Biomedical subjects

J P Freeman

Publications and source records attributed to J P Freeman.

At least 37 records · Page 2Linked to original sources

PubMed1999

Biotransformation of protriptyline by filamentous fungi and yeasts.

1. The potential of various fungi to metabolize protriptyline (an extensively used antidepressant) was studied to investigate similarities between mammalian and microbial metabolism. 2. Metabolites produced by each organism were isolated by high-pressure liquid chromatography and identified by nuclear magnetic resonance and mass spectrometry. The metabolites identified in one or more fungi were 2-hydroxyprotriptyline, N-desmethylprotriptyline, N-acetylprotriptyline, N-acetoxyprotriptyline, 14-oxo-N-desmethylprotriptyline, 2-hydroxy-acetoxyprotriptyline and 3-(5-hydrodibenzo[bf][7]annulen-5-yl)propanoic acid. 3. Among 27 filamentous fungi and yeast species screened, Fusarium oxysporum f. sp. pini 2380 metabolized 97% of the protriptyline added. Several other fungi screened gave significant metabolism of protriptyline, including Cunninghamella echinulata ATCC 42616 (67%), C. elegans ATCC 9245 (17%), C. elegans ATCC 36112 (22%), C. phaeospora ATCC 22110 (50%), F. moniliforme MRC-826 (33%) and F. solani 3179 (12%). 4. F. oxysporum f. sp. pini produced phase I and phase II metabolites and thus is a suitable microbial model for protriptyline metabolism.

Animals↗

PubMed1999

Biotransformation of doxepin by Cunninghamella elegans.

A filamentous fungus, Cunninghamella elegans ATCC 9245, was used as a microbial model of mammalian metabolism to biotransform doxepin, a tricyclic antidepressant drug. Doxepin is produced as an 85:15% mixture of the trans- (E) and cis- (Z) forms. After 96 h of incubation in Sabouraud dextrose broth, 28% of the drug was metabolized to 16 metabolites. No change in the trans- (E) and cis- (Z) ratio of doxepin was observed. Metabolites were isolated by reversed phase HPLC and identified by (1)H NMR and mass spectroscopic analysis. The major metabolites were (E)-2-hydroxydoxepin, (E)-3-hydroxydoxepin, (Z)-8-hydroxydoxepin, (E)-2-hydroxy-N-desmethyldoxepin, (E)-3-hydroxy-N-desmethyldoxepin, (E)-4-hydroxy-N-desmethyldoxepin, (Z)- and (E)-8-hydroxy-N-desmethyldoxepin, (E)-N-acetyl-N-desmethyldoxepin, (E)-N-desmethyl-N-formyldoxepin, (E)-N-acetyldidesmethyldoxepin, (E)-and (Z)-doxepin-N-oxide, and (E)- and (Z)-N-desmethyldoxepin. Six of the metabolites produced by C. elegans were essentially similar to those obtained in human metabolism studies, although nine novel metabolites were identified.

Antidepressive Agents, Tricyclic↗

PubMed1998

Peroxidase-catalyzed oxidation of 2,4,6-trichlorophenol.

2,4,6-Trichlorophenol (TCP) is an environmental contaminant that is toxic, mutagenic, and carcinogenic. We have investigated peroxidase-catalyzed oxidation of TCP as an alternative pathway of TCP bioactivation using horseradish peroxidase (HRP) as a model peroxidase. TCP was shown to function as a reducing substarte for HRP as evidenced by TCP-dependent, HRP-catalyzed reduction of 5-phenyl-4-penten-1-yl hydroperoxide (PPHP) to its corresponding alcohol. In addition, TCP was shown to undergo hydroperoxide (H2O2, ethyl hydroperoxide, or PPHP)-dependent metabolism as evidenced by electronic absorption spectroscopic analysis of reaction mixtures. A single major product was detected by reverse phase HPLC and was identified as 2,6-dichloro-1,4-benzoquinone (2,6-dichloro-2, 5-cyclohexadiene-1,4-dione, CAS no. 697-91-6) on the basis of electronic absorption spectroscopy, mass spectrometry, and cochromatography with synthetic standard. In addition, HRP-catalyzed oxidation of TCP yielded EPR-detectable phenoxyl radical intermediates whose EPR spectrum consisted of a 1:2:1 triplet characterized by proton hyperfine coupling constants aH(3,5) = 2.35 gauss. Mechanisms for the hydroperoxide-dependent, HRP-catalyzed oxidation of TCP are proposed that are consistent with these results.

Catalysis↗

PubMed1998

Changes in nasal tip projection and rotation after septorhinoplasty: a cephalometric analysis.

PURPOSE: This prospective study reports on changes in nasal tip projection and nasal tip rotation before and after septorhinoplasty analyzed cephalometrically. PATIENTS AND METHODS: Forty patients undergoing primary septorhinoplasty were studied prospectively. Lateral cephalometric radiographs taken in the natural head position were obtained before and 6 to 45 months (mean, 17.1) after surgery. In 10 patients, serial radiographs were taken at 6 and 12 months, and in seven patients they were taken at 12 and 24 months after surgery. Nasal tip projection (NTP) was defined as the distance between articulare (Ar) and pronasion (PRN). Nasal tip rotation (NTR) was defined as the change in the angle (N-Ar-PRN) after surgery. A surgical goal to increase, decrease, or maintain NTP and NTR was assigned to each patient before surgery. RESULTS: NTP changed in the desired direction in 16 of 40 patients (40%). NTR changed in the desired direction in 25 of 40 patients (63%). In the patients studied serially, NTP decreased an average 0.7 mm between 6 and 12 months (P = .018), and 0.6 mm between 12 and 24 months (P = .071). CONCLUSIONS: Decreased NTP and NTR were the most easily achieved surgical objectives. Maintaining or increasing NTP is less predictable. Typically, there is a progressive loss of NTP after surgery independent of the surgical goal. Cephalometric analysis is a useful tool to measure changes in NTP and NTR after septorhinoplasty.

Adolescent↗

PubMed1998

Fungal biotransformation of 6-nitrochrysene.

The fungus Cunninghamella elegans was used to biotransform 6-nitrochrysene, a mutagen that is a widespread environmental contaminant. After 6 days, 74% of the 3H-labeled 6-nitrochrysene added had been metabolized to two isomeric sulfate conjugates. These conjugates were separated by high-performance liquid chromatography and identified by UV-visible, 1H nuclear magnetic resonance, and mass spectral techniques as 6-nitrochrysene 1-sulfate and 6-nitrochrysene 2-sulfate.

Biotransformation↗

PubMed1997

Evidence for the role of 2-hydroxychromene-2-carboxylate isomerase in the degradation of anthracene by Sphingomonas yanoikuyae B1.

Sphingomonas yanoikuyae B1 is extremely versatile in its catabolic ability. An insertional mutant strain, S. yamoikuyae EK504, which is unable to grow on naphthalene due to the loss of 2-hydroxychromene-2-carboxylate isomerase activity, was utilized to investigate the role of this enzyme in the degradation of anthracene by S. yanoikuyae B1. Although EK504 is unable to grow on anthracene, this strain could transform anthracene to some extent. A metabolite in the degradation of anthracene by EK504 was isolated by high-pressure liquid chromatography (HPLC) and was identified as 6,7-benzocoumarin by UV-visible, gas-chromatographic, HPLC/mass-spectrometric, and 1H nuclear magnetic resonance spectral techniques. The identification of 6,7-benzocoumarin provides direct chemical and genetic evidence for the involvement of nahD in the degradation of anthracene by S. yanoikuyae B1.

Anthracenes↗

PubMed1997

Cytotoxicity of linoleic acid diols to renal proximal tubular cells.

Monoepoxides of linoleic acid (leukotoxin and isoleukotoxin) have been associated with a variety of pathophysiological diseases in humans including multiple organ failure. They also have been shown to be toxic when injected into experimental animals. Because leukotoxin and isoleukotoxin are excellent substrates for epoxide hydrolases, we tested the hypothesis that the diol metabolites are less toxic than the parent monoepoxides using the rabbit renal proximal tubule (RPT) suspension model. An equimolar mixture of the positional isomers of the methyl esters of leukotoxin and isoleukotoxin did not cause cell death to RPT cells at concentrations up to 1 mm using lactate dehydrogenase release as the endpoint. The corresponding diols, however, caused cell death in a time- and concentration-dependent manner beginning at 4 hr and reaching 42% cell death in 6 hr at 1 mm. Cell death was not due to oxidative stress since malondialdehyde content did not increase and the iron chelator deferoxamine and the antioxidant N,N'-diphenyl-1, 4-phenylenediamine were not cytoprotective. In contrast, cell death was associated with mitochondrial dysfunction with respiration decreasing 54% prior to the onset of cell death. Secondary to the mitochondrial dysfunction, the diols completely inhibited active Na+ transport within 30 min of addition. These results suggest that the in vivo toxicity and pathophysiology previously attributed to the monoepoxides of linoleic acid may be due to the diol metabolites.

Animals↗

PubMed1997

Regiospecificity of peroxyl radical addition to (E)-retinoic acid.

The regiochemistry of peroxyl radical addition to (E)-retinoic acid (RA) was investigated. Peroxyl radicals, generated by reaction of 13-hydroperoxy-(9Z,11E)-octadecadienoic acid with hydroxo(porphyrinato)iron(III) in Tween 20 micelles, were reacted with RA. The major, and virtually exclusive, RA oxidation product was 5,6-epoxy-RA which was identified on the basis of cochromatography with the synthetic synthetic oxirane (in a reverse phase HPLC system), electronic absorption spectroscopy, high-field 1H-NMR, and EI mass spectrometry. These results suggest that peroxyl radicals react with RA by regioselective addition to either C5 or C6 yielding an endocyclic tertiary allylic or tertiary carbon-centered radical adduct, respectively. Subsequent beta-elimination of an alkoxyl radical yields the oxirane. Computational studies were carried out in order to gain mechanistic insights into the observed regiospecificity of the peroxyl radical-dependent epoxidation reaction; molecular mechanics and semiempirical quantum mechanical calculations were carried out using Tripos force field parameters and AM1, respectively. The results suggest that the regiospecific epoxidation may be influenced by the 5,6-olefinic function behaving as a partially-isolated double bond as well as inherent allylic A1,2 strain in the substituted cyclohexene ring as a consequence of substitutions at C1 and C6. In addition, calculated heats of formation indicated preferential peroxyl radical addition to C5 versus C6; this may reflect differences in the geometries of sp2-orbitals containing the radical densities rather than resonance contributions by the highly conjugated polyene system.

Chromatography, High Pressure Liquid↗

PubMed1996

Formation of mammalian metabolites of cyclobenzaprine by the fungus, Cunninghamella elegans.

The fungus, Cunninghamella elegans, was used as a microbial model of mammalian drug metabolism to biotransform a tricyclic antidepressant, cyclobenzaprine. Seventy-five percent of this drug at a concentration of 1 mM was metabolized within 72 h by C. elegans grown on Sabouraud dextrose broth. Milligram amounts of fungal metabolites were isolated by reversed-phase high performance liquid chromatography (HPLC) and their structures were characterized by 1H NMR spectroscopy, mass spectrometry, and UV spectroscopy analyses. The major fungal metabolites of cyclobenzaprine were 2-hydroxycyclobenzaprine (59%), N-desmethylcyclobenzaprine (21%), cyclobenzaprine trans-10,11-dihydrodiol (5%), N-desmethyl-2-hydroxy-cyclobenzaprine (3%), 3-hydroxycyclobenzaprine (3%), and cyclobenzaprine N-oxide (1%). These fungal metabolites were used as standards to investigate the metabolism of cyclobenzaprine by rat liver microsomes. Rat liver microsomes also biotransformed cyclobenzaprine to produce similar metabolites as the fungus. The isotope labeling of 2-hydroxycyclobenzaprine by 18O2 and the trans-configuration of the dihydrodiol suggested that these reactions were catalyzed by cytochrome P-450 monooxygenases in C. elegans. These results also demonstrated that the fungal biotransformation system could be used to predict and synthesize the mammalian drug metabolites.

Amitriptyline↗

PubMed1996

Nonenzymatic reduction of tetrachloro-1, 4-benzoquinone by reduced nicotinamide adenine dinucleotide phosphate in an aqueous system.

NADPH was shown to reduce tetrachloro-1,4-benzoquinone (TCBQ) to tetrachloro-1,4-benzene diol which was identified on the basis of cochromatography with synthetic standard in a reverse phase HPLC system, electronic absorption spectroscopy, and mass spectrometry. Conversely, NADPH was shown to undergo TCBQ-dependent oxidation as evidenced by uv spectroscopic analysis. ESR spectroscopy demonstrated that NADPH-dependent reduction of TCBQ proceeds through the intermediacy of a semiquinone radical intermediate. In addition, molecular mechanics and molecular orbital calculations were carried out on TCBQ to obtain partial atomic charges and the results suggest that the first electron transfer from the reduced nicotinamide moiety to TCBQ occurs at a carbonyl carbon. Kinetic analysis indicated that the rate of NADPH oxidation is first order with respect to [TCBQ], second order with respect to [NADPH], and an Arrhenius plot yielded an activation energy of 26 kJ x mol (-1) for the rate limiting step. Mechanisms are proposed which are consistent with these results.

Chloranil↗

PubMed1996

Biotransformation of quinoxaline by Streptomyces badius.

Quinoxaline, a mutagenic azaarene produced in foods during cooking, was added to cultures of Streptomyces badius ATCC 39117. After 24 h, the cultures were extracted with ethyl acetate. Two major metabolites were purified by liquid chromatography and identified by mass spectrometry and nuclear magnetic resonance spectroscopy as 3,4-dihydro-2(1H)-quinoxalinone and 2(1H)-quinoxalinone.

Biotransformation↗

PubMed1996

Biotransformation of chlorpromazine and methdilazine by Cunninghamella elegans.

When tested as a microbial model for mammalian drug metabolism, the filamentous fungus Cunninghamella elegans metabolized chlorpromazine and methdilazine within 72 h. The metabolites were extracted by chloroform, separated by high-performance liquid chromatography, and characterized by proton nuclear magnetic resonance, mass, and UV spectroscopic analyses. The major metabolites of chlorpromazine were chlorpromazine sulfoxide (36%), N-desmethylchlorpromazine (11%), N-desmethyl-7-hydroxychlorpromazine (6%), 7-hydroxychlorpromazine sulfoxide (36%), N-hydroxychlorpromazine (11%), 7-hydroxychlorpromazine sulfoxide (5%), and chlorpromazine N-oxide (2%), all of which have been found in animal studies. The major metabolites of methdilazine were 3-hydroxymethdilazine (3%). (18)O(2) labeling experiments indicated that the oxygen atoms in methdilazine sulfoxide, methdilazine N-oxide, and 3-hydroxymethdilazine were all derived from molecular oxygen. The production of methdilazine sulfoxide and 3-hydroxymethdilazine was inhibited by the cytochrome P-450 inhibitors metyrapone and proadifen. An enzyme activity for the sulfoxidation of methdilazine was found in microsomal preparations of C. elegans. These experiments suggest that the sulfoxidation and hydroxylation of methdilazine and chlorpromazine by C. elegans are catalyzed by cytochrome P-450.

Antipsychotic Agents↗

PubMed1996

Metabolism of phenanthrene by the white rot fungus Pleurotus ostreatus.

The white rot fungus Pleurotus ostreatus, grown for 11 days in basidiomycetes rich medium containing [14C] phenanthrene, metabolized 94% of the phenanthrene added. Of the total radioactivity, 3% was oxidized to CO2. Approximately 52% of phenanthrene was metabolized to trans-9,10-dihydroxy-9,10-dihydrophenanthrene (phenanthrene trans-9,10-dihydrodiol) (28%), 2,2'-diphenic acid (17%), and unidentified metabolites (7%). Nonextractable metabolites accounted for 35% of the total radioactivity. The metabolites were extracted with ethyl acetate, separated by reversed-phase high-performance liquid chromatography, and characterized by 1H nuclear magnetic resonance, mass spectrometry, and UV spectroscopy analyses. 18O2-labeling experiments indicated that one atom of oxygen was incorporated into the phenanthrene trans-9,10-dihydrodiol. Circular dichroism spectra of the phenanthrene trans-9,10-dihydrodiol indicated that the absolute configuration of the predominant enantiomer was 9R,10R, which is different from that of the principal enantiomer produced by Phanerochaete chrysosporium. Significantly less phenanthrene trans-9,10-dihydrodiol was observed in incubations with the cytochrome P-450 inhibitor SKF 525-A (77% decrease), 1-aminobenzotriazole (83% decrease), or fluoxetine (63% decrease). These experiments with cytochrome P-450 inhibitors and 18O2 labeling and the formation of phenanthrene trans-9R,10R-dihydrodiol as the predominant metabolite suggest that P. ostreatus initially oxidizes phenanthrene stereoselectively by a cytochrome P-450 monoxygenase and that this is followed by epoxide hydrolase-catalyzed hydration reactions.

Biodegradation, Environmental↗

PubMed1996

Initial Oxidation Products in the Metabolism of Pyrene, Anthracene, Fluorene, and Dibenzothiophene by the White Rot Fungus Pleurotus ostreatus.

The initial metabolites in the degradation of pyrene, anthracene, fluorene, and dibenzothiophene by Pleurotus ostreatus were isolated by high-pressure liquid chromatography and characterized by UV-visible, gas-chromatographic, mass-spectrometric, and (sup1)H nuclear magnetic resonance spectral techniques. The metabolites from pyrene, dibenzothiophene, anthracene, and fluorene amounted to 45, 84, 64, and 96% of the total organic-solvent-extractable metabolites, respectively. Pyrene was metabolized predominantly to pyrene trans-4,5-dihydrodiol. Anthracene was metabolized predominantly to anthracene trans-1,2-dihydrodiol and 9,10-anthraquinone. In contrast, fluorene and dibenzothiophene were oxidized at the aliphatic bridges instead of the aromatic rings. Fluorene was oxidized to 9-fluorenol and 9-fluorenone; dibenzothiophene was oxidized to the sulfoxide and sulfone. Circular dichroism spectroscopy revealed that the major enantiomer of anthracene trans-1,2-dihydrodiol was predominantly in the S,S configuration and the major enantiomer of the pyrene trans-4,5-dihydrodiol was predominantly R,R. These results indicate that the white rot fungus P. ostreatus initially metabolizes polycyclic aromatic hydrocarbons by reactions similar to those previously reported for nonligninolytic fungi. However, P. ostreatus, in contrast to nonligninolytic fungi, can mineralize these polycyclic aromatic hydrocarbons. The identity of the dihydrodiol metabolites implicates a cytochrome P-450 monooxygenase mechanism.

Journal Article↗

PubMed1996

Metabolism of 2-amino-alpha-carboline. A food-borne heterocyclic amine mutagen and carcinogen by human and rodent liver microsomes and by human cytochrome P4501A2.

2-Amino-alpha-carboline (A alpha C) is a mutagenic and carcinogenic heterocyclic amine that is formed as a pyrolysis product during the high temperature cooking of food and the burning of tobacco. Human, rat, and mouse hepatic microsomes each catalyzed the NADPH-dependent oxidation of A alpha C to form six products separable by HPLC. The two major metabolites, which together accounted for approximately 85% of the total metabolism, were characterized by UV, fluorescence, proton magnetic resonance, and mass spectral analyses as 3-hydroxy-A alpha C and 6-hydroxy-A alpha C. The remaining 15% were judged to be N-hydroxy-A alpha C and its oxidation products, based on chromatographic and spectral comparisons with a standard, whose synthesis and characterization are also described. Although the proportions of each metabolite were similar across species and individuals, the overall rate of metabolism of A alpha C by human hepatic microsomes showed a wide interindividual variation (37-fold), with a mean activity that was comparable with that observed with rat or mouse liver microsomes. alpha-Naphthoflavone, a selective inhibitor for cytochromes P4501A1 and P4501A2, strongly inhibited formation of both ring-hydroxylation and N-oxidation products by human, rat, or mouse liver hepatic microsomes. In addition, A alpha C oxidation was strongly correlated (r = 0.98; p < 0.001) with the oxidation of 4-aminobiphenyl, a known selective substrate for human and rodent cytochromes P4501A2. Immunoblot analyses confirmed the presence of cytochromes P4501A2, and not P4501A1, in human liver microsomes. Additional studies using recombinant human cytochromes P450 show that high catalytic activity for A alpha C metabolism was associated with human cytochrome P4501A2. Lower, but significant activity was also noted for P4501A1 and P4502C10, which could have important implications for the metabolic activation of A alpha C extrahepatic tissues. Neither A alpha C metabolism nor immunoreactive cytochrome P4501A2 (or P4501A1) was detected in human pancreatic microsomes. Although further carcinogenicity and biomarker studies for A alpha C are needed, the high rate of A alpha C metabolism by human liver cytochrome P4501A2 suggests that humans with the rapid P4501A2 phenotype with may be more susceptible than rodents to this heterocyclic amine carcinogen.

Animals↗

PubMed1995

AC corona-discharge aerosol-neutralization device adapted to liquid chromatography/particle beam/mass spectrometry.

An AC corona-discharge device was inserted upstream of a thermospray vaporizer tip in a liquid chromatography/particle beam mass spectrometer to neutralize static aerosol charging. Response of a test analyte was measured with or without discharge initiation. If the solvent contained no ammonium acetate buffer, increased analyte signal was associated with the discharge. However, in the presence of ammonium acetate the benefit of AC discharge neutralization was either not observed or was more subtle. This led to the conclusion that the previously observed ammonium acetate "carrier" effect is attributable, at least in part, to neutralization of static electric charges produced spontaneously during the solvent nebulization process. In a second experiment, the pattern of particles issuing from the system momentum separator was examined by aiming the particle beam at a cold target located within a mass spectrometer ion source. Variations in particle density were observed depending on (i) whether or not the aerosol had been neutralized and (ii) the proximity of electron-beam-collimating magnets to the particle beam trajectory. These results are consistent with a hypothesis that electrostatic charging occurs spontaneously during the nebulization process in which an aerosol is formed from the high performance liquid chromatography effluent. Such electrostatic charging introduces a factor likely to degrade system performance by at least two modes: through interactions of the charged aerosol particles (i) with the walls of the aerosol transmission pathway, and, after they are accelerated into a particle beam and introduced into the mass spectrometer, (ii) with the magnets used for electron beam collimation in many mass spectrometer ion sources.

Acetates↗

PubMed1995

Biotransformation of amitriptyline by Cunninghamella elegans.

A fungal biotransformation system as an in vitro model for mammalian drug metabolism was investigated. Amitriptyline, a widely used antidepressant, was effectively biotransformed within 72 hr by the filamentous fungus, Cunninghamella elegans. Eight major metabolites in HPLC elution order (11-hydroxyamitriptyline N-oxide, 11-hydroxynortriptyline, 11-hydroxyamitriptyline, 10-hydroxyamitriptyline, 3-hydroxyamitriptyline, 2-hydroxyamitriptyline, nortriptyline, and amitriptyline N-oxide) were produced at estimated molar ratios of 2:1:10:0.6:0.1:1.2.5:0.5, respectively. These metabolites were isolated by HPLC and identified by UV/MS analyses, as well as NMR spectroscopic analysis for most of these metabolites. In some cases, they were also compared with authentic standards. Glucose, culture age, and substrate concentration significantly affected the extent of amitriptyline metabolism. Kinetic studies indicated that nortriptyline and 11-hydroxyamitriptyline were produced as initial major metabolites. The hydroxylated metabolite was excreted from mycelia, but amitriptyline and its N-demethylated metabolite, nortriptyline, were not. An 18O2 labeling experiment showed that the oxygen atoms in 11-hydroxyamitriptyline and 2-hydroxyamitriptyline were derived from molecular oxygen. The cytochrome P450 inhibitors SKF 525-A (1.5 mM), metyrapone (2.0 mM), and 1-aminobenzotriazole (1.0 mM) inhibited the biotransformations of amitriptyline by 50, 75, and 95%, respectively. A microsomal preparation was shown to catalyze the 11-hydroxylation of amitriptyline, which was inhibited by SKF 525-A and carbon monoxide. The similarities of amitriptyline metabolism in C. elegans and in humans and rats are discussed.

Amitriptyline↗

PubMed1994

Extravascular fluid uptake during cardiopulmonary bypass in hypertensive dogs.

We investigated the effects of increases in central venous pressure (CVP) and carotid baroreceptor-induced vasodilation on the rate of extravascular fluid uptake during cardiopulmonary bypass in normotensive and Goldblatt hypertensive dogs. Carotid sinus baroreceptors were selectively perfused to control the level of vasodilation. Central venous pressure was controlled by changing the height of the venous outflow cannula. Extravascular fluid uptake was determined from the rate of change in reservoir volume. After 3 hours of bypass, total fluid accumulation was 56.11 +/- 14.16 mL/kg in normotensive dogs, significantly less than in hypertensive dogs (110.90 +/- 23.20 mL/kg) (p < 0.05). Raising CVP from 1 to 5 mm Hg increased the rate of extravascular fluid uptake in both normotensive (from 0.05 +/- 0.25 to 0.85 +/- 0.22 mL.kg-1.min-1; p < 0.05) and hypertensive dogs (from 0.68 +/- 0.28 to 2.57 +/- 0.46 mL.kg-1.min-1; p < 0.01)). At a constant CVP, baroreceptor-induced vasodilation increased the rate of extravascular fluid uptake in normotensive (from 0.25 +/- .15 to 0.81 +/- .22 mL.kg-1.min-1) and in hypertensive dogs (from 0.84 +/- .12 to 1.72 +/- .32 mL.kg-1.min-1; p < 0.05). Hypertensive dogs were more sensitive to changes in CVP and to baroreceptor-induced vasodilation. The results of this study imply that elevations in CVP or the use of vasodilators may lead to increased extravascular fluid uptake during bypass; this effect may be exacerbated in the hypertensive state.

Animals↗