cre, a pattern also seen in B1-driven enhanced green fluorescent protein transgenic mice. Cre was found to be active in the male reproductive tract and at a low level in limited non-ATP6V1B1 expressing tissues. The B1-Cre transgenic mice are healthy, breed normally, produce regular sized litters, and transmit the transgene in Mendelian fashion. This new cell-specific Cre expressing mouse should prove useful for the study of intercalated cell physiology and development.

Altered vasopressin response to metoclopramide in multiple system atrophy: evidence of a cholinergic defect in the hypothalamus.

Multiple system atrophy (MSA) is a heterogeneous group of central neurological degenerations often associated with diffuse deterioration of the hypothalamic cholinergic neurons. In the hypothesis of an altered cholinergic regulation of vasopressin release, we evaluated vasopressin response to metoclopramide (20 mg i.v.), a cholinomimetic agonist, in 12 MSA patients. In the same patients the hemodynamic and osmolal control of vasopressin was also evaluated. We found that MSA patients had significantly lower basal plasma vasopressin values and higher plasma osmolality than control subjects. However, they displayed a normal vasopressin response to osmotic stimulation. During head-up tilting, orthostatic hypotension occurred in all patients, and the vasopressin response to hypotension was severely blunted in 5 of 12 patients, thus demonstrating the presence of a lesion of the afferent noradrenergic pathways. Metoclopramide increased vasopressin in control subjects, whereas MSA patients did not display any increase in vasopressin. These results clearly indicate that cholinergic neurons that regulate vasopressin release are damaged in MSA. Such an alteration may be dissociated from the lesion of the afferent noradrenergic pathways. As a consequence of the altered vasopressin release, MSA patients show lower plasma vasopressin levels with consequent propensity to dehydration and hypovolemia, which may further aggravate their hypotension.

Effects of the renal medullary pH and ionic environment on vasopressin binding and signaling

The kidney has a cortico-medullary interstitial gradient of decreasing pH and increasing concentrations of sodium chloride and urea, but the influence of these gradients on receptor signaling is largely unknown. Here, we measured G-protein coupled receptor function in LLC-PK1 cells acutely exposed to conditions mimicking different kidney regions. Signaling through the parathyroid hormone receptor, normally expressed in the cortex, was greatly reduced at an acidic pH similar to that of the inner medulla. Parathyroid hormone receptor, tagged with green fluorescent protein, showed no ligand-induced internalization. In contrast, under both acidic and hyperosmotic conditions, vasopressin increased intracellular cAMP, and upon binding to its type 2 receptor (V2R) was internalized and degraded. Dose-displacement binding assays with selective vasopressin/oxytocin receptor ligands under inner medullary conditions indicated a shift in the V2R pharmacological profile. Oxytocin did not bind to the V2R, as it does under normal conditions and the vasopressin type 1 receptor (V1R) had reduced affinity for vasopressin compared to the V2R in low pH and high osmolality. We suggest that the cortico-medullary gradient causes a receptor-specific selectivity in ligand binding that is of functional significance to the kidney. While the gradient is important for urinary concentration, it may also play a substantial role in fine-tuning of the vasopressin response through the V2R.