Dose Of Glycerol Research Articles

VLDL-triglyceride production after alcohol ingestion, studied using [2-13C1] glycerol

We used [2-13C1]glycerol to characterize very low density lipoprotein (VLDL)-triglyceride kinetics and intrahepatic glycerol metabolism in normal men (n = 4) after alcohol (EtOH) ingestion. [2-13C1]glycerol was infused before and after the consumption of 48 g EtOH or a placebo. Three additional subjects also received [1-13C1]acetate in addition to the [2-13C1]glycerol with EtOH treatment. Incorporation of tracer into the glycerol or fatty acid moiety of VLDL-triglyceride was measured by gas chromatography-mass spectrometry and used to calculate VLDL-triglyceride production rates. Intrahepatic triose-phosphate enrichments were also calculated based on mass isotopomer distribution analysis of plasma glucose. There was no difference in VLDL-triglyceride production rates after 48 g EtOH (11.9 +/- 3.7 mg/kg/h) or placebo (14.7 +/- 3. 3 mg/kg/h). The VLDL-triglyceride rate constants calculated by kinetic modeling using the glycerol and acetate tracers in the combined isotope infusion subjects were very closely correlated (r 2 = 0.94). The peak VLDL-glycerol enrichments after EtOH were 22.5 +/- 3.3% versus 7.6 +/- 0.8% after placebo (P < 0.001), while intrahepatic triose-phosphate enrichments were 19.8 +/- 1.3% and 13. 1 +/- 1.2% (P < 0.001), respectively. Moreover, the calculated asymptotic VLDL-glycerol enrichments (representing the hepatic alpha-glycerol phosphate enrichment) were significantly higher after EtOH than placebo. The higher ratio of VLDL-glycerol to triose-phosphate labeling after EtOH suggests a metabolic block at glycerol 3-phosphate dehydrogenase. We conclude that consumption of 48 g EtOH does not increase VLDL-triglyceride production in normal men but does cause accumulation of tracer in hepatic alpha-glycerol phosphate.

Chronic ethanol administration alters hepatic rates of glycerol phosphorylation and glycerol 3-phosphate oxidation: a dynamic in vivo 31P magnetic resonance spectroscopy study

We used dynamic in vivo 31P magnetic resonance spectroscopy to noninvasively study the metabolism of glycerol by the liver in living rats, as a means of detecting subtle metabolic changes induced by chronic ethanol consumption. Rats subjected to chronic ethanol consumption and their pair-fed controls were given a metabolic load of glycerol (0.75 or 1.3 mL glycerol·kg body mass-1, i.p. or i.v) under normoxic or hyperoxic (98% O2) conditions. Changes in the level of glycerol 3-phosphate were followed in situ by monitoring the hepatic 31P phosphomonoester resonance every 7 or 13 min for up to 330 min. When challenged with a large dose of glycerol, chronic ethanol-treated rats exhibited less accumulation of glycerol 3-phosphate than controls, independent of the route of administration of the glycerol or whether the two groups were fasted or fed. For example, 1.3 mL glycerol·kg-1 i.v. under normoxic conditions resulted in a two-fold increase in phosphomonoester in ethanol-treated rats compared with a five-fold increase in controls. The ethanol-treated rats also showed a slower rate of phosphorylation of glycerol and slower oxidation of glycerol 3-phosphate than controls, indicating decreased activities of the glycerol kinase and glycerol 3-phosphate dehydrogenase steps, and hence slower glycerol utilization. The rate of glycerol utilization was dose and oxygen concentration dependent. Kinetic analysis indicated that the chronic ethanol-induced decrease in the glycerol 3-phosphate dehydrogenase reaction was due to a decreased rate of NADH reoxidation in the liver, likely owing to a decrease in oxygen supply or utilization in the ethanol-treated rats. These observations support the hypothesis of pre-existing hypoxia in rat liver after chronic ethanol administration. This study demonstrates the utility of dynamic in vivo 31P magnetic resonance spectroscopy in following the metabolism of a glycerol load as a sensitive, nonperturbing, and potentially clinically applicable test of liver function.Key words: 31P magnetic resonance spectroscopy, ethanol, liver, glycerol, metabolism.

Chronic ethanol administration alters hepatic rates of glycerol phosphorylation and glycerol 3-phosphate oxidation: a dynamic in vivo 31P magnetic resonance spectroscopy study.

We used dynamic in vivo 31P magnetic resonance spectroscopy to noninvasively study the metabolism of glycerol by the liver in living rats, as a means of detecting subtle metabolic changes induced by chronic ethanol consumption. Rats subjected to chronic ethanol consumption and their pair-fed controls were given a metabolic load of glycerol (0.75 or 1.3 mL glycerol x kg body mass(-1), i.p. or i.v) under normoxic or hyperoxic (98% O2) conditions. Changes in the level of glycerol 3-phosphate were followed in situ by monitoring the hepatic 31P phosphomonoester resonance every 7 or 13 min for up to 330 min. When challenged with a large dose of glycerol, chronic ethanol-treated rats exhibited less accumulation of glycerol 3-phosphate than controls, independent of the route of administration of the glycerol or whether the two groups were fasted or fed. For example, 1.3 mL glycerol x kg(-1) i.v. under normoxic conditions resulted in a two-fold increase in phosphomonoester in ethanol-treated rats compared with a five-fold increase in controls. The ethanol-treated rats also showed a slower rate of phosphorylation of glycerol and slower oxidation of glycerol 3-phosphate than controls, indicating decreased activities of the glycerol kinase and glycerol 3-phosphate dehydrogenase steps, and hence slower glycerol utilization. The rate of glycerol utilization was dose and oxygen concentration dependent. Kinetic analysis indicated that the chronic ethanol-induced decrease in the glycerol 3-phosphate dehydrogenase reaction was due to a decreased rate of NADH reoxidation in the liver, likely owing to a decrease in oxygen supply or utilization in the ethanol-treated rats. These observations support the hypothesis of pre-existing hypoxia in rat liver after chronic ethanol administration. This study demonstrates the utility of dynamic in vivo 31P magnetic resonance spectroscopy in following the metabolism of a glycerol load as a sensitive, nonperturbing, and potentially clinically applicable test of liver function.

Antioxidants attenuate glycerol-endotoxin induced acute renal failure in rats

Sepsis sometimes occurs in traumatic rhabdomyolysis; however, the possibility that injection of endotoxin from Gram-negative bacteria may affect the severity of renal injury during rhabdomyolysis has not been directly examined. The aims of this study were: (i) to examine whether injection of glycerol, which causes rhabdomyolysis, simultaneously with a low dose of endotoxin will result in acute renal failure (ARF) in the rat; and (ii) whether this injury is due to the increased formation of free oxygen radicals. Therefore, a low dose of glycerol (0.375 ml/100 g), which does not cause acute renal failure, and endotoxin at a dose that does not cause renal injury (0.0375 mg/100 g) were simultaneously injected. The extent of renal injury was examined 24 h after the simultaneous injection of these two substances. The parameters measured included creatinine, BUN, urine volume, RPF, GFR, percent absorption of sodium and potassium as well as arterial blood pressure. In order to examine whether renal injury due to the combination of glycerol and endotoxin results from free oxygen radicals, DMTU (50 mg/100 g), SOD (8 mg/100 g) and vitamin E (2 mg/kg each day for 7 days) were injected. Acute renal failure was induced by the simultaneous injection of glycerol and endotoxin. Treatment with DMTU or vitamin E significantly reduced renal injury and returned the values of the measured parameters to their control values. The antioxidant SOD also reduced the renal injury; however, with this antioxidant the reduction was less pronounced and the measured parameters did not return to their control values. This study indicates that the severity of renal injury during rhabdomyolysis may increase if endotoxin is present in the body. Furthermore, this study indicates that this increased renal injury may be due to free oxygen radicals. Traumatic rhabdomyolysis is a frequent cause of ARF. Therefore, it is important to create an experimental model that will also include actual possibilities, such as sepsis, which have not been taken into consideration to date.

Heme protein-induced tubular cytoresistance: Expression at the plasma membrane level

Following experimental rhabdomyolysis, animals become resistant to heme protein-induced acute renal failure (ARF). The goals of this study were to: (a) ascertain whether this resistance, previously documented only in vivo, is expressed directly at the proximal tubular cell level; (b) determine whether heme proteinuria (vs. other consequences of rhabdomyolysis) is its trigger; and (c) ascertain some of its subcellular determinants. Rats were injected with a borderline toxic dose of glycerol and 24 hours later proximal tubular segments (PTS) were isolated for study. Their vulnerability to diverse forms of injury (FeSO4-induced oxidant stress, hypoxia, Ca2+ ionophore, cytochalasin D, PLA2) was compared to that found in normal PTS. Post-glycerol PTS manifested significant resistance to each insult (decreased lactate dehydrogenase +/- N-acetyl-beta-D-glucosaminidase release). Protection against FeSO4 was virtually complete and it was associated with a 50% decrease in membrane lipid peroxidation. No decrease in hydroxyl radical generation was noted during the FeSO4 challenge (salicylate trap assessment), suggesting a primary increase in membrane resistance to attack. That PLA2 addition caused less deacylation, plasma membrane enzyme (alanine aminopeptidase) release, and LDH leakage from post-glycerol versus normal tubules supported this hypothesis. To test whether cytoresistance was specifically triggered by heme proteins (vs. being a non-specific filtered protein effect, or a result of endotoxin cascade activation), rats were injected with purified myoglobin, non-heme containing filterable proteins, or endotoxin. Only myoglobin induced cytoresistance. In vivo heme oxygenase inhibition (tin-protoporphyrin) did not block the emergence of cytoresistance and it was expressed despite Na,K-ATPase inhibition (ouabain) or cytoskeletal disruption (cytochalasin D). In vivo heat shock failed to protect. In conclusion, (1) rhabdomyolysis induces broad based proximal tubular cytoresistance; (2) heme proteinuria is its trigger; and (3) it is most easily explained by a primary increase in plasma membrane resistance to attack.

Heme protein-mediated renal injury: A protective role for 21-aminosteroids in vitro and in vivo

21-aminosteroids ("lazaroids") have recently excited much interest by virtue of their ability to inhibit lipid peroxidation in vitro and to protect against neural injury in vivo. We tested the effect of these compounds in models of heme protein-mediated renal injury in vitro and in vivo. We devised an in vitro model of heme protein-induced toxicity in which renal epithelial cells were exposed to heme proteins for one hour, after which they were subjected to glutathione depletion by 1-chloro-2,4-dinitrobenzene (CDNB). This model was associated with more than a threefold increase in lipid peroxidation (as measured by thiobarbituric acid reactive substances, TBARS) and a marked reduction in cellular glutathione content. In this model, 21-aminosteroids virtually prevented cytotoxicity as measured by the 51-chromium release assay, and significantly reduced TBARS in a dose-dependent manner. Catalase was partially protective in this model, thereby indicating hydrogen peroxide-dependent toxicity. While pursuing mechanisms accounting for enhanced cellular generation of hydrogen peroxide, we uncovered the first direct evidence that the heme prosthetic group per se directly stimulates cellular generation of hydrogen peroxide; complementing these findings is the remarkable efficacy of 21-aminosteroids in protecting against cytotoxicity induced by hydrogen peroxide. We also tested the capacity of 21-aminosteroids to protect against heme protein-mediated renal injury in vivo. Prior administration of 21-aminosteroids attenuated reductions in GFR and renal blood flow rates following the systemic infusion of methemoglobin in normal rats. 21-aminosteroids also attenuated renal injury observed over three successive days in the glycerol model of heme protein-mediated injury when this model was induced at a higher dose of glycerol (8 ml/kg body wt) but not at a lower dose (5 ml/kg body wt). We conclude that 21-aminosteroids protect against heme protein-mediated renal injury in vitro and in vivo. We suggest that these compounds are potentially useful in such clinical conditions as rhabdomyolysis, intravascular hemolysis and renal injury associated with hemoglobin-based red blood cell substitutes.

Effects of changes in plasma volume on fatal rhabdomyolysis in the rat induced by glycerol injections.

Rhabdomyolysis can be fatal in both experimental animals and man, but very little is known of the factors causing increased mortality in rhabdomyolysis. The aims of this study were to create an animal model of fatal rhabdomyolysis in rats by a glycerol injection into the leg muscle, and to elucidate some of the factors affecting mortality as a result of rhabdomyolysis formation. In this study, two factors which can result in increased mortality in rats as a result of glycerol injection, were examined. These factors include varying doses of 50% glycerol (0.5-2 ml/100 g) and various stages of dehydration prior to glycerol injection. Dehydration was induced by 1: chronic dehydration, in which the rats underwent water deprivation for a period of 24 to 72 hours prior to injection of glycerol; 2: acute dehydration, by the induction of either diuresis, by injecting sucrose (200-600 mg/100 g) to the femoral vein, or hemorrhage (0.7-2.1 ml/100 g). The results demonstrate that the mortality rate in rats increased in all three models of dehydration as the dose of glycerol injected to the rats increased (above a dose of 0.75 ml/100 g) and as the extent of dehydration increased. Use of a blood substitute before or after glycerol injection in order to compensate for the loss of body fluids did not increase the survival rate of the glycerol-injected rats. In contradistinction, rats treated with non-lethal doses of glycerol exhibited substantial resistance to a second lethal dose of glycerol, injected two weeks following the first injection.

The effect of glycerol on the guinea-pig hydropic ear

The aim of this paper was to investigate the effect of glycerol on experimental endolymphatic hydrops in guinea-pigs. The right endolymphatic sac and duct were obliterated through an extradural posterior fossa approach. Some animals received a 3 g/kg dose of glycerol for a period of 7 days, whereas others received the same dose for 30 days. The activity of glycerol was studied by investigating the volumetric changes in the scala media determined with a computerized planimeter. Glycerol induced a significant reduction of the hydrops showing its effectiveness and suggesting a strial metabolic response.

Evidence for a major role of inhibin in the feedback control of FSH in the male rat

Adult rats (16-18/group) received a single intratesticular injection of 25, 100 or 400 microliters glycerol solution (7:3 in distilled water, v/v). Half of the rats in each group were given implants of testosterone, a testosterone-filled Silastic capsule (1.5 cm length) to provide serum values of testosterone within the normal range. After 1 week all animals were killed by decapitation. Serum concentrations of gonadotrophins, testosterone and immunoactive inhibin as well as testicular concentrations of testosterone and bioactive inhibin were determined. Testicular histology was studied in Paraplast-embedded tissue stained with PAS and haematoxylin-eosin. Glycerol treatment caused a dose-dependent ablation of spermatogenesis in a distinct area around the site of injection. Serum concentrations of FSH increased proportionally with increasing spermatogenic damage while serum LH and testosterone remained unaltered except with the highest glycerol dose. The rise in serum FSH was significantly correlated with serum (r = -0.70, P less than 0.001) and testicular (r = -0.66, P less than 0.001) concentrations of inhibin. A less pronounced correlation was found between LH and serum inhibin (r = 0.48). No correlation was found between the concentrations of LH and testicular inhibin or between serum concentrations of FSH and serum testosterone in the 25 and 100 microliters groups. Maintenance of low to normal serum testosterone concentrations by means of Silastic implants blocked the elevation of FSH in glycerol-treated animals but failed to affect significantly serum FSH in untreated rats. In all testosterone treated rats testicular inhibin concentrations were markedly reduced in the presence of lowered concentrations (7-14%) of testicular testosterone and unaltered serum FSH concentrations.

Electrocochleographic Changes Induced by Glycerol Administration in Hydropic Guinea Pigs

Glycerol is known to improve hearing acuity in Meniere's disease. Experimentally induced endolymphatic hydrops in guinea pigs was used as a model of Meniere's disease, and the effect of glycerol on the cochlear potentials was measured.In 7 albino guinea pigs the endolymphatic sac of one ear was obliterated surgically to produce endolymphatic hydrops. In the 6th postoperative month, glycerol (50 % W/V, 6 ml/kg BW) was injected intravenously, and the electrocochleogram was recorded before, and 1 and 2 hours after the injection. Glycerol did not improve the thresholds of the cochlear microphonics (CM) and compound action potentials (AP). The same dose of glycerol was administered to 5 normal guinea pigs. The elevation in AP threshold for the click and the diminution in the AP amplitude for the click and the tone bursts of the middle and high frequencies were slightly greater in the hydropic ears than in the normal ears. Glycerol caused almost no change in CM thresholds and made the CM amplitudes slightly smaller for the tone bursts of the low and middle frequencies in both of the hydrops and control groups. These findings were contrary to the improvement of hearing in patients treated with glycerol. Furthermore, the amplitudes of +SP for the click were decreased at 1 hour in 4 animals and recovered by 2 hours after the injection in 2 of the 4. This finding was also quite different from that reported in papers describing the diminution of -SP in patients with Meeniere's disease.

Intratesticular injection of glycerol as a model for studying the quantitative relationship between spermatogenic damage and serum FSH.

Intratesticular injection of glycerol (1,2,3-trihydroxypropane) was evaluated as an experimental approach for studying the relationship between spermatogenic activity, i.e. relative proportion of euspermatogenic and aspermatogenic tubules in the testis, and serum concentrations of FSH. Adult rats received a single intratesticular injection of either 400 microliters distilled water or five different doses of glycerol, ranging from 25 to 400 microliters, and were killed after 1 or 4 weeks respectively. Injection of glycerol caused focal destruction, so that the same testes contained intact tubules, tubules with spermatogonia and Sertoli cells only, and tubules devoid of cellular material. There was a close correlation (r = 0.896) between the frequency of intact tubules and the dose of glycerol, and a similarly strong correlation (r = 0.908) between acellular tubules and the dose of glycerol. A correlation existed between FSH and euspermatogenic tubules (r = -0.758, n = 122) and, conversely, between FSH and acellular tubules (r = 0.820, n = 122), while the correlation for tubules containing spermatogonia and Sertoli cells was only marginal (r = -0.055). The exact relationship between FSH and spermatogenic activity in the testis was used to estimate the minimal amount of spermatogenic tissue necessary for maintaining normal serum concentrations of FSH. Only the disruption of spermatogenesis in more than 30% of seminiferous tubules in each testis caused increased serum concentrations of FSH.(ABSTRACT TRUNCATED AT 250 WORDS)

Glycerol-induced changes in the cochlear responses of the guinea pig hydropic ear.

Pigmented guinea pigs were chronically implanted with bilateral round-window electrodes. Endolymphatic hydrops was induced by obstruction of the endolymphatic duct on one side. At 1-5 months post-surgery, glycerol was orally administered to each animal and the acute effect on cochlear and eighth nerve responses was investigated. Doses from half to four times the clinical dose of glycerol failed to improve the CAP audiogram in operated ears and were often found to raise the thresholds. Glycerol was found to diminish the amplitude of the summating potential as well as that of the compound action potential. Similar effects were observed for the higher doses in the control ears, although no effect was seen when doses used were equal to or less than the clinical dose. Our data suggest that the cochlear conditions in the guinea pig model of hydrops differ notably from those seen in patients with Ménière's disease.

Morphologic alteration of mouse Clara cells induced by glycerol: ultrastructural and morphometric studies.

In our studies on activation of the Clara cell by biological substances and its relationship to pulmonary carcinogenesis, we found that large doses of glycerol induced drastic morphologic changes selectively in the Clara cell among distal airway epithelial cells in ddY mice. Subcutaneous injection of glycerol (7.2 g/Kg body weight) caused cytoplasmic edema with disruption of endoplasmic reticulum membranes at 1 and 3 hours, followed by hyperplasia of smooth endoplasmic reticulum (SER) at 12 and 24 hours. Concentric lamination of SER was observed at 48 and 96 hours. Oral administration of 5% glycerol in drinking water for 2 to 8 weeks induced more conspicuous hyperplasia and hypertrophy of SER in the Clara cells. Electron microscopic morphometry revealed a 3-fold increase in the profile area of SER in the Clara cells of the animals at 2 and 8 weeks. Both the profile area and the number of secretory granules increased significantly at 2 and 8 weeks, and those of mitochondria tended to increase with time of glycerol treatment. In both experiments, the mitochondria of the Clara cells exhibited marked elongation and distortion of the contour associated with appearance of prominent cristae. These results suggest that large doses of glycerol induce marked alteration in the functional activity of the mouse Clara cell.

The effect of glycerol on autotomy. An experimental model of neuralgia pain

Autotomy in nerve injured rats has been put forward as an animal model in a broad range of chronic neuralgic pain. We have examined the effect of glycerol, a new and promising therapeutic agent for trigeminal neuralgia, on this animal model. A single dose of glycerol, alcohol or saline was injected directly into experimental sciatic nerve neuromas in rats via a chronically implanted cannula. Injections were made either at the time of nerve injury or 2 weeks afterwards. Both forms of glycerol treatment caused a significant reduction in autotomy behavior relative to saline. Alcohol also suppressed autotomy, but it was less effective than glycerol.

Increases in plasma glycerol levels precede the hypophagia following subcutaneous glycerol injection in rats

Cumulative food intake and plasma glycerol levels following subcutaneous glycerol injections were investigated in rats, because increases in plasma glycerol have been suspected to contribute to glycerol-induced hypophagia. Besides plasma glycerol, plasma non-esterified fatty acids (NEFA), plasma D-(−)-3-hydroxybutyrate (3-HB), blood glucose, and liver glycogen content were also measured. Two daily injections of 80 mg/kg body wt. glycerol did not affect food intake and failed to increase plasma glycerol 30 min after the injection. A single injection of 660 mg/kg body wt. glycerol reduced food intake and increased plasma glycerol 1–2 hours after the injection. This glycerol dose also increased liver glycogen content 1–2 hours after the injection but did not affect plasma NEFA and 3-HB. Rats injected with 660 mg/kg body wt. glycerol did not reduce feeding within the first 2 hours following the injection, when plasma glycerol levels were increased. Inhibition of feeding began at about 3 hours and continued up to 6 hours although plasma glycerol levels had declined to control values 5–6 hours after the injection. It is concluded that metabolic consequences of elevated plasma glycerol levels rather than increases in plasma glycerol levels per se elicit the food intake reduction following exogenous glycerol loads in rats.

Tubular function in glycerol-induced acute renal failure in rats: effect of saline loading and prior acute renal failure.

1. Chronic saline loading and prior induction of acute renal failure are manoeuvres which have been reported to protect against the development of acute renal failure. The underlying mechanisms are unclear. The purpose of the present study was to examine the effect of these protective manoeuvres on glomerular filtration rate (GFR) and proximal and distal tubular function in the glycerol-induced model of acute renal failure. 2. Acute renal failure was induced (50% glycerol, 10 ml/kg body wt. intramuscularly) in three groups of rats: group 1, water drinking; group 2, saline loaded (1% NaCl as drinking fluid for 5 weeks); group 3, rechallenged 7–15 days after a first dose of glycerol, when blood urea nitrogen levels had returned to normal. Control animals in group 3 received only the first glycerol injection, then, like the controls in groups 1 and 2, they were given 0.9% NaCl solution (10 ml/kg body wt. intramuscularly). All animals were then studied 24 h after glycerol or saline injection. 3. Glycerol caused a significant fall in GFR in all three groups (78% group 1; 64% group 2; 59% group 3); blood urea nitrogen levels rose significantly. Saline-loaded animals with acute renal failure (group 2) exhibited glycosuria with normal blood-sugar levels and a striking depression in maximal tubular glucose reabsorption. The capacity to reabsorb HCO−3 was depressed both before and during HCO−3 loading. Distal acidification as assessed by the urine to blood gradient of Pco2 (U—B Pco2) was normal during HCO−3 loading (urine pH 7.8). The presence of hyperchloraemic metabolic acidosis demonstrated that these animals developed proximal renal tubular acidosis. Glycerol-reinjected rats with acute renal failure (group 3) reabsorbed glucose and HCO−3 normally and exhibited normal distal tubule acidification. 4. We conclude from these data that a prior episode of acute renal failure protects proximal tubules against a second glycerol challenge, whereas chronic saline loading is without this protective effect. Both the underlying mechanism for this tubular cell resistance (against a second glycerol challenge) and the role of proximal tubular function in the pathogenesis of acute renal failure remain unclear.

Effect of glycerol and hyperosmolality on intracranial pressure.

Glycerol has been used in cerebral edema for hyperosmolar dehydration of brain tissue, but only empirical relationships govern this use. Since the efficacy of treatment with glycerol would likely increase with data on the relationship between drug blood levels and intracranial pressure (ICP), we examined the clinical pharmacology of the drug. Plasma samples were assayed for glycerol by a new method using gas chromatography with a flame ionization detector. Data were collected from 12 children who were in Children's Hospital of Pittsburgh (CHP) and who had cerebral edema of differing etiology that was treated with glycerol; they were monitored by intraventricular catheter. Glycerol was infused according to CHP guidelines. ICP reduction correlated with glycerol concentration and plasma concentrations of 1 to 3 mg/ml (10 to 30 mOsm/ml) were necessary to maintain an ICP below 20 torr. The relationship between osmolality and plasma glycerol level was also examined; there was good correlation between the idiogenic osmolality and drug concentration. Our studies support the clinical observations that relatively high doses of glycerol (0.2 to 1.0 gm/kg/hr), leading to plasma concentrations of 10 to 30 mOsm/l, are necessary to control ICP in patients with cerebral edema. Glycerol blood levels may be estimated from serum osmolality.

Further observations on the application of the campimetric method for measuring individually tolerated intraocular pressure in glaucoma

The results of campimetric investigations performed in 127 eyes (83 patients) are presented. The vertical diameter of the blind spot and intraocular pressure were measured several times before and after oral intake of a dose of glycerol combined with ascorbic acid. The tonometric value obtained when the blind spot is smallest is considered the individually tolerated level of intraocular pressure. This tolerable pressure was determined in 105 eyes. In the overwhelming majority of the cases (95 eyes) the initial IOP values were within the standard (not exceeding 27 mmHg), according to the present glaucoma classification. However, in 64 eyes the IOP level approached the upper limit of the standard and only in 31 eyes was it between 18 and 22 mmHg. In contrast, the individually tolerated intraocular pressure in 99 eyes (94.3%) shifted to a level of between 18 and 22 mmHg and only in six cases. (5.7%) did the intraocular pressure also remain at the upper limit of the standard after intake of glycerol combined with ascorbic acid. These data show that the individually tolerable intraocular pressure, which does not interfere with the blood circulation in the retina and optic nerve, is in the 18-22 mmHg range in most patients. Under these conditions the vertical diameter of the blind spot (measured at a distance of 1 m with an object 2 mm in diameter) does not exceed 12 cm. This simple method of determining the individually tolerable method of determining the individually tolerable intraocular pressure can be used in any ophthalmological practice.

Variations in glycerol kinetics in Reye's syndrome.

Glycerol kinetics and adverse affects were studied in nine patients with Reye's syndrome. Glycerol was given by continuous infusion over 2 hr, half over the first 0.5 hr and the remainder over the next 1.5 hr. The dose was adjusted to keep intracranial pressure less than or equal to 15 mmHg. At steady state, serial blood samples were collected during glycerol infusion and analyzed by an enzymatic assay specific for glycerol. At 0.75 to 1.75 gm/kg/2 hr glycerol doses, the serum levels ranged from 1.48 to 5.83 mg/ml. Total body clearance ranged from 1.99 to 5.1 ml/kg/min. Glycerol clearance was not related to serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), or serum ammonia levels. Glycerol provided effective control of intracranial pressure in all patients. Temporary elevation of serum creatinine and blood urea nitrogen (BUN) and presence of hemolysis in two patients, appeared to be related to glycerol.

Gluconeogenesis from glycerol by ketotic sheep pregnant with twins

The concentrations of glycerol and glucose in plasma, the entry rates of glycerol and glucose into the plasma pool and the production of glucose from glycerol were measured in four normal sheep pregnant with twins and in the same sheep after the induction of ketosis and after the oral administration of 3 ml/kg body-weight of glycerol in two doses six hours apart. After starvation there was a significant fall in the concentration of glucose and a rise in that of ketone bodies in the plasma. The rise in the concentration of glycerol was not significant. The divided oral dose of glycerol was followed by significant increases in the concentrations of glycerol and glucose and a significant fall in that of ketone bodies in plasma. After starvation, glucose and glycerol entry rates fell significantly from 42.0 +/- 3.5 to 18.1 +/- 1.4 mmol per hour and from 28.1 +/- 4.6 to 13.5 +/- 2.9 mmol per hour respectively. The amount of glucose formed from glycerol decreased from 5.4 +/- 1.2 to 3.0 +/- 0.5 mmol per hour. After a divided oral dose of glycerol, glycerol entry in the ketotic sheep rose significantly from 13.5 +/- 2.9 to 320 +/- 24.1 mmol per hour and glucose entry rate rose significantly from 18.1 +/- 1.4 to 71.5 +/- 10.1 mmol per hour. The amount of glucose produced from glycerol increased from 3.0 +/- 0.5 to 62.1 +/- 9.2 mmol per hour after the administration of glycerol. The oral dose of glycerol had no obvious effect on the clinical signs of induced ketosis.