Effects of dextran-bound inhibitors on carbonic anhydrase activity in isolated rat lungs

1986 ◽  
Vol 61 (5) ◽  
pp. 1849-1856 ◽  
Author(s):  
T. A. Heming ◽  
C. Geers ◽  
G. Gros ◽  
A. Bidani ◽  
E. D. Crandall
Keyword(s):  
Molecular Weight ◽  
Carbonic Anhydrase ◽  
Time Course ◽  
Co2 Concentration ◽  
Carbonic Anhydrase Activity ◽  
Low Molecular Weight ◽  
Co2 Diffusion ◽  
Rat Lungs ◽  
Co2 Excretion ◽  
Isolated Rat

Effects of macromolecular Prontosil-dextran inhibitors (PD) on carbonic anhydrase (CA) activity in isolated rat lungs were studied. Isolated lungs were perfused with Krebs-Ringer bicarbonate (KRB) solutions containing no inhibitor, PD 100,000 (mol wt 100,000), PD 5,000 (mol wt 5,000), or low-molecular-weight inhibitors (Prontosil or acetazolamide). The time course of effluent perfusate pH equilibration was measured in a stop-flow pH electrode apparatus. Pulmonary CO2 excretion (Vco2) was monitored by continuously recording expired CO2 concentration. The lungs were ventilated with room air and perfused at 37 degrees C with KRB prebubbled with 5% CO2- 20% O2- 75% N2. The results obtained show that both the low-molecular-weight inhibitors and PD′s caused postcapillary pH disequilibria (delta pH) in effluent perfusate. However, only acetazolamide and Prontosil caused a reduction in Vco2. These results suggest that there is an intravascular CA, presumably associated with endothelial cell membranes, that is accessible to all inhibitors used and is responsible in part for equilibration of the CO2- HCO3- -H+ reactions in the perfusate but, under the conditions used, does not affect CO2 excretion; and there is an extravascular (possibly intracellular) CA that can be inhibited by low-molecular-weight inhibitors, is primarily responsible for enhanced CO2 transfer across the alveolar-capillary barrier (perhaps via facilitation of CO2 diffusion), and is in part responsible for pH equilibration.

In situ characterization of carbonic anhydrase activity in isolated rat lungs

1990 ◽  
Vol 69 (6) ◽  
pp. 2155-2162 ◽  
Author(s):  
T. A. Heming ◽  
A. Bidani
Keyword(s):  
Carbonic Anhydrase ◽  
Time Course ◽  
Carbonic Anhydrase Activity ◽  
In Situ Characterization ◽  
Rat Lungs ◽  
Isolated Lungs ◽  
Menten Constant ◽  
Co2 Excretion

Lung carbonic anhydrase (CA) participates directly in plasma CO2-HCO3(-)-H+ reactions. To characterize pulmonary CA activity in situ, CO2 excretion and capillary pH equilibration were examined in isolated saline-perfused rat lungs. Isolated lungs were perfused at 25, 30, and 37 degrees C with solutions containing various concentrations of HCO3- and a CA inhibitor, acetazolamide (ACTZ). Total CO2 excretion was partitioned into those fractions attributable to dissolved CO2, uncatalyzed HCO3- dehydration, and catalyzed HCO3- dehydration. Approximately 60% of the total CO2 excretion at each temperature was attributable to CA-catalyzed HCO3- dehydration. Inhibition of pulmonary CA diminished CO2 excretion and produced significant postcapillary perfusate pH disequilibria, the magnitude and time course of which were dependent on temperature and the extent of CA inhibition. The half time for pH equilibration increased from approximately 5 s at 37 degrees C to 14 s at 25 degrees C. For the HCO3- dehydration reaction, pulmonary CA in situ displayed an apparent inhibition constant for ACTZ of 0.9-2.2 microM, a Michaelis-Menten constant of 90 mM, a maximal reaction velocity of 9 mM/s, and an apparent activation energy of 3.0 kcal/mol.

Influence of proton availability on intracapillary CO2-HCO3(-)-H+ reactions in isolated rat lungs

1992 ◽  
Vol 72 (6) ◽  
pp. 2140-2148 ◽  
Author(s):  
T. A. Heming ◽  
A. Bidani
Keyword(s):  
Carbonic Anhydrase ◽  
Buffer Capacity ◽  
Co2 Exchange ◽  
Equilibrium Models ◽  
Co2 Transport ◽  
Capillary System ◽  
Rat Lungs ◽  
Kinetics And Dynamics ◽  
Co2 Excretion ◽  
Isolated Rat

Transcapillary CO2 exchange entails a transient perfusate CO2-HCO3(-)-H+ disequilibrium, leading to net loading or unloading of blood HCO3-. Perfusate reequilibration may or may not reach completion during the time of capillary transit, depending on the rate of intracapillary CO2-HCO3(-)-H+ reactions. Failure to reestablish equilibrium within the “open” capillary system leads to continued reequilibration in the “closed” postcapillary vasculature with resultant shifts in postcapillary perfusate PCO2, pH, and [HCO3-]. In the present study, we determined the effects of perfusate nonbicarbonate buffer capacity (beta) on intracapillary CO2-HCO3(-)-H+ reactions in isolated saline-perfused rat lungs. Effects of beta on the rate of transcapillary CO2 excretion (VCO2) and the magnitude of the postcapillary perfusate pH disequilibrium were measured as a function of luminal vascular carbonic anhydrase (CA) activity. The data indicate that beta markedly influenced the kinetics and dynamics of intravascular CO2-HCO3(-)-H+ reactions. beta affected VCO2 and the relative enhancement of VCO2 by luminal vascular CA. The data emphasize the inadequacies of using traditional “equilibrium” models of the CO2-HCO3(-)-H+ system to investigate capillary CO2 transport and exchange, even in organs (e.g., lungs) that contain significant luminal vascular CA activity.

EFFECTIVENESS AND SAFENESS OF LOW MOLECULAR WEIGHT HEPARINS APPLICATION IN CHILDREN WITH RIGHT ATRIUM THROMBOSES

2018 ◽  
Author(s):  
П.А. Жарков ◽  
Н.М. Ершов ◽  
А.В. Пшонкин
Keyword(s):  
Molecular Weight ◽  
Major Bleeding ◽  
Right Atrium ◽  
Malignant Disease ◽  
Final Analysis ◽  
Low Molecular Weight ◽  
Low Molecular Weight Heparins ◽  
Complete Lysis ◽  
Electronic Hospital ◽  
Isolated Rat

Введение. Тромбозы правого предсердия (ТПП) являются редкой патологией, которая чаще встречается среди новорожденных и детей, перенесших кардиохирургическое вмешательство. Истинная распространенность, а также подходы к лечению ТПП у детей, получающих терапию по поводу злокачественного заболевания, неизвестны. Цель работы: оценить распространенность ТПП, а также эффективность и безопасность применения низкомолекулярного гепарина (НМГ) у детей с ТПП. Материалы и методы. Проведен анализ электронной базы данных пациентов в возрасте 0-17 лет. Для оценки динамики размеров тромбов в анализ были включены только пациенты с объективно подтвержденным ТПП, у которых имелось не менее двух эхокардиографических исследований, и которым проводилась терапия НМГ. Оценка случаев кровотечений и тромбоэмболии легочной артерии/артерий (ТЭЛА) проводилась по записям в историях болезни пациентов. Результаты. Изолированный ТПП или ТПП в комбинации с тромбозами других локализаций был диагностирован у 13,7%, изолированный ТПП – лишь у 5% детей. При проведении антикоагулянтной терапии НМГ отсутствие динамики со стороны размеров тромба наблюдалось в 1 случае, нарастание размеров тромба – в 1 случае, уменьшение размеров тромба или полный лизис – в 13 случаях. За период наблюдения не было выявлено ни одного случая крупных кровотечений и ТЭЛА. Заключение. ТПП встречаются в 13,7% случаев среди пациентов с тромбозом. Мы считаем применение НМГ эффективным и безопасным методом вторичной антитромботической профилактики у детей с ТПП. Introduction. Right atrium thromboses (RAT) are rare pathology which is more specific for neonates and children undergoing cardiac surgery. True RAT prevalence as well as approaches to its treatment in children receiving therapy for malignant disease are unknown. Aim: to assess RAT prevalence as well as effectiveness and safeness of low molecular weight heparin (LMWH) application in children with RAT. Materials and methods. Electronic hospital database analysis was performed to find patients with objectively confirmed RAT. Children aged 0-17 years old with two or more echocardiographic examinations who received LMWH were included in final analysis. Thrombus size dynamics, the rate of pulmonary embolism (PE) and major bleeding served as effectiveness and safeness endpoints. Results. Isolated RAT or RAT in combination with thromboses of other localizations was found in 13,7%, isolated RAT – only in 5% of children. Under anticoagulant therapy with LMWH we found no dynamics in clot size – in 1 case, clot size increasing – in 1 case, reduction of clot size or its complete lysis – in 13 cases. There were no cases of major bleeding and PE during LMWH treatment. Conclusion. RAT occurs in 13,7% of cases among patients with thrombosis. We consider LMWH treatment to be effective and safe method of secondary antithrombotic prophylaxis in children with RAT.

Roles of intra- and extracellular carbonic anhydrase in alveolar-capillary CO2 equilibration

1994 ◽  
Vol 77 (2) ◽  
pp. 697-705 ◽  
Author(s):  
T. A. Heming ◽  
E. K. Stabenau ◽  
C. G. Vanoye ◽  
H. Moghadasi ◽  
A. Bidani
Keyword(s):  
Carbonic Anhydrase ◽  
Driving Forces ◽  
Excretion Rate ◽  
Blood Gas ◽  
Gas Barrier ◽  
Arterial Pco2 ◽  
Co2 Diffusion ◽  
Chemical Equilibration ◽  
Co2 Excretion ◽  
Alveolar Capillary

Alveolar-capillary CO2 equilibration involves diffusive equilibration of CO2 across the blood-gas barrier and chemical equilibration of perfusate CO2-HCO-3-H+ reactions. These processes are governed by different, but related, driving forces and conductances. The present study examined the importance of pulmonary carbonic anhydrase (CA) for diffusive and reactive CO2 equilibration in isolated rat lungs. Lungs were perfused with salines containing membrane-impermeant or -permeant inhibitors of CA. Measurements of CO2 excretion rate, equilibrated venous and arterial PCO2 and pH, and postcapillary pH and PCO2 disequilibria were used, together with our previous model of CO2-HCO-3-H+ reactions and transport in saline-perfused capillaries (Bidani et al. J. Appl. Physiol. 55: 75–83, 1983), to compute the relevant driving forces and conductances. Reactive CO2 equilibration was markedly affected by extracellular (vascular) CA activity but not by the activity of intracellular (cytosolic) CA. The driving force for CO2 diffusion was strongly influenced by vascular CA activity. The conductance for CO2 diffusion was independent of CA activity. The minimum conductance for CO2 diffusion was estimated to be 700–800 ml.min-1.Torr-1. The results indicate that extracellular vascular CA activity influences both diffusive and reactive CO2 equilibration. However, cytosolic CA has no detectable role in alveolar-capillary CO2 equilibration.

Pharmacodynamic Differences of An Anti-Xa Enriched Low Molecular Weight Heparin, AVE 5026 in Comparison to Enoxaparin and Unfractionated Heparin.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4171-4171
Author(s):  
Debra Hoppensteadt ◽  
Angel Gray ◽  
Evangelos Litinas ◽  
Brigitte Kaiser ◽  
Jawed Fareed
Keyword(s):  
Molecular Weight ◽  
Unfractionated Heparin ◽  
Half Life ◽  
Low Molecular Weight Heparin ◽  
Thrombin Generation ◽  
Time Course ◽  
Fold Increase ◽  
Low Molecular Weight ◽  
Thrombin Time ◽  
Primate Model

Abstract Abstract 4171 AVE5026 (Sanofi-Aventis, Paris, France) represents an anti-Factor (F) Xa enriched ultra low molecular weight heparin (ULMWH) (Mw=2.4 Kda; anti-FXa activity ∼160 U/mg). In comparison to Enoxaparin it has a lower anti-FIIa activity (∼2 U/mg). The oligosaccharide composition of AVE5026 also differs from Enoxaparin and other LMWHs. Besides the molecular and compositional differences, the biologic half-life of AVE5026 (18-20 hours) is significantly longer than Enoxaparin (4-6 hours). In order to compare the other pharmacodynamic differences between AVE5026, Enoxaparin and unfractionated heparin (UFH), a primate model (macaca mulatto) was used since its tissue factor pathway inhibitor (TFPI) profile is comparable to the human response. Individual groups of primates (n=6) were administered with 1 mg/kg SC of either AVE5026, Enoxaparin or UFH. Heptest and APTT measurements were determined on whole blood (WB) and plasma was analyzed for APTT, Heptest, thrombin time (TT), anti-FXa and anti-FIIa effects at varying periods up to 28 hours. TFPI antigen was measured using the assay from Stago (Parsipanny, NJ). Functional TFPI measurements were determined using the kit from American Diagnostica (Stamford, CT). In contrast to UFH, in the WB assays, neither the AVE5026 nor the Enoxaparin produced a strong effect on the APTT and TT, however both demonstrated a strong effect on the heptest assay. AVE5026 produced a much stronger effect with a longer half-life (T½=11 hrs) in comparison to Enoxaparin (T½=6 hrs). In the plasma based systems only UFH produced a measurable effect on the APTT and TT. However, in the heptest and anti-FXa assays, both AVE5026 and Enoxaparin produced a stronger effect, which was much longer with AVE5026 (2-3 fold increase). The plasma time course of TFPI antigen release was longer with AVE5026 in comparison to Enoxaparin and UFH. The ratios of immunologic to functional TFPI levels were also higher in the primates administered with AVE 5026. In the thrombin generation test, AVE5026 produced a sustained effect which lasted longer than Enoxaparin (T½ =16.8 hrs vs. 9.2 hrs.). These results show that AVE5026 produces stronger anti-FXa effects in primates which are associated with a higher circulating level of TFPI and more pronounced suppression of thrombin generation compared to Enoxaparin and UFH. Disclosures: Hoppensteadt: Sanofi-Aventis: Research Funding.

Time course of production of low molecular weight viral-neutralizing substance(s) in chickens

1983 ◽  
Vol 17 (4) ◽  
pp. 387-397 ◽  
Author(s):  
Craig Whitfill ◽  
Edward Weck ◽  
James Blankenship ◽  
N. R. Gyles ◽  
J. A. Thoma
Keyword(s):  
Molecular Weight ◽  
Time Course ◽  
Low Molecular Weight

Distribution of luminal carbonic anhydrase activity along rat inner medullary collecting duct

1991 ◽  
Vol 260 (5) ◽  
pp. F738-F748 ◽  
Author(s):  
S. M. Wall ◽  
M. F. Flessner ◽  
M. A. Knepper
Keyword(s):  
Carbonic Anhydrase ◽  
Collecting Duct ◽  
Co2 Concentration ◽  
Carbonic Anhydrase Activity ◽  
Inner Medullary Collecting Duct ◽  
Proton Source ◽  
Total Ammonia ◽  
Medullary Collecting Duct ◽  
Disequilibrium Ph ◽  
Ammonia Flux

The isolated perfused tubule technique was utilized to determine whether endogenous luminal carbonic anhydrase is present in the initial or terminal parts of the inner medullary collecting duct (IMCD) of the rat. This was accomplished by measuring the luminal disequilibrium pH in the presence of a large luminal proton source created by perfusing the lumen with a solution containing 10 mM NH4Cl. (NH3 efflux causes H+ to be released from NH+4 in the lumen). The disequilibrium pH was calculated by subtracting the equilibrium pH from the measured pH at the end of the tubule lumen. The end-luminal equilibrium pH was calculated from the total CO2 concentration in the collected fluid, as measured by microcalorimetry. The end-luminal pH was determined by measuring the fluorescent signal from the the pH-sensitive dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF), which was added to the luminal perfusate in its nonesterified form. In the initial IMCD, there was no measurable disequilibrium pH. With the addition of the carbonic anhydrase inhibitor acetazolamide to the luminal fluid, a significant acidic pH disequilibrium was elicited. In the terminal IMCD under control conditions a statistically significant acidic disequilibrium pH was measured. The disequilibrium was obliterated when exogenous carbonic anhydrase was added to the luminal perfusate. These findings were verified by measuring total ammonia flux by ultramicrofluorometry. The results demonstrate endogenous luminal carbonic anhydrase activity in the initial IMCD but a lack of enzyme activity in the terminal IMCD.

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