Impaired Water Excretion and Elevated Plasma Vasopressin in Patients with Alcohol-withdrawal Symptoms

SUMMARY Reports describing the fluid balance status of alcoholics inwithdrawal are varied, and conflicting. We examined this questionby recording values for a variety of parameters in responseto a standard water load test. Compared with age and sex matchedhealthy volunteers (n=14), alcoholics in withdrawal (n=17) exhibitedlower cumulative urine output (p=0. 0001), higher minimum urineosmolality (p=0. 0001), lower serum sodium (p=0. 0024 beforeloading) and elevated plasma arginine vasopressin levels (p=0.0045 before loading). We believe that these findings are bestexplained by a resetting of osmoreceptors, a supposition inkeeping with contemporary views on the pathogenesis of alcoholdependence and withdrawal. This additional evidence of an antidiuretic state in alcoholwithdrawal leads us to question the practice of fluid supplementationin its management and we suggest that this policy be revised.     

Mechanism of Impaired Water Excretion in the Hypothyroid Rat

The ability to excrete an oral water load and the renal diluting mechanism were studied in hypothyroid rats and in age-matched euthyroid controls. Hypothyroid animals excreted a significantly smaller fraction of a 50-ml/kg oral water load than controls, demonstrating the same limited ability to excrete free water as thyroid-deficient man. During hypotonic (0.45%) saline infusion, absolute sodium delivery to the diluting segment and free water clearance were markedly lower in hypothyroid rats. However, both fractional distal sodium delivery and fractional free water clearance were similar in hypothyroid and control animals, suggesting that the reduced absolute free water formation in hypothyroid rats was due to decreased net distal delivery. In support of this hypothesis was the observation that fractional distal sodium reabsorption was equal or higher in thyroid-deficient rats, which indicates that the sodium reabsorptive capacity of the diluting segment was preserved in these animals. The results cannot be attributed to incomplete suppression of antidiuretic hormone (ADH) since they were identical in diabetes insipidus rats, nor to different rates of non-ADH-dependent backflux of filtrate since tissue osmolality and solute concentrations in the cortex, medulla, and papilla were similar in hypothyroid and control rats of both Sprague-Dawley and Brattleboro strains.The functional integrity of the diluting segment in hypothyroid rats was further demonstrated in experiments in which distal delivery was increased by contralateral nephrectomy or by administration of carbonic anhydrase inhibitors which decrease proximal sodium reabsorption. In both studies, fractional free water clearance increased markedly reaching levels significantly greater than in euthyroid controls.These results demonstrate that the impaired ability of the hypothyroid rat to excrete a water load is not due to incomplete suppression of ADH or decreased reabsorptive capacity of the diluting segment but results from decreased filtrate delivery to this site secondary to reduced GFR.     

Radioimmunoassay of Vasopressin in Unextracted Plasma

A radioimmunoassay (RIA) for arg₈-vasopressin (AVP) in unextracted human plasma was based on a sensitive anti-AVP rabbit antiserum, inhibition of enzymatic damage to [¹²⁵I]AVP and AVP, and the use of an individual plasma blank, to correct for interference of plasma factors with the RIA. Sensitivity was 0.4 pg of synthetic AVP detected, corresponding to 1.2 pg/ml of AVP in human plasma. Recovery of AVP added to pooled plasma was 94 ± 9.3% (mean± S.D.) in the low range (AVP, 2.8 pg/ml added) and 106 ± 11.7% in the high range (45.0 pg/ml added). In 26 healthy, ambulatory subjects on ad lib. water intake, plasma AVP concentration was 2.0 ± 1.22 pg/ml in the supine position and in 28 healthy subjects, 6.2 ± 4.3 pg/ml in the upright position. Water loading suppressed the plasma AVP concentration. Smoking caused increased plasma AVP in 3 subjects despite water loading.     

糖皮质激素对体外培养的胎盘组织促肾上腺皮质激素释放激素分泌水平的影响

目的观察糖皮质激素对胎盘组织促肾上腺皮质激素释放激素(CRH)的分泌水平的影响。方法收集2006年1月-3月住院分娩的正常妊娠妇女的胎盘组织与妊娠肝内胆汁淤积症(ICP)患者胎盘及其血清各10例。分3组进行胎盘组织培养,即正常胎盘组、ICP胎盘组,正常胎盘组织加ICP患者血清组,分别用放射免疫法测定各组加与不加地塞米松胎盘组织培养液中CRH的水平。结果正常组与正常胎盘加地塞米松组培养24、48、72、96 h其CRH分泌水平分别为(:74.81±27.92)、(63.71±24.72)、(91.87±41.64)、(98.90±42.52)pg/mL(;66.94±29.62)、(77.39±31.84)、(61.89±33.94)、(75.13±36.98)pg/mL,两组比较差异有统计学意义(P>0.05)。ICP组与ICP加地塞米松组培养上清液中CRH水平在24、48、72、96 h其CRH分泌水平分别为(:48.28±16.56)、(60.20±29.97)、(72.92±31.65)、(69.22±29.33)pg/mL(;41.81±25.00)、(57.36±39.75)、(57.72±23.29)、(61.43±20.77)pg/mL,两组比较差异有统计学意义(P>0.05);正常胎盘加ICP血清培养组与正常胎盘加ICP血清加地塞米松培养组上清液中CRH水平在24、48、72、96 h其CRH分泌水平分别为:(84.9±34.98)、(74.5±29.93)、(71.1±27.26)、(81.0±37.18)pg/mL;(76.29±33.11)、(63.70±24.20)、(64.85±28.39)、(67.65±33.20)pg/mL,两组比较差异有统计学意义(P>0.05)。3组加入地塞米松培养的胎盘组织,CRH分泌水平并无明显改变。结论地塞米松不影响体外培养胎盘组织CRH分泌。     

Urinary Excretion of Adenosine 3'5' Monophosphate in Vitamin D Deficiency

Urinary cyclic adenosine 3'5'monophosphate (AMP) excretion has been determined by radioimmunoassay in children with rickets and in control children. Cyclic AMP was greatly increased in children with rickets. The excretion of cyclic AMP correlated significantly with parathyroid hormone levels (PTH) and alkaline phosphatase, but not with age, calcaemia and serum inorganic phosphate. Calcium infusion led to a decrease in the excretion of cyclic AMP. The data are consistent with following hypothesis. During vitamin D deficiency, high PTH levels can increase the renal excretion of cyclic AMP. The effects of PTH on bone resorption fail to maintain the levels of serum calcium due to the lack of vitamin D. The mechanism by which the secondary hyperparathyroidism develops during vitamin D deficiency remains to be investigated.     

Postural Augmentation of Plasma Renin Activity and Aldosterone Excretion in Normal People

Peripheral plasma renin activity and aldosterone excretion rates have been measured in normal people during recumbency, recumbent exercise, tilting, and continuous ambulation. Upright posture induces a prompt elevation in peripheral plasma renin activity beginning in 15 minutes and peaking between 60 and 120 minutes. Aldosterone excretion is increased during 120 minutes of upright posture and correlates directly with the elevation in renin activity. Upright posture induces increased plasma renin activity regardless of the level of sodium intake in the preparatory diet. Concomitant measurements of endogenous creatinine clearance and the rates of excretion of sodium and potassium suggest that a fall in renal arterial perfusion resulting from upright posture induces increased release of renin and the subsequent secondary stimulation of aldosterone secretion. Our data indicate that the changes in plasma renin activity are due to changes in the amount of the enzyme rather than to changes in other elements of the reninangiotensin systm. This report discusses the physiologic importance of postural augmentation of renin production, emphasizing that for proper interpretation of values of plasma renin activity, posture as well as dietary factors must be considered and controlled.     

Increased Plasma Arginine Vasopressin in Clinical Adrenocortical Insufficiency and Its Inhibition By Glucosteroids

Trichloroacetic acid extracts of plasma were fractionated on a CG-50 resin column and the 50% acetic acid eluents chromatographed on silicic acid-impregnated glass paper in butanol-acetic acid-water. The specific arginine vasopressin (AVP) zone was eluted and assayed for antidiuretic activity in the diuretic rat. Thioglycolate inactivation was used to confirm AVP activity. Recovery of as little as 4 muU AVP per ml plasma ranged between 80 and 90%. In normal subjects after an overnight fast, plasma AVP ranged between 2.5 and 10.0 muU per ml. AVP secretion was inhibited by hemodilution and stimulated with nicotine and hypertonic saline. Plasma AVP was absent in patients with diabetes insipidus even after neurohypophyseal stimulation. Plasma AVP was abnormally elevated during mild dehydration and remained above the normal range despite hemodilution in patients with untreated adrenocortical insufficiency demonstrating a delayed water diuresis. Glucosteroid therapy lowered plasma AVP to normal in dehydrated patients. A normal diuretic response to hydration was accompanied by a fall in plasma AVP to zero in steroid-treated patients. These findings suggest that hypersecretion of AVP may play an important role in the abnormal water metabolism of adrenocortical insufficiency and that the glucosteroids promote normal water diuresis by inhibiting the secretion of AVP from the neurohypophysis.     

Increased Thirst and Plasma Arginine Vasopressin Levels during 2-Deoxy-d-glucose-induced Glucoprivation in Humans

Insulin-induced hypoglycemia by unknown mechanism(s) increases plasma arginine vasopressin (AVP) levels in humans. Mechanisms for increased AVP levels during central nervous system glucoprivation were investigated by administering 20-min i.v. infusions of 2-deoxy-d-glucose (50 mg/kg), a competitive inhibitor of glucose utilization, or normal saline (sham), to 24 normal volunteers. Some of the infusions were administered in combination with neuropharmacological blocking agents (placebo). The behavioral, physiological, metabolic, and hormonal correlates of 2-deoxy-d-glucose (2DG)-induced gluco-privation and AVP secretion were studied in a group (n = 5) pretreated for 1 wk with either mazindol (1 mg per os three times per day), a potent norepinephrine and dopamine-reuptake blocker, or placebo. A second group (n = 5) received either propranolol (3 mg/3 min followed by 80 μg/min) or normal saline infusion before and during 2DG administration. With 2DG alone, plasma AVP levels increased from 1.3±0.3 pg/ml at base line to a peak of 4.5±1.4 pg/ml at 60 min and remained elevated for 150 min. From 30 to 180 min after 2DG administration, the 2DG-infused volunteers increased their water intake in comparison with sham-infused volunteers. Marked increases in epinephrine and slight increases in norepinephrine were associated with increases in plasma glucose and renin activity and decreases in plasma potassium. Plasma sodium and osmolality increased transiently and mean arterial pressure (MAP) fell. These changes, however, were small and inconstant and could not account for the observed increases in thirst and AVP levels. Pretreatment with mazindol prevented the decrease in MAP and the increase in plasma renin activity (PRA) following 2DG infusions without modifying increased thirst, water intake, or AVP responses to glucoprivation. Pretreatment with propranolol effectively blocked β-adrenoreceptors as evidenced by increased MAP and plasma epinephrine, and abolition of the RPA increases during 2DG-induced glycoprivation, but did not suppress AVP and thirst responses. A cervical cord-sectioned patient lacking descending sympathetic out-flow had a potentiated thirst response to 2DG-induced glucoprivation in the absence of increases in sodium, catecholamines, and PRA. Thus 2DG administration activates mechanisms for increased thirst and AVP which are unrelated to changes in peripheral catecholamines, MAP, PRA, and osmolality.     

Mechanism of Effect of Hypoxia on Renal Water Excretion

The effect of lowering the pressure of oxygen from 80 to 34 mm Hg was examined in anesthetized dogs that were undergoing a water diuresis. This degree of hypoxia was associated with an antidiuresis as urine osmolality (Uosm) increased from 107 to 316 mosmol/kg H₂O (P < 0.001) and plasma arginine vasopressin increased from 0.06 to 7.5 μU/ml, (P < 0.05). However, hypoxia was not associated with significant changes in cardiac output (CO, from 4.2 to 4.7 liters/ min), mean arterial pressure (MAP, from 143 to 149 mm Hg), glomerular filtration rate (GFR, from 46 to 42 ml/min), solute excretion rate (SV, from 302 to 297 mosmol/min), or filtration fraction (from 0.26 to 0.27, NS). Hypoxia was associated with an increase in renal vascular resistance (from 0.49 to 0.58 mm Hg/ml per min, P < 0.01). The magnitude of hypoxia-induced antidiuresis was the same in innervated kidneys and denervated kidneys. To further examine the role of vasopressin in this antidiuresis, hypoxia was induced in hypophysectomized animals. The effect of hypoxia on CO, MAP, GFR, SV, and renal blood flow in hypophysectomized animals was the same as in intact animals. In contrast to intact animals, however, hypoxia did not induce a significant antidiuresis in hypophysectomized animals (Uosm from 72 to 82 mosmol/kg H₂O). To delineate the afferent pathway for hypoxia-stimulated vasopressin release, hypoxia was induced in dogs with either chemo- or baroreceptor denervation. The effect of hypoxia on CO, MAP, GFR, SV, and renal blood flow in the denervated animals was the same as in nondenervated animals. Hypoxia resulted in an antidiuresis in chemoreceptor (Uosm from 113 to 357 mosmol/kg H₂O, P < 0.001) but not in baroreceptor (Uosm from 116 to 138 mosmol/kg H₂O, NS) denervated animals. To determine if hypoxia alters renal response to vasopressin, exogenous vasopressin was administered to normoxic and hypoxic groups of dogs. The antidiuretic effect of vasopressin was no different in these two groups. These results demonstrate that hypoxia induces an antidiuresis which is independent of alterations in CO, MAP, SV, filtration fraction, renal nerves, or renal response to vasopressin and occurs through baroreceptor-mediated vasopressin release. The nature of the baroreceptor stimulation remains to be elucidated.     

The Role of Blood Osmolality and Volume in Regulating Vasopressin Secretion in the Rat

A sensitive and specific radioimmunoassay for plasma arginine vasopressin (AVP) has been used to study the effects of blood osmolality and volume in regulating AVP secretion in unanesthetized rats. Under basal conditions, plasma AVP and osmolality were relatively constant, averaging 2.3+/-0.9 (SD) pg/ml and 294+/-1.4 mosmol/kg, respectively. Fluid restriction, which increased osmolality and decreased volume, resulted in a progressive rise in plasma AVP to about 10 times basal levels after 96 h. A 2-3-fold increase in plasma AVP occurred as early as 12 h, when osmolality and volume had each changed by less than 2%. Intraperitoneal injections of hypertonic saline, which had no effect on blood volume, also produced a rise in plasma AVP that was linearly correlated with the rise in osmolality (r > 0.9) and quantitatively similar to that found during fluid restriction (plasma AVP increased 2-4-fold with each 1% increase in osmolality). Intraperitoneal injection of polyethylene glycol, which decreased blood volume without altering osmolality, also increased plasma AVP but this response followed an exponential pattern and did not become significant until volume had decreased by 8% or more. At these levels of hypovolemia, the osmoregulatory system continued to function but showed a lower threshold and increase sensitivity to osmotic stimulation. We conclude that AVP secretion is regulated principally by blood osmolality but that the responsiveness of this mechanism may be significantly altered by modest changes in blood volume.     

Involvement of the V2 Vasopressin Receptor in Adaptation to Limited Water Supply

Mammals adapted to a great variety of habitats with different accessibility to water. In addition to changes in kidney morphology, e.g. the length of the loops of Henle, several hormone systems are involved in adaptation to limited water supply, among them the renal-neurohypophysial vasopressin/vasopressin receptor system. Comparison of over 80 mammalian V2 vasopressin receptor (V2R) orthologs revealed high structural and functional conservation of this key component involved in renal water reabsorption. Although many mammalian species have unlimited access to water there is no evidence for complete loss of V2R function indicating an essential role of V2R activity for survival even of those species. In contrast, several marsupial V2R orthologs show a significant increase in basal receptor activity. An increased vasopressin-independent V2R activity can be interpreted as a shift in the set point of the renal-neurohypophysial hormone circuit to realize sufficient water reabsorption already at low hormone levels. As found in other desert mammals arid-adapted marsupials show high urine osmolalities. The gain of basal V2R function in several marsupials may contribute to the increased urine concentration abilities and, therefore, provide an advantage to maintain water and electrolyte homeostasis under limited water supply conditions.     

Development and Clinical Application of a New Method for the Radioimmunoassay of Arginine Vasopressin in Human Plasma

A radioimmunoassay has been developed that permits reliable measurements of plasma arginine vasopressin (AVP) at concentrations as low as 0.5 pg/ml in sample volumes of 1 ml or less. Nonhormonal immunoreactivity associated with the plasma proteins is eliminated by acetone precipitation before assay, leaving unaltered a component that is immunologically and chromatographically indistinguishable from standard AVP. Storage of plasma results in a decline in AVP concentration and, thus, must be carefully regulated. The plasma AVP values obtained by our method approximate the anticipated levels and vary in accordance with physiologic expections. In recumbent normal subjects, plasma AVP ranged from (mean ±SD) 5.4±3.4 pg/ml after fluid deprivation to 1.4±0.8 pg/ml after water loading, and correlated significantly with both plasma osmolality (r=0.52; P<0.001) and urine osmolality (r=0.77; P<0.001). After fluid restriction, plasma AVP was uniformly normal relative to plasma osmolality in patients with nephrogenic diabetes insipidus and primary polydipsia but was distinctly subnormal in all patients with pituitary diabetes insipidus. The infusion of physiologic amounts of posterior pituitary extract caused a dose-related rise in plasma vasopressin that afterwards declined at the expected rate (t½=22.5±4 min). We conclude that, when used appropriately, our radioimmunoassay method provides a useful way of assessing AVP function in man.     

Mechanism of Effect of Prostaglandin E1 on Renal Water Excretion

The present study examined the effect of prostaglandin E(1) (PGE(1)) on renal water excretion in the anesthetized dog. Renal perfusion pressure was kept constant by adjustment of a suprarenal aortic clamp. In seven experiments the intravenous administration of PGE(1) (7 mug/min) significantly increased urinary osmolality from 76 to 381 mosmol (P < 0.001) and decreased free water clearance from 2.2 to - 0.02 ml/min (P < 0.001). These effects promptly were reversed with cessation of the infusion. This antidiuretic effect occurred both in innervated and denervated kidneys and was not associated with changes in glomerular filtration rate, renal vascular resistance, or solute excretion rate. In 10 experiments in hypophysectomized dogs no effect of intravenous PGE(1) on free water clearance and urinary osmolality was observed. The intrarenal administration of PGE(1) (1 mug/min) to six water-loaded and two hypophysectomized dogs caused no systemic vascular changes and increased rather than decreased free water clearance (2.83 to 4.08 ml/min, P < 0.001). No significant change in urinary osmolality occurred. Glomerular filtration rate was not altered by the intrarenal infusion, but reversible changes in solute excretion rate and renal vascular resistance occurred. These results thus indicate that the antidiuresis associated with intravenous PGE(1) is mediated primarily by the release of vasopressin rather than alterations in renal hemodynamics or solute excretion. The diuretic effect of intrarenal PGE(1) occurs in the absence of vasopressin and is most likely mediated primarily by increased distal delivery of tubular fluid to the diluting segment of the nephron rather than changes in water permeability of the renal tubular epithelium.