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Biomedical subjects

T E Nicholas

Publications and source records attributed to T E Nicholas.

At least 55 records · Page 3Linked to original sources
PubMed1986

Determination of time constants in kinetic studies involving radiolabeled tracer molecules.

In tracer kinetic studies, two homogeneous well-mixed compartments may be related as precursor and product. The time constant for the product compartment can then be estimated from the two specific activity vs. time curves. We examine ten methods of estimating this time constant for data with several different error patterns, and conclude that the present practice of transforming the data to a straight line yields an inefficient but unbiased estimate of the time constant. A least squares estimate, appropriately weighted and taking into account that both precursor and product specific activities are subject to error is expected theoretically and found in practice, to be most efficient. It is however, mathematically complicated. A modified approach using a minimum chi 2 estimate in which precursor specific activities are treated as error-free, is almost as efficient. It is mathematically simple, and outperforms the currently used estimators.

Algorithms↗
PubMed1986

Analysis of pulmonary phospholipid compartments in the unanesthetized rat during prolonged periods of hyperpnea.

We exposed rats to 4% CO2-10% O2-86% N2 for 24 h before infusing with 20 microCi kg-1 (methyl-3H)choline chloride. They were then exposed for periods up to 48 h, at which times their lungs were degassed and lavaged. The lavage fluid was divided into a tubular myelin-rich (PLalv-1) and a tubular myelin-poor (PLalv-2) fraction. Lamellar body (lb) and microsomal (m) fractions were prepared from the lung tissue and the amount of phospholipid (PL) was determined in each of the 4 fractions. Specific activity (sp.act.) curves were constructed for both control and hyperpneic groups. Exposure to the gas doubled both tidal volume and frequency of breathing. Total PLalv, PLlb and PLm were all markedly elevated, which, when taken in conjunction with the changes in sp.act. in these fractions, suggests that the rate of surfactant PL synthesis was increased within 24 h. The shapes of the sp.act. curves suggest precursor-product relationships between PLlb and PLalv-1 and between PLalv-1 and PLalv-2. However, when we applied analysis based on the Zilversmit steady-state equation, instead of the expected straight line, we found a marked clockwise hysteresis that did not return to the origin. Whereas this may reflect PLalv being supplied from 2 tissue pools, we argue that, in fact, we are not dealing with classic compartmental precursor-product relationships.

Animals↗
PubMed1984

Limitations of Zilversmit approach to analysis of precursor-product relationships.

Recently, a modification of the Zilversmit method has been used to establish the extent to which a precursor-product relationship exists between the phospholipids of the lamellar bodies (PLlb) and those in the alveolar compartment (PLalv) of the rabbit lung. According to this analysis, if a plot of specific activity (sp act) of PLalv vs. the integral with respect to time of (sp act PLlb-sp act PLalv) results in a straight line, then a presumptive precursor-product relationship exists; the slope of this line will indicate the turnover time of the product compartment. We have established analytically and confirmed numerically that collinearity is, in fact, a poor test of precursor-product relationship. We examine some causes of hysteresis and the direction of hysteresis of this plot for compartmental configurations other than precursor product. Finally, we apply the conclusions of our analysis to some of the published data relating to the relationship between PLlb and PLalv, and we indicate where previous conclusions may now be considered premature.

Body Fluid Compartments↗
PubMed1984

Alveolar type I and type II cells.

The alveolar epithelium comprises two main cell types: the alveolar type I and alveolar type II cell. The type I cell is a complex branched cell with multiple cytoplasmic plates that are greatly attenuated and relatively devoid of organelles; these plates represent the gas exchange surface in the alveolus. On the other hand, the type II cell acts as the "caretaker" of the alveolar compartment. It responds to damage of the vulnerable type I cell by dividing and acting as a progenitor cell for both type I and type II cells. In addition, it synthesises, stores and releases pulmonary surfactant into the alveolar hypophase, where it acts to optimise conditions for gas exchange.

Animals↗
PubMed1983

The release of surfactant in rat lung by brief periods of hyperventilation.

We investigated the release of surfactant-type phospholipids (S) using the isolated perfused rat lung (IPL). Following a 20 min equilibration period the lungs were hyperventilated for up to 15 min and then lavaged. Changing the peak inspired pressure (PIP) from 10 to 20 cm H2O rapidly increased the rate of release of S; this rate declined after 2 min. In contrast, doubling frequency of ventilation while maintaining the control tidal volume had no effect. The increase in alveolar S reflected release. rather than redistribution, and after 2 min amounted to about 8% of total S in lung tissue. Equivalent hyperventilation in an open-chested intact rat released significantly less S, suggesting possible tonic neurohumoral suppression in vivo. The release of S in the IPL was depressed by reducing temperature, but was not affected by hypoxia, 2,4 dinitrophenol, phenylephrine or dibutyrylguanosine 3',5'-cyclic monophosphate. We suggest that increasing tidal volume may directly distort the alveolar type II cell; each cell reacts to its own threshold distortion by releasing a pool of S in all-or-none fashion.

Animals↗
PubMed1983

Urea metabolism in isolated perfused lungs of the laboratory rat and of a desert rodent, Notomys alexis.

1. Using the isolated perfused lung preparation we have demonstrated a low-activity ureolytic enzyme present in rodent lung tissue. The enzyme shares four characteristic features with jack bean urease (EC 3.5.1.5). 2. Ureolytic activity was inhibited by fluoride ions and methionine hydroxamic acid; using the latter inhibitor, the I50 value and maximum inhibition were similar to those reported for jack bean urease. The apparent Km for rat lung urease was similar to the plasma urea level. 3. The low level of urease activity in the rat lung and in that of Notomys alexis, a desert rodent, suggests that the enzyme is not involved in urea excretion, rather that pulmonary ammonia production may influence fluid balance at the alveolus.

Animals↗
PubMed1983

High-frequency oscillations via the pleural surface: an alternative mode of ventilation?

We applied high-frequency oscillatory ventilation (HFOV) of low amplitude to the pleural surface of the isolated rat lung (IPL) perfused at 10 ml X min-1 with Krebs bicarbonate containing 4.5% albumin (hematocrit 34%). Lung volume was held constant by a continuous positive airways pressure (CPAP) of 5 cmH2O. Varying CPAP from 2 to 15 cmH2O did not affect O2 uptake. Tidal volume (VT) was estimated with an impedance pneumograph, and it bore a direct linear relationship to the amplitude of both the loudspeaker input signal and the pressure change in the chamber up to 30 Hz; VT was inversely proportional to the frequency (f). However, at a constant loudspeaker input of 10 V, minute expired ventilation (VE) remained constant (mean 104 ml X min-1) as f increased from 5 to 30 Hz. Hemoglobin saturation increased by more than 80% during HFOV of 5-40 Hz and amplitude of 10 V, the maximum O2 uptake being 14.6 ml O2 per 100 ml perfusate. Whereas dead space was approximately 335 microliters, a VT of less than 40 microliters could effect normal O2 uptake, suggesting that bulk flow is playing only a minor role in gas exchange. HFOV for 60 min (CPAP 5 cmH2O) did not affect the amount of alveolar surfactant compared with conventional ventilation at the same mean airway pressure. We conclude that normal O2 uptake can be maintained by applying HFOV to the pleural surface of the IPL held at constant volume.

Animals↗
PubMed1983

Transfer of 3H-cortisone and 3H-cortisol between the amniotic, allantoic, and fetal blood compartments in the rabbit at day 25 of gestation.

We have examined the rate of disappearance and the form of the radiolabel following the injection of either [1,2-3H]-cortisone (3H-E) or [1,2,6,7,n-3H]-cortisol (3H-F) into the amniotic sac of rabbits at day 25 of gestation. The half-life of 3H-E was approximately 35 min and was very much shorter than that of 3H-F. Concurrent with the disappearance of 3H-E was an increase in the amount of tritium in both the allantoic and the fetal blood compartments. Whereas following injection of 3H-E there was a rapid conversion of E to F that was reflected in all three compartments, following injection of 3H-F the vast majority of the tritium label remained as F. We conclude that amniotic E may act as a ready source of fetal F.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1982

The physiological significance of 11 beta-hydroxysteroid dehydrogenase in the rat lung.

We have examined the interconversion of cortisone (E) and cortisol (F) in rat lung homogenate and microsomal fraction and in the isolated rat lung perfused with Krebs bicarbonate solution containing 4.5% albumin. In the perfused lung the apparent Km was 5.1 microM E and the Vmax was 9 nmol . g(-1) . min-1. The ability of the lung to reduce E to F was enhanced both by 7 days prior exposure of the rat to an ambient temperature of 2 degrees C and by starvation of the rat for 3 days. The activity was inhibited by adrenalectomy and castration of 7 days duration. Whereas little steroid oxidation occurred in the perfused lung, preparations of lung homogenates and microsomal fraction readily reduced or oxidised the 11-position of the corticoid molecule depending on the preponderance of either NADPH or NADP, respectively. We conclude, that the predominance of the reductive reaction in the whole rat lung under physiological conditions reflects the very active pentose-phosphate shunt in the lung, which produces NADPH. We suggest that this ability of the lung to activate E to F may exert a fine control over the arterial concentration of unbound, physiologically active, 11-hydroxylated steroid.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1982

The pulmonary consequences of a deep breath.

We used the isolated rat lung perfused with Krebs bicarbonate and 4.5% albumin, to examine the effect of a transient increase in peak inspired pressure (PIP). The lung was ventilated with 5% CO2 in O2 at a Vr of 2.5 ml, an f of 60 min-1 and an end expired pressure of 2 cm H2O. After 30 min we increased the PIP from 9 to 18 cm H2O for one breath; following a further 30 sec of normal ventilation we lavaged the lung. The large breath increased the amount of alveolar surfactant phospholipids (PLalv) (control: 7.0 +/- 0.73 (11); large breath: 8.3 +/- 1.33 (14), mean +/- SD in mg . g dry lung-1), and decreased the percentage of PLalv associated with tubular myelin (control: 30.2 +/- 3.49% (9); deep breath: 25.4 +/- 2.99% (9). In rats that had received 20 microCi . kg-1 of [methyl-3H]choline chloride 3 h previously, there was also an increase in the tritium in PLalv expressed as a percent of that in tissue (control: 4.4 +/- 0.77% (5); deep breath: 5.7 +/- 1.0% (7). The deep breath also resulted in an increase in oxygen diffusing capacity. We conclude, that a single deep breath results in the opening of atelectatic alveoli, the release of pulmonary surfactant and possibly also the transfer of PLalv from the tubular myelin to the monomolecular phase.

Animals↗
PubMed1982

Surfactant homeostasis in the rat lung during swimming exercise.

Swimming rats for up to 2 h in water at 34 +/- 1 degree C increased the rate of breathing by 60% and tidal volume by 200-300%. In each case we infused 20 muCi X kg-1 [methyl-3H]choline chloride, via a caudal vein, 3 h prior to the end of swimming. Maximum specific activity of tissue phospholipid (PL) and alveolar PL (PLalv) occurred in 1 and 12 h, respectively. Total PLalv, specific activity of PLalv and the percentage of total PL released (%A/T) increased within 10 min of start of swimming and were sustained for at least 2 h of swimming [PLalv in mg X g dry lung-1: 5 s swim, 7.3 +/- 0.96 (mean +/- SD; n = 15 rats); 1-h swim, 10.1 +/- 1.1 (n = 23 rats)]. After a 1-h swim, PLalv returned to control within 4 h. Pretreatment with propranolol hydrochloride (10 mg X kg-1) (P), atropine methyl nitrate (3 mg X kg-1) (A), indomethacin (15 mg X kg-1), and cyproheptadine (1 mg X kg-1) did not alter the increase in PLalv with swimming, however, both P and A reduced the increase in specific activity of PLalv and %A/T. We suggest that the exercise releases surfactant from two pools: a readily released pool that responds to direct distortion of the alveolar type II cell and a pool that is under sympathetic nervous control.

Animals↗
PubMed1981

The pharmacokinetics of the intravenous steroid anesthetic alphaxalone in the isolated perfused rat lung.

We have examined four mathematical systems modeling the transit of the steroid anesthetic alphaxalone (3 alpha-hydroxy-5 alpha-pregnane-11,20-dione) through the lung. Using the isolated rat lung perfused with a plasma substitute containing 14C-alphaxalone and 3H-dextran, we have obtained results that are incompatible with models involving (a) anatomical variations in the microcirculation, (b) high solubility, or (c) specific binding. We develop a stochastic model of a physical process analogous to the sequence of events that takes place in a chromatography column. This model closely fits the experimental data and predicts a peak effluent concentration of alphaxalone that may occur after washout with several exclusion volumes. It represents a delay with the pulmonary compartment that may explain a difference in induction times observed between various intravenous anesthetic agents.

Anesthetics↗
PubMed1981

Control of release of surfactant phospholipids in the isolated perfused rat lung.

We used the isolated rat lung to investigate surfactant release. The lung was ventilated at 60.min-1 with 5% CO2-95% O2 and perfused at 10 ml.min-1 with Krebs-bicarbonate (4.5% albumin). After 20 min during which antagonist drugs were present, the lungs were either hyperventilated or agonist drugs were added. After another 15 min lungs were lavaged. Peak inspired pressures (PIP) in excess of 12 cmH2O produced progressively greater phospholipid (PL) yields. Whereas ventilating with PIP of 9 cmH2O and end-expired pressure(EEP) of 5 cmH2O produced 5.9 +/- 0.8 (mean +/-SD) (n = 17) mg PL. g dry lung-1, ventilating with PIP of 20 cmH2O and EEP of 0 cmH2O produced 10.1 +/- 1.3 (n = 26). PL release was unaffected by tetrodotoxin, propranolol, atropine, cyproheptadine, or indomethacin. PL was increased by salbutamol and dibutyryl adenosine 3',5'-cyclic monophosphate but not by pilocarpine or dibutyryl guanosine 3',5'-cyclic monophosphate. We conclude, that increasing tidal volume immediately releases surfactant, probably by distorting the type II cell and elevating cAMP. An intrapulmonary neural reflex is not involved in this response of the isolated rat lung, nor is histamine, 5-hydroxytryptamine, or a prostaglandin.

Albuterol↗
PubMed1981

Phospholipid synthesis in isolated perfused lungs of rats made tolerant to 100% oxygen.

Tolerance to 100% oxygen is readily induced in the rat by prior exposure to 80% oxygen for 7 days. In order to determine whether the rate of synthesis, or te alveolar content, of pulmonary phospholipids is altered in the tolerant rat, we perfused the isolated lung with medium containing 20 muM [14C]methyl choline chloride for 30 min at 10 ml/min, and then we measured the incorporation of carbon-14 into tissue phospholipids. We also measured the phospholipids in the lavage. There was no difference in the rate of incorporation in the tolerant rats (201 +/- 11 nmol/g dry lung, n = 8, mean +/- SEM) compared to control rats (210 +/- 9 nmol/g dry lung, n = 4) that had been exposed to air for 7 days under identical conditions. Whereas the induction of tolerance did not alter the total amount of phospholipid lavaged from the lung (tolerant: 251 +/- 31 microgram lipid phosphorus/g dry lung, n = 10; control: 228 +/- 9, n = 5) or the amount that was disaturated (tolerant: 44.7 +/- 4.2%, n = 5; control 45.0 +/- 2.1%, n = 4), there were marked increases in the relative amounts of phosphatidylcholine and phosphatidylethanolamine in the lavage from tolerant rats. Static compliance measurements revealed that the pressure required to maintain the tolerant lungs at 50% of total lung capacity was half that required in the control rats. At this stage it is not possible to say what role, if any, these changes have in the induction of tolerance to 100% oxygen.

Animals↗
PubMed1980

Cortisone and cortisol in maternal and fetal blood and in amniotic fluid during the final ten days of gestation in the rabbit.

We have used instant thin-layer chromatography and radioimmunoassay to measure the concentrations of total cortisone (E) and cortisol (F) in the fetal and maternal compartments of the rabbit. The concentration of F in fetal blood increased markedly at day 25; this is just prior to the rapid increase in the surfactant phospholipids in lung tissue in this species. This increase coincided with a peak in the concentration of E and F in the maternal blood and may reflect the maternal levels. There was no 'surge' in the concentration of total F in fetal blood at term. The concentration of E in fetal blood varied between 5 and 15 ng/ml during this last stage of gestation, hence providing ready substrate for the 11 beta-reductase present in lung and other tissues. The concentration of E and F in maternal blood was significantly higher and more variable than that in blood from nonpregnant female rabbits, and there was a pronounced peak in concentration at day 30 (term: 31 days). The concentrations of both E and F in amniotic fluid were lower than those in either maternal or fetal blood until day 30 when the concentration of F increased fivefold to 19.2 +/- 2.58 (mean +/- SEM of 6 samples).

Amniotic Fluid↗
PubMed1979

Uptake of [14C]choline and incorporation into lung phospholipid by the isolated perfused rat lung.

We have used the isolated perfused lung (IPL) preparation from the rat to determine whether uptake of choline from the vascular compartment could limit the rate of synthesis of phosphatidyl-choline (PC). The uptake of choline was rapid and did not saturate at a concentration of 10 mM. The rate of incorporation of choline into phospholipid was saturated above 0.1 mM choline. Whereas, uptake and incorporation were depressed at 4 C, uptake was neither dependent on the extracellular sodium concentration nor inhibited by equimolar concentrations of hemicholinium-3 (HC-3). We could find no evidence that uptake might limit synthesis of lung lecithin and conclude that uptake is either by free diffusion, or by a carrier-mediated process with a very high Km.

Animals↗