Effects of time of day, gender, and menstrual cycle phase on the human response to a water load.

Estrogen and progesterone interference with renal actions of arginine vasopressin (AVP) has been shown. Thus we hypothesized that women will have a higher water turnover than men and that the greatest difference will be during the luteal phase of the menstrual cycle. Seven men (32 +/- 3 yr) and six women (33 +/- 2 yr) drank 12 ml water/kg lean body mass on different days at 0800 and at 2000 following 10 h of fast and a standardized meal at 0600 and 1800. Women participated on days 4-11 and 19-25 of the menstrual cycle. Initial urine and plasma osmolalities and urine flow rates were similar in all experiments. The cumulative urine voided over 3 h following the morning drink was less in men (73 +/- 12% of the water load) compared with women in either the follicular (100 +/- 3%) or luteal phases (102 +/- 10%) of the menstrual cycle. Nighttime values (30-43% of the water load) were lower in all experiments and were not different between sexes or menstrual cycle phases. Plasma AVP was higher at night and may contribute to this diurnal response. The data are generally consistent with the stated hypothesis; however, possibly owing to the greatly reduced urine flow in both sexes at night, a difference between sexes was not observed at that time.

Renal, endocrine, and cardiovascular responses during head-out water immersion in legless men.

BACKGROUND: The hydrostatic pressure gradient during head-out water immersion (HOI) causes a blood shift from the legs into the thoracic cavity to stretch the receptors in the cardiac atria and results in a diuresis in hydrated subjects. The present study was conducted to examine whether the HOI-induced diuresis and related circulatory and hormonal changes were attenuated in the subjects who had no legs (legless men). METHODS: Two legless men served as the subjects. They lost both legs 15 and 17 yr ago by accidents and were otherwise healthy. Six normal males participated as controls. The experimental protocol was consisted of a 1-h control, a 3-h HOI (water temperature, 34.5 degrees C) and a 1-h recovery. RESULTS: Average urine flow (0.6 ml x min(-1)), urinary excretion of sodium (90 microeq x min(-1)), and osmolal clearance (1.4 ml x min(-1)) of the legless subjects increased in the first h of immersion to 0.7 ml x min(-1), 139 microeq x min(-1), and 1.8 ml x min(-1), respectively. These values remained elevated during HOI, however, the magnitude of the increase was smaller compared with the control subjects. Plasma arginine vasopressin was significantly (p < 0.05) decreased from 1.0+/-0.4 microU x 100 ml(-1) to 0.4+/-0.2 microU x 100 ml(-1) during HOI in the normal subjects, but was not in the legless subjects (from 0.5 at control period to 0.4 microU x 100 ml(-1) during HOI). A concurrent reduction of aldosterone and plasma renin activity was observed with an increase in atrial natriuretic peptide during HOI in both subject groups, however, the magnitude of the changes was smaller in the legless subjects compared with the control subjects. Similarly, the average increase in cardiac output during HOI in the legless subjects (by 17%) was less compared with the control subjects (by 31%). CONCLUSION: The magnitude of renal, endocrine, and cardiovascular changes in response to HOI in the legless subjects were less than in control subjects, but the responses were qualitatively similar. Accordingly, we suggest that the cephalad blood expansion during immersion is not only due to translocation of blood from the legs but also the abdominal region.

Prospective randomized double blind placebo-controlled evaluation of azithromycin for treatment of cat-scratch disease.

OBJECTIVE: To determine the efficacy of azithromycin in the treatment of patients with typical cat-scratch disease. DESIGN: Prospective, randomized, double blind, placebo-controlled clinical trial. SETTING: Large military medical center and its referring clinics. PATIENTS: Active duty military members and their dependents with laboratory-confirmed, clinically typical cat-scratch disease. INTERVENTION: Study participants assigned by randomization to treatment with oral azithromycin or placebo for 5 days. OUTCOME MEASURES: Lymph node volume was calculated using three dimensional ultrasonography at entry and at weekly intervals. The ultrasonographer was blinded to the treatment groups. Endpoint evaluations were predetermined as time in days to 80% resolution of the initial total lymph node volume. RESULTS: Demographic and clinical data showed that the azithromycin and placebo treatment groups were comparable at entry although the placebo group tended to be older. Eighty percent decrease of initial lymph node volume was documented in 7 of 14 azithromycin-treated patients compared with 1 of 15 placebo-treated controls during the first 30 days of observation (P = 0.026). After 30 days there was no significant difference in rate or degree of resolution between the two groups. CONCLUSIONS: Treatment of patients with typical cat-scratch disease with oral azithromycin for five days affords significant clinical benefit as measured by total decrease in lymph node volume within the first month of treatment.

Renal function in hyperbaric environment.

During mixed gas saturation diving (to 3-49.5 ATA) daily urine flow increases by about 500 ml/day, with no changes in fluid intake and glomerular filtration rate. The diuresis is accompanied by a significant decrease in urine osmolality and increase in excretion of such solutes as urea, K+, Na+, Ca2+ and inorganic phosphate (Pi). The fall in urine osmolality is mainly due to a reduction of free water reabsorption which is associated with a suppression of insensible water loss and the attendant inhibition of antidiuretic hormone (ADH) system. The increase in urea excretion may be associated with a reduction of urea reabsorption at the collecting duct as a consequence of ADH suppression. The rise in K+ excretion is due to a facilitated K+ secretion at the distal tubule as a result of increased aldosterone, urine flow and excretion of impermeable anions such as Pi. The activation of aldosterone system is partly attributed to a transient dehydration induced by early hyperbaric diuresis. The increase in Na+ excretion in the face of enhanced aldosterone secretion indicates that the Na+ transport in the proximal tubule is markedly inhibited (by unknown mechanism). The Pi excretion increases with no changes in plasma level of parathyroid hormone (PTH), thus it may be due to an inhibition of Na(+)-Pi cotransport in the proximal tubule. The increase in Ca2+ excretion may be secondary to the inhibition of Na+ transport at the proximal tubule. Precise information on the proximal tubular Na+ transport is important to understand the mechanisms of impaired solute transport under hyperbaric conditions.

Renal and hormonal responses to exercise in man at 46 and 37 atmospheres absolute pressure.

BACKGROUND: Exercise increases plasma arginine-vasopressin (PAVP), plasma atrial natriuretic peptide (PANP), plasma renin activity (PRA), and plasma aldosterone (PALDO) in an intensity-dependent manner. With acute exercise, urine osmolality (UOSM) is often decreased despite increased PAVP. The hyperbaric environment lowers PAVP and UOSM, and increases urine flow. HYPOTHESIS: If work produced similar renal effects at hyperbaria, greater than normal dehydration could result from larger free water losses. METHODS: To test this hypothesis, hormonal and renal responses were assessed during exercise at 80% of maximum heart rate at 46 atmospheres absolute (atm abs) in 3 males, and during maximum exercise at 37 atm abs in 4 males. RESULTS: This maximum exercise was performed at the highest pressure thus far reported and revealed no loss in peak power output. Maximum O2 consumption and heart rate were only slightly reduced, 9.5% and 7% respectively, despite a 41% reduction in maximum minute ventilation. Basal levels and the changes resulting from maximum exercise in PRA and PALDO were unaffected by pressure, but basal and exercise-stimulated levels of PANP and PAVP were reduced compared with 1.5 atm abs control values. UOSM was not significantly affected during maximal exercise at sea level, but during maximum exercise at 37 atm abs and submaximum exercise at 46 atm abs UOSM increased over 300 mosm.kg-1 and 180 mosm.kg-1, respectively. CONCLUSION: Contrary to the hypothesis, UOSM was increased by about 200 mosm.kg-1 by both exercise protocols during hyperbaric exposure and free water was conserved.

Furosemide-induced airway relaxation in guinea pigs: relation to Na-K-2Cl cotransporter function.

This study tested the hypothesis that airway relaxation to furosemide is mediated via the Na-K-2Cl cotransporter. If this mechanism exists in airway smooth muscle like in vascular smooth muscle, changes in airway relaxation should be associated with changes in Na-K-2Cl cotransporter function, and both should be substrate dependent. Tracheal rings from newborn guinea pigs were bathed in standard (STD) or varying low Cl- concentration ([Cl-]) N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES). Isometric relaxation to 300 microM furosemide or 10(-8) to 10(-5) M salbutamol was measured. Airway segments were incubated with rubidium-86 (86Rb) in STD or varying low [Cl-] HEPES, with and without 300 microM furosemide or 25 microM salbutamol. Furosemide was unable to reduce 86Rb uptake at 10 mM [Cl-], although relaxation was still observed in 10 mM [Cl-]. Salbutamol did not affect 86Rb uptake. This study demonstrated that there is a furosemide-sensitive Na-K-2Cl cotransporter in newborn guinea pig trachea. However, the effect of furosemide on cotransporter function did not always directly correspond to differences in relaxation, suggesting that the Na-K-2Cl cotransporter may play a major, but not exclusive, role in furosemide-induced airway relaxation.

Mechanism for changes in vasopressin during acute exposure at 3 atm abs air.

Plasma arginine vasopressin (AVP) concentration is reduced in human subjects during prolonged saturation dive exposures of 4 atmospheres absolute (atm abs) and greater. The objectives of the present study were to determine if AVP would be reduced in eight male subjects during a 1-h exposure of 3 atm abs air and, if so, to determine the mechanisms responsible for the AVP response. Assessments of transmural central venous pressure (central venous pressure-esophageal pressure) and cardiac volume measurements were made to evaluate the possible role of cardiopulmonary receptors on the AVP response. Also, plasma osmolality (P(osmol)), venous blood gases, and mean corpuscular volume (MCV) were determined to evaluate potential effects of osmoreceptor and other fluid shifts on AVP release. AVP decreased (P < 0.05) by 0.5 microU/ml at 3 atm abs, whereas the transmural central venous pressure and cardiac volume remained unchanged throughout the experimental periods. A significant reduction (P < 0.05) in P(osmol) (by approximately 3 mosmol/kgH2O) was detected at 3 atm abs. Therefore, we conclude that the reduction in P(osmol) may cause the reduction in AVP during exposure to 3 atm abs pressure. The reduction in P(osmol) without water intake requires the postulation of an internal source of water. We propose that the threefold increase (P < 0.01) in venous PO2 and concomitant decrease (P < 0.05) in venous MCV suggest that the red blood cell may contribute to hypotonicity at 3 atm abs.

Diurnal renal responses in man to water loading at sea level and 31 atm abs.

The hyperbaric environment causes a sustained diuresis accompanied by normal water intake and a decrease in insensible water loss. The maintained water intake may be necessary for the maintenance of water balance because of a reduced ability of the kidney to retain water, or may be causal in the diuresis. This problem was studied in four male subjects. Each ingested 1 liter of water (15 degrees C) at 0800 and 2000 h on different days, at 1 atm abs during a predive control, at 31 atm abs, and at 1 atm abs during the postdive control period. Urine was collected 30 min before and 3 h after the drink. Plasma vasopressin (VP) showed a circadian rhythm only at 1 atm abs, higher during the daytime. Because of this, and slightly lower VP levels at hyperbaria, a decrease in VP in response to the water load was significantly detectable only at 1 atm abs during the daytime. At 60 min after all water loads, there were no differences in plasma VP or plasma or urinary osmolality. Variability in the length of time of similarly reduced urine osmolality and increased free water excretion accounted for the increased urine flow during day compared to night (P < 0.05) at 120 and 150 min after the water load. The ability to excrete a water load both day (free water clear-ance, P < 0.05 at 60 min post-drink) and night (free water clearance, P < 0.05 at 60, 90, and 120 min post-drink) at 31 atm abs was enhanced. It is concluded that maintained water intake at hyperbaria is necessary to maintain water balance because there is a reduced ability of the body through renal mechanisms to retain a water load.

Changes in muscle sympathetic nerve activity and renal function during positive-pressure breathing in humans.

The possibility that the decreased urinary flow during continuous positive-pressure breathing (CPPB) may be a consequence of a reflex mediated via the cardiopulmonary baroreceptors to increase neurohumoral secretion or to change the sympathetic outflow was assessed. Muscle sympathetic nerve activity (MSNA) on the right peroneal nerve, vasoactive hormones, and renal and cardiovascular responses were measured during CPPB (+12 mmHg) in 10 male subjects (22.0 +/- 0.6 yr, 66.8 +/- 1.5 kg body wt). The experiments consisted of a 1-h control, 1 h with CPPB (experimental) or without CPPB (a time control), and a 1-h recovery period. Two blood samples were taken during each period for measurements of arginine vasopressin (AVP), plasma aldosterone (PAldo), plasma renin activity (PRA), norepinephrine, and atrial natriuretic peptide (ANP), and urine was collected hourly for the measurement of urine volume and electrolytes and clearances. MSNA rapidly increased (P < 0.05) at the onset of CPPB, continued to increase during exposure, and rapidly returned to the normal level at recovery. The MSNA changes coincided with increased plasma NE and were concurrent with a reduced (P < 0.05) urine output associated with a reduction of both free water and osmolal clearances, Na+ and osmolal excretions, and creatinine clearance (glomerular filtration rate). AVP and PRA increased (P < 0.05), whereas PAldo and ANP were unchanged. The results are consistent with the concept that increased sympathetic outflow may play a role in the reduction of urinary output and Na+ excretion during unloading of the cardiopulmonary receptors.

Technique for placement of chronic third cerebroventricular cannula in female goats (Capra hircus).

A practical method for chronic catheterization of the third cerebroventricular space in goats was developed by using a stereotaxic device. In female goats of various ages and weights, a stereotaxically mounted drill was positioned at an angle of 11.5 degrees with the tip of the drill bit located at a skull reference point 2 to 3 mm rostral to the posterior border of Bregma (intersection of the coronal with the sagittal sutures). The hole that was drilled served as the guide for a tight-fitting cannula, which was 20-gauge stainless steel with a stylet. The cannula was advanced by hand to a depth of approximately 40 mm from the top of the skull, positioning the cannula tip in the anterior region of the third ventricle anterior to the massa intermedia. Copious flow of cerebrospinal fluid verified appropriate positioning. The cannula was anchored with dental acrylic and a subcutaneous port system attached via plastic tubing. Cannula placement was assessed after surgery by use of fluoroventriculography. Cannula patency was maintained for 23 months. Minimal complications were seen, maintenance was minimal, and animals were allowed complete freedom of movement with no requirement for jackets or wraps and were used in several consecutive studies. No anesthetic complications were noticed.

Metabolism of neurohypophysial hormones.

Over the past decade several new routes of neurohypophysial hormone metabolism have been identified. These include nonhepatic splanchnic clearance and renal clearance in addition to filtration that appears to be receptor mediated. The intraluminal degradation of VP in the proximal tubule, and distal tubular secretion, at least in one species, has been identified. The brain has been identified as a site for VP and OT metabolism, and the amniotic sac may be a major site for VP clearance in the guinea pig fetus. There have been generalized findings regarding VP and OT metabolism. First, VP metabolism in the whole body and in the amniotic sac appears to increase with increasing concentrations of hormone; this does not appear to be the case with OT. Also, evidence has been presented that suggests a potential for the formation of biologically active metabolites. There have been several associations of pathophysiological states with altered VP or OT metabolism, sometimes with plasma levels remaining unchanged. Lastly, caution is emphasized when measuring these hormones by RIA, and differences in specificities of antisera toward hormone metabolites must be considered.

Hypoxia attenuates the renin response to hemorrhage.

We studied hypoxia and hypotensive hemorrhage in conscious female goats. After control, goats continued an experimental period in normoxia or hypoxia [fractional inspired oxygen concentration (FIO2) = 0.10] for 120 min. After 60 min in the experimental period, a hemorrhage (0.5 ml.kg-1.min-1 for 30 min) was initiated (normoxic hemorrhage, NH; hypoxic hemorrhage, HH). Heart rate (HR) increased 51 +/- 18 beats/min with NH after 30 min of hemorrhage. HR increased 40 +/- 10 beats/min after hypoxic gas introduction, with no further increase during HH. Mean arterial blood pressure (MABP) was reduced 23 +/- 7 mmHg 30 min after completion of blood loss with normoxia but was reduced 23 +/- 7 mmHg at 20 min of HH. Arginine vasopressin (AVP) was increased to 2.60 +/- 2.08 and 160.40 +/- 49.74 microU/ml after 10 and 20 min of HH, respectively, and was only increased after 30 min (87.33 +/- 67.18 microU/ml) of NH. Unexpectedly, plasma renin activity (PRA) increased in parallel in both groups and was doubled at 30 min of hemorrhage. Atrial natriuretic factor was reduced to 8.8 +/- 1.6 pg/ml by 10 min of NH and to 11.4 +/- 3.3 pg/ml at 30 min of HH. Thus hypoxia leads to an earlier development of hypotension and increase in AVP with blood loss but may attenuate the PRA response to blood pressure reduction.

Renal responses during a dry saturation dive to 450 msw.

Four subjects were compressed to a simulated depth of 450 msw (46 bar) for 37 days in the main research chamber of the German underwater simulator diving facility at the GKSS Research Center, Geesthacht. The ambient gas was trimix. Urine was collected at 0700, 1300, and 1900 h each day for analysis of Na+, K+, volume, osmolality, and creatinine. Urine, antidiuretic hormone (ADH), and aldosterone were analyzed separately. Daily fluid, Na+, and K+ intake were analyzed throughout the dive. The aim of the investigation was to confirm the existence of a diuresis and natriuresis which had been observed in earlier saturation dives to 31 atm abs using He-O2. A significant diuresis was observed during compression despite a decrease in fluid intake. After compression the diuresis decreased somewhat but remained significantly above precompression control levels during the entire hyperbaric exposure. No significant change in fluid intake was observed. Daily Na+ and K+ excretion increased significantly during compression, which was accompanied by a significant increase in nocturnal excretion of Na+ and K+. Daily intake of Na+ and K+ decreased throughout the dive. Daily urine ADH decreased immediately upon compression and was associated with a parallel decrease in urine osmolality. In contrast, urinary aldosterone excretion exhibited no change during the dive despite the increase in Na+ and K+ excretion and decrease in Na+ intake.

Urinary vasopressin and aldosterone and plasma volume during a saturation dive to 450 m.

Urinary vasopressin (VP), aldosterone (ALDO), osmotic substances, sodium excretion, and plasma volume were assessed in 4 healthy male divers during 2 predive control days, 2 compression days, 6 days at 46 atm abs, and 26 days of decompression with stops at 37 and 27 atm abs. At pressure the ambient gas was trimix (0.5 atm abs O2:5% N2:remainder He). All urine was collected throughout the dive. Samples were divided into daytime (0700-1900) and nighttime (1900-0700). Indocyanine green dye dilution was used to determine plasma volume at predive 1, 46, and 24 atm abs. In agreement with previous dives at 31 atm abs, there was a decrease in VP excretion during compression lasting until return to 1 atm abs (P less than 0.05). Also similar to the shallower dives at 31 atm abs, the normal diurnal pattern of VP excretion, daytime higher than nighttime (P less than 0.05), disappeared at pressure. Urine osmolality showed alterations compatible with responses to VP. In contrast to previous studies at 31 atm abs, but in agreement with a previous study at 49.5 atm abs, there was no sustained increase in urinary ALDO excretion and only a transient natriuresis during the compression phase, followed by a reduced sodium excretion. In confirmation of earlier conclusions from indirect evidence, direct measurements of plasma volume indicated a reduction of about 20% (P less than 0.05) at 46 atm abs which remained reduced after decompression to 24 atm abs.

Effect of inspiratory-phase negative pressure breathing on urine flow in man.

We investigated the effect of negative pressure breathing during the inspiratory phase only (intermittent NPB) in 9 healthy male subjects who were in a sitting position and had no food or fluid intake for 12 h before the study. Intermittent NPB was without effect on urine flow and urinary sodium excretion but caused a significant increase in creatinine clearance. Plasma renin activity was significantly reduced, whereas plasma antidiuretic hormone (ADH), atrial natriuretic factor (ANF), and aldosterone levels were unaffected. To determine whether the blunted urinary response to intermittent NPB was a postural phenomenon, the study was repeated in 6 of the subjects while supine. Under these conditions there was a significant increase in urine flow and plasma ANF levels, but no change in all other measured variables. These results are consistent with a role for ANF, but not ADH, in the diuresis seen in supine subjects during NPB.

Comparative effects of Des Leu Angiotensin I and Angiotensin II on AVP secretion from the hypothalamoneurohypophysis and pituitary of the rat.

In the present study we compared the effects of Des Leu Angiotensin I (Des Leu AI) with Angiotensin II (AII) on the secretion of vasopressin (AVP) from the isolated hypothalamoneurohypophyseal system (HNS) and isolated posterior pituitary gland of the rat. Administration of 10(-6)M, 10(-5) M and 10(-4) M Des Leu AI was without significant effect on AVP secretion from the HNS. A similar phenomenon was seen in the posterior pituitary with 10(-6) M and 10(-5) M Des Leu AI, although 10(-4) M significantly increased AVP release. Administration of 10(-6) M AII was without significant effect in either preparation, although 10(-5) M and 10(-4) M AII caused significant dose-dependent increases in AVP secretion over control release that were similar in both the HNS and posterior pituitary gland. These results suggest that Des Leu AI is not a physiologically relevant stimulus of AVP secretion when restricted to this area of the rat brain. They are also consistent with the presence of receptors sensitive to AII in the pituitary gland of the rat.

Big ANF: large-molecular-weight ANF in rabbit plasma. II. Acid dissociation and HPLC of dissociated irANF.

A large-molecular-weight form of atrial natriuretic factor (ANF) was found in rabbit plasma. When extraction of plasma utilizing octadecylsilane cartridges is employed, this big ANF is not retained by the cartridge. When this material is dissociated with acid, immunoreactive ANF (irANF) is released. Of the acids tested, formic and acetic acid (0.05 M) were indicated as the most effective in causing the dissociation. High-performance liquid chromatography analysis of dissociated ANF, confirmed by coelution with synthetic peptides, disclosed the presence of ANF-(99-126) and ANF-(103-126) in a ratio of approximately 2:1. Atriopeptin I was detected in most of the samples analyzed, but atriopeptin II was only detected in one analysis. Despite the wide spectrum of the antiserum used for detection of irANF in the eluent fractions, only immunoreactive peaks coeluting with the four standards were detected. We therefore conclude that big ANF is a bound form of atrial peptides found in normal circulation.

Effect of V2 antagonist on clearance of arginine vasopressin by isolated perfused rat kidneys.

Isolated rat kidneys were perfused with Krebs-Henseleit-bovine serum albumin solution at a mean pressure of 99 +/- 2.6 mmHg. After control periods, arginine vasopressin (AVP) was added to the perfusate at a final calculated concentration of 25 pg/ml (2.5 x 10(-11) M). Urine and perfusate samples were collected at 15-min intervals for the following 60 min to measure kidney function and the renal clearance of immunoreactive AVP (irAVP). At 15-30 min after the addition of AVP, total renal clearance of irAVP was 1,623 +/- 190 microliters.min-1.g kidney wt-1. Glomerular filtration accounted for 35 +/- 3.0% of the total clearance, and 65 +/- 10.3% was cleared by peritubular pathways. Of the filtered irAVP, 48 +/- 4.8% was recovered in the urine. To investigate the importance of V2 receptors in the metabolism of AVP, clearance measurements were made in the presence of the V2 antagonist [d(CH2)5,D-Ile2,Ile4,Arg8]AVP (5 x 10(-9) M). Total renal clearance of irAVP was reduced by 48% to 848 +/- 79 microliters.min-1.g-1. This reduction was entirely accounted for by the complete inhibition of peritubular clearance of irAVP. In the presence of the V2 antagonist, irAVP was cleared only by filtration. The proportion of filtered AVP recovered in the urine (53 +/- 8.7%) was not significantly altered by the presence of the V2 antagonist. We conclude that a major component of the renal clearance of AVP depends on receptor-mediated uptake of AVP in the kidney cells.