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C D Thron

Publications and source records attributed to C D Thron.

At least 37 records · Page 2Linked to original sources
PubMed1989

Cyanide metabolism in the isolated, perfused, bloodless hindlimbs or liver of the rat.

Female CD1 rats weighing 250-300 g were anesthetized with ip pentobarbital, 50 mg/kg, and either the liver or the hindlimbs were surgically isolated and perfused in situ with a Krebs-Henseleit buffer, pH 7.4, at 38 degrees C, containing 40 g/liter dextran and 30 mg/liter papaverine. Perfusion pressure was continuously monitored, and in most experiments, flow was maintained at the physiological rate of 8.5 ml/min. In-line Clark-type electrodes allowed the continuous measurement of oxygen extraction. Potassium cyanide to 0.15 mM was usually added to the perfusate just prior to the start of a run. After a period of equilibration, samples of the perfusate were taken periodically for cyanide (CN) and thiocyanate (SCN) analyses. The results were used to determine CN extraction ratios or clearance and rates of SCN formation. When it was apparent that a steady state had been reached with respect to the above, sodium thiosulfate (TS) was added to the perfusate (to 0.1, 1.0, or 2.0 mM), and periodic samples were again collected after an equilibration period. In the absence of albumin, TS rapidly and significantly increased the rate of conversion of CN to SCN in both the liver and the hindlimbs. The rate of CN clearance in milliliters per minute per kilogram perfused tissue was 20-fold greater in the liver than in the hindlimbs. However, when the results from hindlimbs were extrapolated to the total body skeletal muscle mass, the rate of CN clearance by the total liver mass was only 1.5-fold greater than in total muscle mass. In the absence of TS, total muscle mass cleared CN at a rate that was 2.6-fold greater than the total liver mass, but the rates in both tissues were very much less than in the presence of TS. The extraction ratio for CN in the liver was 0.8 and the clearance was dependent on the flow rate. The extraction ratio for CN in the hindlimbs was 0.2, and the clearance was independent of the flow rate. Thus, CN clearance by the liver probably increases (within limits) with increasing portal blood flow. Evidence was obtained for the existence of a significant CN "sink," particularly in the liver, which presumably represents reversible binding to unknown tissue constituents.

Animals↗
PubMed1989

Does atrial natriuretic factor protect against right ventricular overload? I. Hemodynamic study.

We studied the effects of synthetic atrial natriuretic factor (ANF, 28-amino acid peptide) on base-line perfusion pressures and pressor responses to hypoxia and angiotensin II (ANG II) in isolated rat lungs and on the following hemodynamic and renal parameters in awake, chronically instrumented rats: cardiac output (CO), systemic (Rsa) and pulmonary (Rpa) vascular resistances, ANG II- and hypoxia (10.5% O2)-induced changes in Rsa and Rpa, and urine output. Intra-arterial ANF injections lowered base-line perfusion pressures and blunted hypoxia- and ANG II-induced pressor responses in the isolated lungs. Bolus intravenous injection of ANF (10 micrograms/kg) into intact rats decreased CO and arterial blood pressures of both systemic and pulmonary circulations and increased Rsa. ANG II (0.4 micrograms/kg) increased both Rsa and Rpa, and hypoxia increased Rpa alone in the intact rats. ANF (10 micrograms/kg) inhibited both ANG II- and hypoxia-induced increases in Rpa but did not significantly affect the ANG II-induced increase in Rsa. The antagonistic effect of ANF on pulmonary vasoconstriction was reversible and dose-dependent. The threshold doses of ANF required to inhibit pulmonary vasoconstriction were in the same range as those required to elicit diuresis and natriuresis. The data demonstrate that ANF has a preferential relaxant effect on pulmonary vessels constricted by hypoxia or ANG II. Both the renal and the pulmonary vascular effects of ANF may represent fundamental physiological actions of ANF. These actions may serve as a negative feedback control system that protects the right ventricle from excessive mechanical loads.

Angiotensin II↗
PubMed1987

Time course of cardiopulmonary responses to high altitude in susceptible and resistant rat strains.

We have identified two strains (H and M) of Sprague-Dawley rat with distinctly different susceptibilities and cardiopulmonary responses to hypoxia. In this study, we studied the development of cardiopulmonary and hematological responses to hypoxia and the post-hypoxic regression of these responses in the two strains over time. Under sea level conditions, there were no differences between the two strains. On exposure to hypobaric hypoxia (0.5 atm), right ventricular peak systolic pressure (RVPP) and right ventricular hypertrophy (RVH) increased more rapidly in the susceptible (H) than in the resistant (M) strain. In contrast, post-hypoxic reversal of these changes occurred at comparable rates. Hematocrits rose at similar rates in the two strains until after two weeks, when that of the H strain slightly exceeded that of the M strain. With the progression of RVH, left ventricular plus septal to body weight ratio (LV + S) g/100 g bw decreased in M rats but increased in the H rats. As a result, a conspicuous overall cardiac hypertrophy developed in the H rats but only a minimal cardiac hypertrophy occurred in the M strain. The data show that susceptibility to hypoxia in H rats is associated with more rapid development of RV systolic hypertension and biventricular hypertrophy than in M rats. The mechanism for the accelerated cardiopulmonary responses in the H rats most likely involves greater hypoxic pulmonary vasoconstriction or pulmonary vascular remodeling. Differences in hematocrit between the strains do not contribute to the early cardiopulmonary responses.

Altitude↗
PubMed1987

Nitrite conversion to nitric oxide in red cells and its stabilization as a nitrosylated valency hybrid of hemoglobin.

The authors describe a method for the preparation, isolation and purification from human red blood cells of a stable form of hemoglobin containing both oxidized and reduced subunits. After isoelectric focusing across a pH gradient, it occupies the same position as the synthetically reconstituted or chemically generated species, (alpha 2+ beta 3+)2 (I). Unlike its synthetic or chemically generated counterpart, however, it (HbX) does not bind oxygen. A different method for the preparation in situ of the (alpha 3+ beta 2+)2 valency hybrid results in a pigment with chemical and spectral properties identical with those ascribed to its synthetically reconstituted counterpart, and both bind oxygen. HbX is generated in highest yield when red cells are incubated under N2 in the presence of glucose, methylene blue and nitrite for several hours. Its visible absorption spectrum differs from that reported for I, and it reacted very slowly with ferricyanide. Exposure to CO did not result in spectral shifts over that for HbX in air, but spectral shifts were produced with CO exposure of (alpha 3+ beta 2+)2. HbX had an inositol hexaphosphate difference-binding spectrum quite unlike that described for I. HbX also had a distinctive electron paramagnetic resonance spectrum that shifted after inositol hexaphosphate addition with a new three-line hyperfine pattern. Both spectra were characteristic for an unpaired electron in an iron-centered orbital with a hyperfine coupling to the nitrogen nuclear spin of a nitrosyl ligand on heme iron. The authors conclude that HbX is a form of I, but it has NO bound to its reduced subunits.

Electron Spin Resonance Spectroscopy↗
PubMed1985

Carcinogen-induced lesions in the rat pancreas: effects of varying levels of essential fatty acid.

The ingestion of high levels of fats, especially unsaturated fats, has been shown to enhance carcinogenesis in a variety of experimental model systems. Recently attention has focused upon the unsaturated linoleic fatty acid (18:2 omega 6) as a key component for this postinitiation enhancement. We have investigated the dose-effect relationship of this essential fatty acid (EFA), in a well-characterized experimental model of pancreatic cancer. Male Lewis rats were given injections i.p. of azaserine (30 mg/ kg) at 14 days of age. The pups were weaned to test diets that contained 20% total dietary fat with EFA compositions varying from 0.5 to 11.5% of the diet. After 4 months of feeding these 20% fat diets, the pancreases were evaluated in situ for grossly visible tumors and microscopically for the number and size of the azaserine-induced, putative preneoplastic lesions (foci). Grossly visible tumors increased significantly in number as the EFA content of the diet increased. Two populations of microscopic foci were observed in these azaserine-initiated rats; namely, acidophilic foci and basophilic foci. Quantitative stereological analyses of these foci revealed that the acidophilic population of foci increased in both number and size as the EFA content of the diet increased. This increase was particularly apparent from 4.4 to 8.5% dietary EFA content. The basophilic population showed no similar response to increasing dietary EFA. These results indicate that the minimum dietary EFA required for enhancement of azaserine-induced, pancreatic carcinogenesis by a high fat diet lies in the range of 4 to 8%.

Animals↗
PubMed1984

Lack of protection against ouabain cardiotoxicity after chronic ablation of the area postrema in cats.

We evaluated the hypothesis that the area postrema facilitates the cardiac arrhythmias caused by toxic doses of digitalis. The arrhythmic dose of ouabain was determined in four cats with chronic selective destruction of the area postrema, and in a control group of two sham-operated cats and three normal unoperated cats. The cats were anesthetized with pentobarbital, and polygraph records were made of end-tidal Pco2, arterial blood pressure, heart rate, and the electrocardiogram (lead II and a bipolar lead in the superior vena cava). The vagosympathetic trunks were cut bilaterally, and 1 h later an i.v. infusion of [3H]ouabain was begun at the rate of 1.71 nmol/kg/min. This was continued until ventricular tachycardia appeared, as determined electrocardiographically. The total ouabain dosage required for ventricular tachycardia was recorded, and the ouabain concentrations in the arterial plasma and in the myocardium were determined by liquid scintillation counting. No statistically significant difference was found between the chronically postremectomized cats and the controls in any of these measures of ouabain cardiotoxicity. These results indicate that the area postrema plays no important role in the cardiotoxic action of ouabain in pentobarbital-anesthetized, vagotomized cats.

Animals↗
PubMed1984

Inhibition by retinoids of the growth of azaserine-induced foci in the rat pancreas.

The usefulness of a short-term azaserine [CAS: 115-02-6; diazoacetate serine (ester)]-rat model for the screening of retinoids (known chemopreventive agents) and the effect of two retinoids on the growth of azaserine-induced, presumptive preneoplastic foci of acinar cells were examined. At 14 days of age, male Lewis rats were each given injections of a single dose of 30 mg azaserine/kg body weight. These rats were weaned to test diets to which retinoids were added. At 4 months post initiation, pancreata were examined by quantitative stereologic methods to determine number and mean size of foci. Two phenotypically different populations of foci were observed and characterized as acidophilic or basophilic. Retinylidene dimedone and N-2-hydroxyethylretinamide decreased the number and size of the acidophilic foci but not the basophilic foci. The inhibition of growth of the acidophilic foci correlates well with the known effects of these retinoids in long-term carcinogenicity studies.

Animals↗
PubMed1984

Characterization of two populations of pancreatic atypical acinar cell foci induced by azaserine in the rat.

Multiple and single intraperitoneal injections of azaserine in male Wistar/Lewis rats induced a 100% incidence of atypical acinar cell foci. The foci were histologically classified into one of two populations, basophilic or acidophilic. The number and size of transections of the foci in tissue sections were determined. By means of known mathematical relationships, focal transectional data were transformed into three-dimensional data (i.e., foci/unit volume, foci/pancreas, mean diameter and volume of foci, and focal volume as percentage of pancreas volume). In general, initiation with azaserine resulted in more acidophilic than basophilic foci. An increase in the azaserine dose from 10 to 30 mg/kg resulted in the initiation of more acidophilic and basophilic foci. Over a 6-month period following initiation, basophilic foci showed a small increase in number and no increase in size. In these same pancreases, acidophilic foci significantly increased in both number and size. A promoter of pancreatic carcinogenesis (20% unsaturated fat diet) enhanced the number and percentage of the pancreas volume occupied by acidophilic foci. This modulator of the postinitiation phase of pancreatic carcinogenesis did not have a significant effect on the basophilic foci. Unlike the basophilic foci, the acidophilic foci show considerable growth potential and appear to be responsive to modulators of carcinogenesis. Further study of this population of carcinogen-induced pancreatic foci is warranted.

Animals↗
PubMed1984

A possible bias in growth-kinetic estimates of the thickness of the growing layer in multicellular tumor spheroids.

Yuhas and Li (Cancer Res., 38: 1528-1532, 1978) have proposed a method for estimating the thickness of the growing layer in multicellular tumor spheroids. Their method assumes, however, that the thickness of the growing layer is independent of spheroid radius; this assumption seems implausible in view of the fact that, for purely geometrical reasons, oxygen diffusion distance is greater in small than in large spheroids. In this communication, theoretical growth rates are calculated for a growth kinetic model based on Burton's (Growth, 30: 157-176, 1966) model of oxygen diffusion, and it is shown that for this model the Yuhas-Li estimates of thickness of the growing layer are 10 to 30% below the true thickness of this layer in the larger of the two spheroids used for the estimation. To generalize beyond this particular model, it is shown that, for any model where the growing layer is thicker in small than in large spheroids, the Yuhas-Li method underestimates the thickness of the growing layer. However, for our particular model at least, the bias in the Yuhas-Li estimates is fairly constant and relatively small, so that these estimates may be quite serviceable, especially for purely comparative studies.

Cell Division↗
PubMed1980

Linear pharmacokinetic systems.

This paper discusses the analysis of linear, time-invariant pharmacokinetic systems. For compartmental systems, we briefly review important structural features such as strong components and traps, and methods of analysis and system identification. For noncompartmental systems, we note some properties of the impulse response, and we show that total drug exposure (Formula: see text) depends only on the total dose, and not on the rate or schedule of administration. We extend this and other laws to certain partially nonlinear systems. Finally, we note that peak drug levels usually decrease with slower rates of drug administration; but this is not necessarily true unless the impulse response is unimodal. The ratio of peak drug levels in two tissues does not necessarily increase or decrease uniformly as a function of the injection rate, but may be maximal at an intermediate injection rate.

Drug Administration Schedule↗
PubMed1977

Quick estimation of kinetic parameters for a compartment with exponential absorption rate and first-order elimination rate.

Two methods are presented for the quick estimation of kinetic parameters for a compartment with an exponential absorption rate and a first-order elimination rate. The first method is by direct computation from the observed levels of substance in the compartment at times t. 2t, and 3t, where t is arbitrary. The second method uses a numerical table to estimate the parameters from the observed peak level, the time of the peak level (or the time when the level rises to half on the peak level), and the time when the level has declined to half of its peak value. Some approximation equations also are given.

Absorption↗