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Biomedical subjects

C S Patlak

Publications and source records attributed to C S Patlak.

At least 55 records · Page 3Linked to original sources
PubMed1988

Dexamethasone effects on vascular volume and tissue hematocrit in experimental RG-2 gliomas and adjacent brain.

We have studied the effects of dexamethasone, a corticosteroid commonly used to treat brain tumors, on vascular volume and tissue hematocrit in RG-2 experimental rat gliomas. 125I-RISA (radioiodinated serum albumin) was used to measure tissue plasma vascular volume (Vp) and 51Cr labeled red cells were used to measure tissue red cell volume (Vrbc). Quantitative autoradiography was used to obtain local measurements of Vp and Vrbc in different brain and tumor regions. From these experimentally measured values, we calculated the tissue vascular volume (Vv), tissue hematocrit (THct) and systemic arterial hematocrit (AHct). The value reported primarily reflect capillary and small vessel volumes since blood drained from larger vessels during tissue processing and large vascular structures were avoided during analysis of the autoradiographic images. A total of 110 tumors were studied in 29 animals. There was a consistent trend for Vp and Vv to be reduced in all tumor regions after dexamethasone treatment, although a significant decrease was seen only in tumor center. Dexamethasone did not affect Vp or Vv in tumor-free brain regions. Dexamethasone appeared to have little effect on Vrbc in any brain or tumor region. THct was consistently, although not significantly, higher in tumors after treatment with dexamethasone; THct in tumor-free brain regions was unaffected by dexamethasone treatment.

Animals↗
PubMed1988

Local cerebral glucose utilization in controlled graded levels of hyperglycemia in the conscious rat.

Local cerebral glucose utilization assayed by the [14C]deoxyglucose ([14C]DG) method and calculated by means of its operational equation with values for the rate constants and lumped constant determined in rats under physiological conditions remains relatively stable with variations in arterial plasma glucose concentration within the normoglycemic range. Large changes in arterial plasma glucose level may, however, significantly alter the values of these constants and lead to artifactual results. Values for the lumped constant have been measured and reported for a wide range of arterial plasma glucose concentrations ranging from hypoglycemia to hyperglycemia in the rat (Schuier et al., 1981; Suda et al., 1981; Pettigrew et al., 1983). In the present study we have redetermined the rate constants in rats with arterial plasma glucose levels clamped at approximately 350, 450, and 550 mg/dl (i.e., 19, 25, and 31 mM) by a glucose clamp technique. The rate constants for the transport of DG from plasma to brain, K1*, and its phosphorylation in tissue, k3*, were found to decline with increasing plasma glucose levels, while the rate constant for its transport back from brain to plasma, k*2, remained relatively unchanged from its value in normoglycemia. These rate constants were used together with the previously determined values for the lumped constants to calculate local rates of cerebral glucose utilization in three groups of rats in which arterial plasma glucose levels were clamped at approximately 350, 450, and 550 mg/dl (i.e., 19, 25, and 31 mM). Average glucose utilization in the brain as a whole was unchanged in hyperglycemia from the values calculated in normoglycemic rats with the standard normal set of constants. Changes in the rate of glucose utilization were found, however, in the hypothalamus, globus pallidus, and amygdala during hyperglycemia.

Animals↗
PubMed1988

Brain slice glucose utilization.

The metabolism of 2-deoxyglucose has been studied in 540 micron and 1,000 micron hypothalamic brain slices. Slice 2-deoxyglucose (2DG) and 2-deoxyglucose-6-phosphate (2DG6P) levels were measured after tissue homogenization and perchloric acid extraction. By analyzing the uptake and washout kinetics with nonlinear least-squares methods, we have determined the rate constants for three-, four-, or five-parameter kinetic models and obtained a value for the in vitro lumped constant (LC). The kinetic analysis reveals a small, slowly decaying, 2DG component that is not predicted by any of the models. If this component is treated as a separate, parallel compartment, then the four- and five-parameter models are essentially equivalent. To compare our data to prior in vivo data, we combined 2DG and 2DG6P to produce Ci*, the total slice radioactivity, and analyzed the first 45 min of uptake. These data were fit best by a three-parameter model and the slowly decaying pool was not identified. Calculation of glucose utilization from total tissue radioactivity, measured by whole slice homogenization and by image analysis of autoradiograms, showed excellent correlation between the two methods. Image analysis of radioactivity in the suprachiasmatic nucleus, which is present in these slices, revealed a spontaneous diurnal variation in in vitro glucose utilization in close quantitative agreement with prior in vivo measurements. The kinetic analysis of the 1,000 micron slice was qualitatively similar to that of the 540 micron slice but revealed an increase in the LC and a large decrease in k1 as well as the expected large increase in the hexokinase rate constant, k3. Overall, in vitro glucose utilization increased by about 60%. These results are consistent with our prior studies of the 1,000 micron slice and support our interpretation that the 1,000 micron slice is an excellent in vitro model for brain ischemia without infarction.

Animals↗
PubMed1987

Regional localization of a glioma-associated antigen defined by monoclonal antibody 81C6 in vivo: kinetics and implications for diagnosis and therapy.

The pharmacokinetics and regional tissue distribution of two IgG2b immunoglobulins were studied in athymic mice with D54MG human glioma xenografts. Monoclonal antibody (Mab) 81C6, an antiglioma antibody, had a plasma half-life of 2.7 +/- 0.3 (SE) days; 45.6, a control immunoglobulin, had a plasma half-life of 3.3 +/- 0.4 days. The immunoreactive fraction of 81C6 in plasma fell slowly from 0.37 to 0.23 over 9 days. The blood-to-tissue transfer constant (K1) of Mab was 0.11 +/- 0.05 ml/g/h in brain xenografts and 0.07 +/- 0.02 ml/g/h in s.c. xenografts. In contrast, K1 in muscle (0.005 +/- 0.002) and brain (0.0004 +/- 0.0001 ml/g/h) was much lower. The equilibration half-time of Mab in extracellular space was 1.1 +/- 0.2 h in the brain xenografts, 3.6 +/- 1.4 h in s.c. xenografts, and 8.1 and 24 h in muscle and brain, respectively. Distribution and binding of 81C6 was heterogeneous in the xenografts. A binding potential of 5-14 was found centrally and a binding potential of 0.8-1.0 was found peripherally in the brain xenografts. In the s.c. xenografts, the binding potential was higher peripherally than centrally. The exposure of D54MG xenograft tissue to Mab 81C6 was not significantly limited by the permeability of the blood vessels or blood flow due to the long plasma half-life of the immunoglobulin. A comparison of Mab and alpha-aminoisobutyric acid influx constants suggests that Mab entry into intracerebral xenografts occurs through large pores without significant sieving or steric restriction. Under such conditions the differences in influx constants between immunoglobulin and smaller immunoglobulin fragments will be proportional to the differences in their aqueous diffusion constants.

Animals↗
PubMed1987

Rapid dynamic CT scanning to distinguish schizophrenic from normal subjects.

Rapid dynamic computerized axial tomography (CT) density-time curves were used to detect abnormal brain regions in groups of controls and DSM-III diagnosed schizophrenics. Density-time curves were designated as plateau curves if, following a bolus injection of contrast material, they exhibited a plateau from the peak value rather than a decrease. Five of the 10 schizophrenics versus none of the 11 controls were found to possess two or more plateau curves. The physiological basis for the plateau curves is not known, but an increase in blood-brain-barrier permeability could be involved.

Adult↗
PubMed1987

The microcirculation of rat circumventricular organs and pituitary gland.

Blood volume, blood flow, and blood-to-tissue transfer of an amino acid in circumventricular organs, such as the median eminence and subfornical organ, and the pituitary gland of conscious rats were measured by using quantitative autoradiographic techniques and computer-assisted processing of the tissue images. Retained erythrocyte and plasma volumes observed in circumventricular organs and the anterior and neural lobes of the pituitary gland were dissimilar but in all cases greater by several times than those in cerebral grey matter; these findings suggest the presence of a dense network of high-resistance microvessels in circumventricular organs. The rate of capillary blood flow in the subfornical organ and median eminence was similar to that of grey matter, whereas blood flow in the pituitary neural lobe was several times higher than in grey matter. Thus the apparent velocity of intracapillary blood flow is much higher in the neural lobe than in the subfornical organ. Blood-to-tissue transfer of a small neutral amino acid, alpha-aminoisobutyric acid, was 200 to 700 times more rapid in circumventricular organs and pituitary neural lobe than in the inferior colliculus and caudate nucleus, structures having a blood-brain barrier (BBB). Morphometric analyses indicated that capillary volume and surface area were two times larger in the neural lobe than in the subfornical organ. Moreover, capillaries of the neural lobe and subfornical organ had numerous endothelial fenestrations and cytoplasmic pits or vesicles, whereas capillaries of the inferior colliculus had no fenestrations and fewer vesicles. These studies demonstrate quantitative differences in the microcirculatory systems not only between circumventricular organs and BBB structures but also among circumventricular organs.

Aminoisobutyric Acids↗
PubMed1987

Dexamethasone effects on [125I]albumin distribution in experimental RG-2 gliomas and adjacent brain.

A total of 72 RG-2 transplanted gliomas were studied in 58 rats at three time points (1, 30, 240 min) after intravenous injection of [125I]radioiodinated serum albumin ([125I]RISA). The animals were divided into two groups: a control group that received no treatment and a second group that was treated with five doses of 1.5 mg/kg of dexamethasone over 2.5 days. Local tissue concentrations of [125I]RISA were measured with quantitative autoradiography based on morphological features of the tumors and used to calculate the tissue distribution space. Two models were used to analyze the data. A two compartment model yielded estimates of local blood-to-tissue influx constants (K1), lower limit extracellular volumes (Ve), and plasma vascular volumes (Vp) in different tumor regions. Treatment with dexamethasone consistently reduced the RISA distribution space in the RG-2 tumors; the reduction in Ve was statistically significant in almost all tumor regions: whole tumor Ve (mean +/- SE) was reduced from 0.14 +/- 0.02 ml g-1 in control animals to 0.08 +/- 0.01 ml g-1 in dexamethasone treated animals. K1 and Vp were also decreased in all tumor regions after treatment with dexamethasone (whole tumor K1 decreased from 2.36 +/- 0.89 to 0.83 +/- 0.29 microliter g-1 min-1 and Vp decreased slightly from 0.016 +/- 0.013 to 0.010 +/- 0.005 ml g-1 after dexamethasone treatment), but these changes were not statistically significant. A comparison of the tumor influx constants in control animals and the aqueous diffusion constants of two different size molecules (RISA and aminoisobutyric acid) suggests that the "pores" across RG-2 capillaries are large and may not restrict the free diffusion of RISA (estimated minimum pore diameter greater than 36 nm) and that the total pore area is approximately 6.2 X 10(-5) cm2 g-1 in RG-2 tumor tissue. The second model, which allows for diffusion and solvent drag of RISA across tumor capillaries and through the tissue, was used to analyze the distribution profiles of RISA in peripheral tumor and adjacent brain. This analysis was consistent with a small bulk flow of plasma-derived edema fluid (capillary filtration rate approximately equal to 0.8 microliter g-1 min-1) and a larger component of free diffusion of RISA (K approximately equal to 2 microliter g-1 min-1) through pores in the tumor vessels of control animals. Dexamethasone treatment markedly reduced or eliminated the filtration of plasma-derived fluid across tumor capillaries and the movement of RISA through the extracellular space by solvent drag.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

The influence of tissue heterogeneity on results of fitting nonlinear model equations to regional tracer uptake curves: with an application to compartmental models used in positron emission tomography.

An analytical method based on Taylor expansions was developed to analyze errors caused by tissue heterogeneity in dynamic positron emission tomography (PET) measurements. Some general rules concerning the effect of parameter variances and covariances were derived. The method was further applied to various compartmental models currently used for measurement of blood flow, capillary permeability, glucose metabolism, and tracer binding. Blood flow and capillary permeability are shown to be generally underestimated in heterogeneous tissue, the underestimation being more severe for slowly decaying, constant or increasing input functions rather than for bolus input, and increasing with measurement time. Typical errors caused by the heterogeneity due to insufficient separation between gray and white matter by a PET scanner with full width at half-maximum (FWHM) = 5 to 10 mm resolution range between -0.9 and -6% in dynamic CBF measurements with intravenous (i.v.) bolus injection of 15O-water or inhalation of 18F-fluoromethane and total measurement times of 6 or 10 min, respectively. Binding or metabolic rates determined with tracers that are essentially trapped in tissue (e.g., FDG for measurement of cerebral glucose metabolism) are only slightly overestimated (0.5-3.0%) at typical measurement times and are essentially independent of the shape of the input function. The error increase considerably if tracer accumulation is very slow, however, or if short measurement times [less than 5/(k2 + k3)] are used. Some rate constants are also subject to larger errors.

Blood-Brain Barrier↗
PubMed1987

Volume regulatory loss of Na, Cl, and K from rat brain during acute hyponatremia.

This study quantitatively evaluates the contribution of tissue Na, Cl, and K loss to brain volume regulation during acute dilutional hyponatremia (DH) and examines the mechanism of Na loss. DH was produced in pentobarbital sodium-anesthetized rats by intraperitoneal infusion of distilled water and brain water and electrolytes analyzed 30 min, 1 h, 3 h, 4 h, or 6 h later. The rate of Na and Cl loss was greatest during the first 30 min of DH (0.43 and 0.47 meq X kg tissue dry wt-1 X min-1, respectively). Net loss of Na and Cl was maximal after 3 h of DH. K loss was slower, achieving significance after 3 h. Electrolyte loss was sufficient to account for observed brain volume regulation after three or more hours of DH. Measurements of 22Na influx and efflux across the blood-brain barrier showed that barrier permeability to Na is unchanged during DH. Analysis of results using a two-compartment model of plasma-brain exchange suggests that loss of brain Na during DH does not result solely from a shift of electrolyte across the blood-brain barrier to plasma, and thus provides indirect evidence for an additional pathway for Na loss, presumably via cerebrospinal fluid.

Animals↗
PubMed1987

Regulation of brain water and electrolytes during acute hyperosmolality in rats.

Regulation of brain water and electrolytes during acute hyperosmolal states has been studied in anesthetized rats. Rats were injected intravenously or intraperitoneally with hypertonic NaCl, mannitol, or sucrose (hyperosmolal series) or with isotonic NaCl (isosmolal controls). Terminal plasma osmolality varied from 290 to 385 mosmol/kg and the experimental duration from 15 to 120 min. Osmotically induced water loss from brain tissue for the different protocols was only 26-78% of that predicted for ideal osmotic behavior, revealing a degree of tissue volume regulation, and the brain gained Na, Cl, and K. This gain was sufficient to account quantitatively for tissue volume regulation at 120 min of hypernatremia but not at shorter times or during mannitol- or sucrose-induced hyperosmolality. Water loss and electrolyte uptake occur simultaneously, over 30 min, which limits the degree of brain shrinkage. Results of this analysis of the time course and magnitude of tissue electrolyte gain during acute hyperosmolality form the basis for the following two studies of the volume regulatory influx of electrolyte from plasma and CSF, respectively.

Animals↗
PubMed1987

Volume regulatory influx of electrolytes from plasma to brain during acute hyperosmolality.

Brain volume is regulated during acute hyperosmolal states based, in part, on the tissue gain of Na, Cl, and K [H. F. Cserr, M. DePasquale, and C.S. Patlak, Am. J. Physiol. 253 (Renal Fluid Electrolyte Physiol. 22): F522-F529, 1987]. This study evaluates the contribution of influx from plasma to the volume regulatory gain of electrolyte. Blood-to-brain transfer constants, K1, were measured as a function of plasma osmolality, over the range 300-385 mosmol/kg, for sodium (22Na) and potassium (42K or 86Rb) and as a marker for nonselective changes in permeability for [14C]mannitol. Osmolality was elevated by intraperitoneal injection of hypertonic NaCl, mannitol, or sucrose. K1 for Na, K, and mannitol each increased linearly with plasma osmolality. Increases in K1 for Na and mannitol were small and were proportional to their respective diffusion coefficients, consistent with the development of a small leak pathway. Increases in K1 for K were much larger, consistent with osmotic stimulation of a selective permeability pathway. Quantitative analysis of the results suggests that uptake from plasma accounts for most of the K gained by brain tissue in response to acute hyperosmolality but for only a small fraction of the Na. This provides indirect evidence for an additional source of Na, presumably from cerebrospinal fluid.

Animals↗
PubMed1986

Apparent glucose utilization in Walker 256 metastatic brain tumors.

Regional rates of apparent glucose utilization (GU) in metastatic Walker 256 (WL-256) brain tumors produced by the intracarotid injection of WL-256 tumor cells in rats were measured using 14C-deoxyglucose and quantitative autoradiography. Apparent glucose utilization was uniform within individual small and medium size tumors without necrosis, varied considerably among different tumors within this group, and did not correlate with tumor size or location. High values of GU in medium and large-size tumors correlated with viable-appearing tissue in contrast to necrotic tissue and were always 1.3 to 3 times higher than that of adjacent and contralateral nontumorous brain. The apparent net extraction of glucose (En) in viable tumor regions was estimated to be several fold higher than that in remote brain tissue; analysis of this data for medium and large tumors indicates that the calculated values of GU and En overestimate the actual rates of utilization and net extraction of glucose. Local cerebral glucose utilization (LCGU) was higher than normal adjacent to small tumors and lower than normal adjacent to large tumors. The LCGU in many gray-matter structures remote from the intracerebral tumors was reduced and roughly proportional to the metastatic tumor burden. The comparatively high uptake of 2-deoxyglucose by viable tumor cells has diagnostic and localization value and suggests that appropriate glucose analogues could be developed to produce a tumor-selective inhibition of glycolysis and tumoricidal effect.

Animals↗
PubMed1986

Effect of vasopressin on ependymal and capillary permeability to tritiated water in cat.

Ependymal cells line the cerebral ventricles forming the interface that separates the cerebrospinal (CSF) and interstitial fluids (ISF). Extracellular molecules move between ependymal cells, whereas lipid soluble molecules pass both between and through cells. We measured the transfer of tritiated water (TOH) from CSF to blood across the ependymal and capillary interfaces by ventriculocisternal (VC) steady-state tissue clearance. Adult cats anesthetized with pentobarbital sodium underwent VC perfusion with the extracellular marker [14C]sucrose and TOH added to the artificial CSF. Brain tissue was analyzed for depth of penetration of the isotopes into periventricular gray matter. We found that TOH distribution space was lower than expected from water content measurements, whereas sucrose space was normal. Using VC steady-state equations we calculated an ependymal permeability that was similar to the permeability of the cerebral capillary. When arginine vasopressin (AVP) was added to the perfusate in different amounts, both capillary transfer times and ependymal permeability increased. Our results show that the ependyma may be important in water movement in the brain and support the suggestion that AVP influences water exchange in mammalian brain tissue.

Animals↗
PubMed1985

Apparent glucose utilization in Walker 256 metastatic brain tumors.

Regional rates of apparent glucose utilization (GU) in metastatic Walker 256 (WL-256) brain tumors produced by the intracarotid injection of WL-256 tumor cells in rats were measured using 14C-deoxyglucose and quantitative autoradiography. Apparent glucose utilization was uniform within individual small and medium size tumors without necrosis, varied considerably among different tumors within this group, and did not correlate with tumor size or location. High values of GU in medium and large-size tumors correlated with viable-appearing tissue in contrast to necrotic tissue and were always 1.3 to 3 times higher than that of adjacent and contralateral nontumorous brain. The apparent net extraction of glucose (En*) in viable tumor regions was estimated to be several fold higher than that in remote brain tissue; analysis of this data for medium and large tumors indicates that the calculated values of GU and En* overestimate the actual rates of utilization and net extraction of glucose. Local cerebral glucose utilization (LCGU) was higher than normal adjacent to small tumors and lower than normal adjacent to larger tumors. The LCGU in many gray-matter structures remote from the intracerebral tumors was reduced and roughly proportional to the metastatic tumor burden. The comparatively high uptake of 2-deoxyglucose by viable tumor cells has diagnostic value and suggests that appropriate glucose analogues could be developed to produce a tumor-selective inhibition of glycolysis and tumoricidal effect.

Animals↗
PubMed1985

Metabolic and kinetic considerations in the use of [125I]HIPDM for quantitative measurement of regional cerebral blood flow.

The metabolic degradation and the kinetics of the cerebral uptake of N,N,N'-trimethyl-N'-(2-hydroxy-3-methyl-5-[125I]iodobenzyl)-1, 3-propanediamine ([125I]HIPDM) have been studied in conscious, adult male Sprague-Dawley rats to determine its suitability as a tracer for the quantitative measurement of regional CBF (rCBF). rCBF was calculated by the indicator fractionation and the tissue equilibration methods in experiments of different durations up to 1 h. The values of rCBF obtained with [125I]HIPDM were compared with those obtained in concurrent measurements with [14C]iodoantipyrine in the same animals. Results of the experiments demonstrate that [125I]HIPDM is an inadequate tracer for use with the indicator fractionation method and that any method that employs [125I]HIPDM for the determination of rCBF must take into account its metabolic degradation, diffusion limitations, and bidirectional flux across the blood-brain barrier. With the tissue equilibration method, consistent determinations of rCBF may be possible with [125I]HIPDM by measurement of the time course of its concentration in arterial blood, corrected for the presence of 125I-labeled metabolic products, and its concentration in the brain at any time up to 1 h after its administration. The method may be adapted to measure rCBF in humans by means of single-photon emission tomography with [123I]HIPDM.

Animals↗
PubMed1985

Rapid amino acid uptake in rat pituitary neural lobe during functional stimulation by chronic dehydration.

We studied the transfer of a small neutral amino acid, alpha-aminoisobutyric acid, from arterial blood into the pituitary neural lobe in normal rats and in rats deprived of water for 5 days. A threefold increase in the neural lobe uptake of the amino acid was found in the chronically dehydrated rats. Possible causes for this effect include enlargement of the capillary and pituicyte membrane surface areas available for solute flux and increased permeability of these membranes. Such functional and structural alterations may be associated with an increase in protein turnover in the neural lobe during dehydration.

Aminoisobutyric Acids↗
PubMed1985

A spatial analysis of the blood-brain barrier damage in experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis was induced in young male Lewis rats. Following the development of neurological signs, the local distribution of perivascular inflammatory cellular infiltrates and the local blood-to-tissue transfer constants (K1) of alpha-aminoisobutyric acid (AIB) were determined, and these results were compared. Perivascular infiltrative lesions were generally found near areas of the CNS that normally lack an effective blood-brain barrier (BBB) such as the choroid plexus and the entry zones of the cranial and spinal nerve roots. This distribution pattern indicates that the entry of the causative agent into CNS tissue may be by way of the permeable microvessels of these structures. In tissue around inflamed veins, the mean transfer constant was slightly but significantly increased (2.8 +/- 1.5 microliter g-1 min-1) compared with uninvolved regions (0.9 +/- 0.2 microliter g-1 min-1) and similar areas in control animals (0.9 +/- 0.3 microliter g-1 min-1). Analysis of the autoradiographic method of determining transfer constants suggested that the AIB influx rate in the lesion areas may actually be manyfold larger than measured, that BBB permeability may be greatly increased at such sites, and that the areas of lymphocytic infiltration and increased K values may be virtually identical.

Aminoisobutyric Acids↗