The effects of acetazolamide and spironolactone on the body water distribution of rabbits during acute exposure to simulated altitude

The role of body water metabolism on acute altitude exposure was studied. The studies were carried out in rabbits divided into four groups, namely, (i) control, (ii) exposed to acute hypoxia, (iii) exposed to acute hypoxia after treatment with 250 mg acetazolamide and (iv) exposed to acute hypoxia after treatment with 25 mg spironolactone. Total body water, extracellular water, intracellular water and blood volume decreased by an insignificant amount on exposure to hypoxia and plasma volume decreased by 5.7% (P<0.025). Treatment with either acetazolamide or spironolactone resulted in further marginal decrease in total body water. In the case of acetazolamide, the loss occurs from both intracellular and extracellular compartments, while treatment with spironolactone resulted in significant loss only from extracellular compartment. Treatment with both the drugs resulted in a small rise in pO₂ and pCO₂ with a slight decrease in pH. Our data suggested spironolactone to be a better prophylactic agent for use on acute high altitude induction.     

Tissue weights and adaptation response of the toad after 96 hours of exposure to simulated high altitude — A body fluid and hematological study

Adult male toads were exposed to simulated high altitude of 24,000 feet for 96 hrs of continuous exposure in a decompression chamber. The animals were sacrificed immediately after the exposure period. Significant increase of the weight of the ventricle and spleen is observed in altitude exposed animals. Red blood cell, hemoglobin concentration, hematocrit ratio and red cell mass are significantly increased in high altitude exposed animals in comparison to control. MCV (mean corpuscular volume) and MCH (mean corpuscular hemoglobin) are decreased in altitude exposed group. Plasma volume, blood volume, extracellular fluid volume, intracellular fluid volume and total body water are decreased significantly after altitude exposure for 96 hrs. These physiological changes are thought to be due to dehydration of this animal at simulated high altitude and it is highly affected after 96 hrs of exposure as evidenced by the significant reduction of total body water and intracellular fluid volume.     

Variations in skinfold thickness during de-acclimatisation and re-acclimatisation to high altitude. Relation to body fat content

Skinfold thickness, body weight, body water, anthropometric measurements and segment volumes were determined in 28 young and healthy Indian soldiers on return to Delhi (200 m) after staying for more than 24 months at high altitude (3500 m). The measurements were made on the 2nd day and after 3 weeks. Ten subjects were then randomly selected from this group and returned by air to the high-altitude station, and the measurements were repeated on the 3rd and 12th day of their reinduction. Though body weight and total body water increased marginally on transfer to the lower altitude, body density remained more or less unchanged. There were significant increases in the thickness of skinfolds, even when body density had increased. During this period hand and foot volumes decreased significantly. Despite significant increases in thoracic skinfold thickness, the torso volume decreased slightly. On returning to high altitude, the soldiers lost body weight, were hypohydrated and showed reduced skinfold thickness. Fat losses calculated on the basis of reduction in skinfold thickness were far in excess of those calculated from losses in body weight and in total body water. As the reduced skinfold thickness was unrelated to changes in body water content at high altitude, it seems that such reductions are due to redistribution of blood in the skin. From the results of these investigations it is concluded that variations in skinfold thickness during acclimatisation to high altitude do not accurately represent the changes in body fat content.     

Comparative study of acetazolamide and spironolactone on body fluid compartments on induction to high altitude

Studies were conducted on 29 male healthy subjects having no previous experience of living at high altitude. These subjects were divided into three groups, i.e., subjects treated with placebo, acetazolamide and spironolactone. These subjects were first studied in Delhi. The drug schedule was started 24 hour prior to the airlift of these subjects to an altitude of 3,500 m and was continued for 48 hour after arrival at high altitude. Total body water, extra cellular water, plasma volume, blood electrolytes, pH, pO₂, pCO₂ and blood viscosity were determined on 3rd and 12th day of their stay at high altitude. Total body water, extra cellular water intracellular water and plasma volume decreased on high altitude exposure. There was a further slight decrease in these compartments with acetazolamide and spironolactone. It was also observed that spironolactone drives out more water from the extracellular compartment. Loss of plasma water was also confirmed by increased plasma osmolality. Increase in arterial blood pH was noticed on hypoxic exposure but the increase was found less in acetazolamide and spironolactone cases. This decrease in pH is expected to result in better oxygen delivery to the tissues at the low oxygen tension. It was also confirmed because blood pO₂ increased in both the groups. No significant change in plasma electrolytes was observed in subjects of various groups. Blood viscosity slightly increased on exposure to high altitude. The degree of rise was found less in the group treated with spironolactone. This study suggests that both the drugs are likely to be beneficial in ameliorating/prevention of AMS syndrome.     

Changes in body fluid compartments on re-induction to high altitude and effect of diuretics

Studies were carried out in 29 healthy young adults in the Indian Army stationed in the plains and posted at an elevation of 3500 m for more than 6 months. After exposure to a low elevation in Delhi (260 m) for 3 weeks they were reinduced to a height of 3500 m. The subjects were divided into three groups, each of which was treated with either placebo or acetazolamide or spironolactone. The drug treatment was started immediately after their landing at high altitude and continued for 2 days only. Total body water, extracellular fluid, intracellular fluid, plasma volume, blood pH, PaO₂, PaCO₂ and blood viscosity were determined on exposure at Delhi and on re-induction to high altitude. Plasma volume was increased after the descent from high altitude and remained high for up to 21 day's study. This increased plasma volume may have some significance in the pathogenesis of pulmonary oedema. Total body water and intracellular fluid content were increased at 260 m elevation, while extracellular fluid decreased. On re-induction there was a decrease in total body water with no change in the extracellular fluid content.This paper was presented in part at the 17th annual conference of the Society of Nuclear Medicine, India held at Bangalore, January 2–4, 1986     

Glucoregulatory hormones in man at high altitude

Concentrations of glucose, lactic acid, free fatty acid (FFA), insulin, cortisol and growth hormone (GH) in the blood were monitored in 15 euglycaemic men (sojourners, SJ) at sea level (SL) and while at altitudes of 3500 m and 5080 m, in acclimatised low landers (ALL) and in high altitude natives (HAN). In SJ, blood glucose and insulin concentrations showed a significant increase on the 3rd and 7th day after arrival at high altitude (HA), thereafter returning to sea level values and remaining the same during the entire period of their stay at 3500 m. Subsequently, on arrival at higher altitude (5080 m) the glucose concentrations again showed an increase over the preceding values and returned to SL values on day 41 while at 5080 m. A significant increase in cortisol concentrations was seen on day 3 after arrival at HA and the increased levels were maintained until day 21 at 3500 m. The cortisol concentrations on day 30 after arrival at 5080 m came down to SL values and remained unchanged thereafter. No appreciable change in GH and FFA was seen during the sojourn at HA. On the other hand, blood lactic acid concentration decreased significantly. There was no difference between the fasting glucose concentrations in ALL at 3500 m and in HAN at 3500 m and 4200 m compared to values of SJ at SL, whereas ALL at 4200 m had higher glucose values. Concentrations of plasma insulin and GH in ALL and HAN were higher than the values of SJ at SL, whereas cortisol values did not show any difference. These observations indicated that at HA the glucose values were high for the insulin concentration observed and might have been due to increased secretion of GH by the pituitary gland.     

Fluid distribution and tissue thickness changes in 29 men during 1 week at moderate altitude (2,315 m)

To quantify fluid distribution at a moderate altitude (2,315 m) 29 male subjects were studied with respect to tissue thickness changes [front (forehead), sternum, tibia], changes of total body water, changes of plasma volume, total protein concentrations (TPC), colloid osmotic pressure (COP), and electrolytes. Tissue thickness at the forehead showed a significant increase from 4.14 mm to 4.41 mm 48 h after ascent to the Rudolfshuette (2,315 m) (P < 0.05). At 96 h after ascent the tissue thickness at the tibia was decreased to 1.33 mm compared to the control value of 1.59 mm (P < 0.01). Body mass increased from 75.5 kg (control) to 76.2 kg on the last day (P < 0.05) and body water from 44.21 to 45.01 during the week (P < 0.01). The accumulation fluid in the upper part of the body was paralleled by a decrease in TPC and COP. At 48 h after the ascent COP dropped from 29.5 mmHg to 27.5 mmHg (P < 0.01). After 96 h at moderate altitude COP was still significantly decreased compared to the control level. At 1.5 h after the return from the Rudolfshuette in Saalfelden (744m) COP was back to the control values. The TPC also showed an initial drop from 7.75 g · dl^–1 to 7.48 g · dl^–1 after 48 h at altitude and remained below the control value during the whole week (P < 0.01). It seems from our study that even with exposure to moderate altitude measurable fluid shifts to the upper part of the body occurred which were detected by our ultrasound method.     

The effect of inhibitors of prostaglandin synthesis on hematocrits of mice

Four experiments were performed to evaluate the effects of nonsteroidal anti-inflammatory drugs (NSAID) on hematocrit of mice. Indomethacin (experiment I) and meclofenamic acid (experiment II) reduced (P<.01) the hematocrit by the fourth day of treatment. Following withdrawal of the drug, hematocrit values rose (P<.01) but the degree of recovery four days after withdrawal was dependent on the dose of drug administered. Decreased hematocrit values were accompanied by a decrease (P<.01) in the number of red blood cells per unit volume of blood. However, there were no significant changes in white blood cell numbers (experiment III). Replacement therapy (experiment IV) with PGE₂ partially reversed (P<.01) the effect of indomethacin on hematocrit, but PGF₂α was without effect. The results of these studies indicate that inhibitors of prostaglandin synthesis decreased hematocrit by increasing plasma volume.     

Body fluid status on induction,reinduction and prolonged stay at high altitude of human volunteers

Studies on adaptation to high altitude (HA) of 3500 m in the Himalayas were conducted in three phases, each including 10 normal and healthy males normally resident at sea-level. Phase I subjects had no previous experience of HA, phase II subjects after 4–6 months at HA were airlifted to sea-level and phase III subjects stayed continuously for 6 months at 3500 m. Body fluid compartments and blood gases were determined in all three groups. Plasma volume was highly elevated in the phase II subjects on reinduction to sea-level from HA. In comparison to phase I subjects, the retention of fluid in extracellular compartment was increased at HA leading to increased susceptibility to high altitude illness. Phase III subjects were hyperhydrated with decreased plasma volume and increased PO₂ in comparison to the other two groups.     

Estimates of body water content in normally grown baboons during the first postnatal month

Water contents of various body compartments were estimated within 9 h of birth in eight baboon neonates and at a mean of 29 days (27-32 days) in seven baboons. All animals were normally grown and delivered spontaneously at term. There was no difference in mean antipyrine space, corrected bromide space, intracellular water, interstitial water, and plasma and blood volumes observed on day 1 and day 29. Mean estimate of red cell volume was lower on day 29 than on day 1.     

Effect of saline acclimation on body water and sodium compartmentalization in Pekin ducks (Anas platyrhynchos)

The compartmentalization of body fluids was measured in individual Pekin ducks ( Anas platyrhynchos) drinking freshwater and after sequential acclimation to 300 mM NaCl and 400 mM NaCl. Total body water, extracellular fluid volume, plasma volume and exchangeable sodium pool were measured using (3)H(2)O, [(14)C]-polyethylene glycol, Evans Blue dye, and (22)Na dilution, respectively. Following acclimation to 300 mM NaCl, body mass decreased, but total body water and total exchangeable sodium pool were unaltered. Na and water were redistributed from the extracellular fluid (interstitial fluid) compartment into the intracellular fluid compartment. Following further acclimation to 400 mM NaCl, body mass, total body water and intracellular fluid volume decreased, but exchangeable sodium pool and extracellular fluid volume were unchanged. Our results suggested that, when Pekin ducks drink high but tolerable salinities, they maintain total body water, but redistribute Na(+) and water from interstitial fluid to the intracellular fluid compartment. When stressed beyond their ability to maintain total body water, they lose water from the intracellular fluid.     

Serial estimates of body water content and distribution during the first postnatal month in baboons

Water content of the various body compartments was estimated serially during the first postnatal month in six term baboon neonates. In absolute volumes (mL), total body water, intracellular water, and plasma volume all increased linearly with body weight and postnatal age, although the effect of weight was predominant. In proportion to body weight (mL/kg), total body water, intracellular water, and plasma volume increased linearly with postnatal age whereas extracellular water and red cell volume decreased. There was no linear relation between the proportions of any of the water volumes and body weight.     

The secretion and metabolic clearance rates of growth hormone,insulin and prolactin in high- and low-yielding cattle at four stages of lactation

The basal plasma concentration, secretion rate (SR), distribution space (DS) and metabolic clearance rate (MCR) of GH, insulin and prolactin were measured in groups of 4 high- (HY) and 4 low-yielding (LY) cows at around 30, 90 and 150 days of lactation and after the cattle had been dried off. The kinetic parameters were determined using the single injection technique and measuring the disappearance of each hormone from the plasma by radioimmunoassay. Throughout lactation the DS for GH was higher in the HY cows (P<0.01) falling significantly in both groups when they were dry (HY, P<0.001; LY, P<0.01). There was no difference between the lactating group in the MCR of GH, but in both there was a significant (P<0.001) drop in the dry period which was accompanied by a fall in the SR (P<0.05). No differences were found in the DS and MCR of insulin between the groups during lactation but the average SR of insulin in the LY group was more than twice that in the HY group (P<0.05). Overall differences between stages of lactation were found in both groups for the SR (P<0.05), DS (P<0.01) and MCR (P<0.001) of insulin. None of the kinetic parameters differed for prolactin in the two groups. The DS (P<0.05) and MCR (P<0.001) of prolactin increased from day 30 to day 150 of lactation in both groups and then fell significantly (DS, P<0.05; MCR, P<0.01) when the animals were dry. In both groups the SR (P<0.01) and basal plasma concentration (P<0.01) of prolactin were higher in the dry period than at 30 and 90 days of lactation; probably due to the influence of season on the hormone.     

Carbonic anhydrase activity in the red blood cells of sea level and high altitude natives

Red blood cell carbonic anhydrase (CA) activity has not been studied in high altitude natives. Because CA is an intraerythocytic enzyme and high altitude natives are polycythemic, it is important to know if the activity of CA per red cell volume is different from that of their sea level counterparts. Blood was collected from healthy subjects living in Lima (150m) and from twelve subjects from Cerro de Pasco (4330m), and hematocrit and carbonic anhydrase activity were measured. As expected, the high altitude natives had significantly higher hematocrits than the sea level controls (p = 0.0002). No difference in the CA activity per milliliter of red cells was found between the two populations. There was no correlation between the hematocrit and CA activity.     

Distribution of body fluid and change of blood viscosity in broilers (Gallus domesticus) under high temperature exposure

This study was to observe the distribution of body fluid by measuring blood volume, extracellular and intracellular fluid volumes and total body water under heat exposure, in order to clarify the mechanism of decrease in whole blood viscosity of the heat-exposed broilers. Whole blood viscosity, haematocrit, plasma protein concentration, plasma osmolality and extracellular fluid volume decreased during high temperature exposure, while plasma and blood volumes increased. No significant changes were found in both intracellular fluid volume and total body water between thermoneutral and high temperature exposure. These results indicate the decreased whole blood viscosity is induced by a plasma volume expansion, in which water may come from the interstitial space and alimentary tract, under heat exposure.     

Developmental,genetic, and environmental components of aerobic capacity at high altitude

The aerobic capacity of 268 subjects (158 males and 110 females) was evaluated in La Paz, Bolivia situated at 3,750 m. The sample included 1) 39 high altitude rural natives (all male); 2) 67 high altitude urban natives (32 male, 35 female); 3) 69 Bolivians of foreign ancestry acclimatized to high altitude since birth (37 male, 32 female); 4) 50 Bolivians of foreign ancestry acclimatized to high altitude during growth (25 male, 25 female); and 5) 43 non-Bolivians of either European or North American ancestry acclimatized to high altitude during adulthood (25 male, 18 female). Data analyses indicate that 1) high altitude urban natives, acclimatized to high altitude since birth or during growth, attained higher aerobic capacity than subjects acclimatized to high altitude during adulthood; 2) age at arrival to high altitude is inversely related to maximum oxygen consumption (V?O² max) expressed in terms L/min or ml/min/kg of lean body mass, but not in terms of ml/min/kg of body weight; 3) among subjects acclimatized to high altitude during growth, approximately 25% of the variability in aerobic capacity can be explained by developmental factors; 4) as inferred from evaluations of skin color reflectance and sibling similarities, approximately 20 to 25% of the variability in aerobic capacity at high altitude can be explained by genetic factors; 5) except among the non-Bolivians acclimatized to high altitude during adulthood, the aerobic capacity of individuals with high occupational activity level is equal to the aerobic capacity of high altitude rural natives; and 6) the relationship between occupational activity level and aerobic capacity is much greater among subjects acclimatized to high altitude before the age of 10 years than afterwards. Together these data suggest that the attainment of normal aerobic capacity at high altitude is related to both developmental acclimatization and genetic factors but its expression is highly mediated by environmental factors, such as occupational activity level and body composition. © 1995 Wiley-Liss, Inc.     

Inhibition of prostaglandin synthesis and contractility in the rabbit and rat uterus by ibuprofen

Sixty uterine strips were excised from 8 pregnant and 7 post partum rabbits andstimulated electrically in vitro until they developed maximum isometric tension. The non-steroidal anti-inflammatory agent, Ibuprofen, at concentrations of 125, 250 and 500 μg/ml, signidicantly reduced tension of the 55 experimental uteri (P<0.001) within 7.5 minutes, in comaparison with the pretreatment value. Tension in 15 solvent-treated controls remained stable during the same observation period. The reduction in tension was greater in the post partum than the pregnant uteri (P<0.05). Sixteen additional uterine strips, excised from 4 preganant and 4 post partum rabbits were treated either with 500 μg Ibuprofen or solvent for 7.5 minutes. Radioimmunoassay showed that Ibuprofen significantly reduced the uterine levels of PGE (P<0.001) and PGE (P<0.001 post partum; P<0.05 pregnant) and again the effect was greater in the post partum unteri. These findings suggest that the suppression of uterine function by Ibuprofen is mediated by inhibition of PG-synthesis.In a subsequent study, 36 rats were treated with Ibuprofen on days 20 and 21 of pregnancy, at the ineffective dose level of 4 mg/day and the effective levels of 12, 20 and 30 mg/day, In comparison with the first group. Spontaneous labor was significantly delayed in the other three groups (P<0.05, P<0.01 and P<0.001, respectively). In addition, 7 rats were treated with 30 mg/day Ibuprofen and 7 with solvent on days 19 and 20 of pregnancy. In day 21, the Ibuprofen-treated rats showed a significant (P<0.001) reduction in the uterine PGF and PGE concentrations, indicating that the prolongation of pregnancy is mediated by an inhibition of uterine PG-synthesis.     

Hormonal and electrolyte response to exposure to 17,500 ft.

Hormone, electrolyte, and body fluid compartment changes were studied in subjects who either spent time at 10,000 ft before flying to 17,500 ft or were premedicated with acetazolamide and flown directly to 17,500 ft. In the former group, at 10,000 ft, renin and aldosterone were not different from control. Cortisol increased significantly from 9.8 to 19.5 mug/100 ml on the third day. At 17,500 ft, renin, aldosterone and cortisol were significantly elevated on day 3 but had returned to control levels by day 5. Sodium and potassium excretion was significantly reduced at both altitudes. Total body water, extracellular and plasma volume were reduced (P less than 0.05) at 17,500 ft. Subjects pretreated with acetazolamide and flown directly to 17,500 ft had significant increases (P less than 0.001) in plasma renin, aldosterone, and cortisol levels during the first 4 days at altitude. On day 1 there was a decrease of 45% in sodium and 38% in potassium excretion. On day 4 there was a decrease of 63% and 51%, respectively. These changes are not associated with the premedication. The initial changes may reflect the immediate response to stress and alkalosis followed by a return to control levels as the body adapts to altitude.     

Increased dietary protein for lactating sows affects body composition,blood metabolites and milk production

Hyper-prolific sows nurse more piglets than less productive sows, putting a high demand on the nutrient supply for milk production. In addition, the high production level can increase mobilization from body tissues. The effect of increased dietary protein (104, 113, 121, 129, 139 and 150 g standardized ileal digestible (SID) CP/kg) on sow body composition, milk production and plasma metabolite concentrations was investigated from litter standardization (day 2) until weaning (day 24). Sow body composition was determined using the deuterium oxide dilution technique on days 3 and 24 postpartum. Blood samples were collected weekly, and milk samples were obtained on days 3, 10 and 17 of lactation. Litter average daily gain (ADG) peaked at 135 g SID CP/kg (P < 0.001). Sow BW and back fat loss reached a breakpoint at 143 and 127 g SID CP/kg (P < 0.001). Milk fat increased linearly with increasing dietary SID CP (P < 0.05), and milk lactose decreased until a breakpoint at 124 g SID CP/kg and 5.3% (P < 0.001) on day 17. The concentration of milk protein on day 17 increased until a breakpoint at 136 g SID CP/kg (5.0%; P < 0.001). The loss of body protein from day 3 until weaning decreased with increased dietary SID CP until it reached a breakpoint at 128 g SID CP/kg (P < 0.001). The body ash loss declined linearly with increasing dietary SID CP (P < 0.01), and the change in body fat was unaffected by dietary treatment (P=0.41). In early lactation (day 3 + day 10), plasma urea N (PUN) increased linearly after the breakpoint at 139 g SID CP/kg at a concentration of 3.8 mmol/l, and in late lactation (day 17 + day 24), PUN increased linearly after a breakpoint at 133 g SID CP/kg (P < 0.001) at a concentration of 4.5 mmol/l. In conclusion, the SID CP requirement for sows was estimated to 135 g/kg based on litter ADG, and this was supported by the breakpoints of other response variables within the interval 124 to 143 g/kg.     

Skeletal muscle changes after endurance training at high altitude.

The effects of endurance training on the skeletal muscle of rats have been studied at sea level and simulated high altitude (4,000 m). Male Wistar rats were randomly assigned to one of four groups: exercise at sea level, exercise at simulated high altitude, sedentary at sea level, and sedentary at high altitude (n = 8 in each group). Training consisted of swimming for 1 h/day in water at 36 degrees C for 14 wk. Training and exposure to a high-altitude environment produced a decrease in body weight (P less than 0.001). There was a significant linear correlation between muscle mass and body weight in the animals of all groups (r = 0.89, P less than 0.001). High-altitude training enhanced the percentage of type IIa fibers in the extensor digitorum longus muscle (EDL, P less than 0.05) and deep portions of the plantaris muscle (dPLA, P less than 0.01). High-altitude training also increased the percentage of type IIab fibers in fast-twitch muscles. These muscles showed marked metabolic adaptations: training increased the activity levels of enzymes involved in the citric acid cycle (citrate synthase, CS) and the beta-oxidation of fatty acids (3 hydroxyacyl CoA dehydrogenase, HAD). This increase occurred mainly at high altitude (36 and 31% for HAD in EDL and PLA muscles; 24 and 31% for CS in EDL and PLA muscles). Training increased the activity of enzymes involved in glucose phosphorylation (hexokinase). High-altitude training decreased lactate dehydrogenase activity. Endurance training performed at high altitude and sea level increased the isozyme 1-to-total lactate dehydrogenase activity ratio to the same extent.(ABSTRACT TRUNCATED AT 250 WORDS)