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R H Adamson

Publications and source records attributed to R H Adamson.

At least 55 records · Page 3Linked to original sources
PubMed1994

Cardiac damage induced by 2-amino-3-methyl-imidazo[4,5-f]quinoline in nonhuman primates.

The heterocyclic aromatic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is a potent hepatocarcinogen in cynomolgus and rhesus monkeys. The finding of high cardiac IQ-DNA adduct levels prompted a histopathological study of perfusion-fixed hearts from 10 tumor-bearing monkeys chronically dosed with IQ at 10 mg/kg or 20 mg/kg 5 days per week for 48-80 months. Two monkeys dosed only with the vehicle for IQ, hydroxypropylcellulose, served as controls. All the monkeys had normal heart weights, and no abnormalities were observed upon gross inspection of the hearts. Microscopically, focal myocardial lesions were observed in 8 of 10 monkeys dosed with IQ. Light microscopic abnormalities included myocyte necrosis with or without chronic inflammatory infiltrates, interstitial fibrosis with myocyte hypertrophy or atrophy, and vasculitis. Electron microscopic findings included disruption of the mitochondrial architecture (i.e., mitochondrial swelling and clearing of matrix densities), myofibrillar loss, disorganization of the normal alignment of sarcomeres, and occasional myocytes showing nuclear hypertrophy or peripheral clumping of the nuclear chromatin. There was some correlation between the cumulative dose of IQ and the extent of the myocardial abnormalities. These findings suggest that chronic exposure to IQ can lead to myocardial damage in monkeys. Although focal and not associated with clinical evidence of heart failure, these abnormalities may represent the initial stages of IQ-induced toxic cardiomyopathy.

Animals↗
PubMed1994

Quantitative laser scanning confocal microscopy on single capillaries: permeability measurement.

OBJECTIVE: We tested the hypothesis that there is significant solute loss to the superfusate during microvessel solute permeability measurement in frog mesentery which leads to underestimation of permeability coefficient. This is the first application of laser-scanning confocal microscopy to measure microvessel permeability. METHODS: Microvessel permeability to sodium fluorescein (0.5 mg/ml, MW 376) was measured in the presence of bovine serum albumin (10 mg/ml) in Ringer's solution. Every 11-12s an optical section transverse to the vessel axis (x-z section) was collected. The images were corrected for fluorescence attenuation in the z direction and nonuniformity of light collection (shading) in the x direction by comparison to a fluorescent standard. Extravascular fluorescence, which increased linearly with time, and the step increase in fluorescence intensity of the vessel lumen were used to calculate an apparent permeability. Measurements were made first with the tissue superfused with Ringer and second after changing the superfusate to mineral oil in order to retain solute potentially lost to Ringer superfusate. RESULTS: The permeability to fluorescein measured with Ringer superfusate (5.0 +/- SD 2.6 x 10(-5) cm/s; n = 3) was not different from that measured with mineral oil covering the upper mesothelial surface (4.5 +/- 1.9). CONCLUSIONS: Therefore, the loss of sodium fluorescein through the upper mesothelium does not significantly alter permeability under these conditions. These techniques enable detailed analysis of solute concentration gradients surrounding microvessels.

Animals↗
PubMed1993

Studies on the mutagenic activation of heterocyclic amines by cynomolgus monkey, rat and human microsomes show that cynomolgus monkeys have a low capacity to N-oxidize the quinoxaline-type heterocyclic amines.

A number of mutagens and carcinogens have been isolated from cooked meats. In the current study we investigated the ability of hepatic microsomes from cynomolgus monkeys, Fischer-344 rats and humans to metabolically activate these compounds. Monkeys had almost no capacity to activate the quinoxaline-type compounds to mutagens in the Ames test relative to rats and humans but were able to activate the quinoline, pyridoindole and pyridoimidazole compounds. Differences in the mutagenicity of the quinoline and quinoxaline compounds by monkeys and rats was related to differences in cytochrome P-450-mediated N-oxidation between the species. This suggests that monkeys and rats may have different hepatic cytochrome P-450 isozymes, which are important for the metabolic activation of quinolines and quinoxalines, or that the orthologous monkey cytochromes show a select substrate specificity for the quinolines over the quinoxalines.

Animals↗
PubMed1993

Microvascular endothelial cell shape and size in situ.

To estimate total cleft length per unit surface area, previous studies assumed that endothelial cell clefts were oriented randomly with respect to the axis of the microvessel (Bundgaard and Frøkjaer-Jensen, Microvasc. Res. 23, 1-30, 1982). In the present study, silver precipitation along the intercellular clefts of capillary endothelium ("silver lines") in the frog mesentery allowed observation of cleft orientation as well as estimation of cell shape, cell area (CA), and cleft length per unit area (CL). In all vessels, the endothelial cells were highly elongated polygons, usually hexagonal, which were oriented along the vessel axis. The clefts were highly oriented with a preferred orientation which was parallel to the vessel axis. Clefts exhibited very little local meandering, with a contour length only 7% greater than endpoint-to-endpoint length. Therefore, the assumption of random cleft orientation was not valid, and its use yielded an overestimate of CL. New estimates of CL were 0.16, 0.12, and 0.12 microns-1 for arterial, true, and venous capillaries, respectively. Cell lengths (mean +/- SD, n) were 135 microns (+/- 28, 79) in arterial capillaries, 98 microns (+/- 28, 19) in true capillaries, and 139 microns (+/- 20, 21) in venous capillaries.

Animals↗
PubMed1993

Mutagenic activation of IQ, PhIP and MeIQx by hepatic microsomes from rat, monkey and man: low mutagenic activation of MeIQx in cynomolgus monkeys in vitro reflects low DNA adduct levels in vivo.

Cooked meat, poultry and fish contain a number of mutagenic and carcinogenic heterocyclic amines, including 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). In the present study we examined the capacity of hepatic microsomes from Fischer 344 rats, cynomolgus monkeys and humans to metabolically activate IQ, MeIQx and PhIP in vitro using the Ames Salmonella mutagenicity assay. The mutagenic activation of IQ was similar among the three species; however, there were significant differences among the species in the activation of PhIP and MeIQx. Liver microsomes from humans showed the greatest capacity to activate PhIP and MeIQx, followed by rats, and then monkeys. The largest differences between the species were observed when MeIQx was used as the mutagen. MeIQx-DNA adducts formed in vivo were then compared among rats and monkeys given MeIQx by gavage (20 mg/kg/day, 10 doses). 32P-Postlabeling analysis, carried out under intensification conditions, was used to examine MeIQx-DNA adducts in the liver, kidney, heart, colon and white blood cells. MeIQx-DNA adducts were highest in all tissues examined from male rats, followed by female rats, and much lower in monkeys. In the liver, the total MeIQx-DNA adduct levels of monkeys were approximately 19 and approximately 10 times lower than in male and female rats respectively. In extrahepatic tissues, the differences in MeIQx-DNA adduct levels between monkeys and rats were even greater. The results suggest that the low level of MeIQx-DNA adducts found in vivo in cynomolgus monkeys reflects a low capacity to activate MeIQx via the hepatic cytochrome P450 monooxygenase system.

Animals↗
PubMed1993

Pathways through the intercellular clefts of frog mesenteric capillaries.

1. The three-dimensional ultrastructure of endothelial intercellular clefts of frog mesenteric capillaries of known hydraulic permeability (Lp) has been investigated in the absence and presence of lanthanum ions as tracers of extracellular solute. 2. Experiments were carried out on the exposed mesenteries of pithed frogs and Lp of a chosen microvessel perfused with a Ringer solution containing serum albumin (10-40 mg ml-1) was determined. In some experiments the mesentery was fixed in situ with 2.5% glutaraldehyde immediately after Lp had been measured. In other experiments, measurement of Lp was followed by brief microperfusion (10-20 s) with a second Ringer solution containing 1% lanthanum nitrate as a tracer before in situ fixation of the tissue. The tissue was prepared for electron microscopy using standard techniques. The perfused capillary was identified in the block and serial transverse sections were cut along its length over regions where Lp had been measured. 3. In six capillaries where the tissues were fixed immediately after measurement of Lp, Lp had a mean value (+/- S.E.M.) of 4 (+/- 0.5) x 10(-7) cm s-1 (cmH2O)-1. Serial (30-40 nm) sections of these vessels revealed that a single short narrow region of the intercellular clefts ran almost continuously from section to section. Additional tight regions were regularly seen, but they usually extended for relatively few sections. In 13.36 microns of reconstructed cleft, there were three interruptions of the tight region of 0.14, 0.14 and 0.17 microns respectively. In the region of these discontinuities, the wide region was uninterrupted from luminal to abluminal surface. 4. Examination of the tight junction on a tilting stage revealed that the outer leaflets of the adjacent cells were not fused, but separated by a gap of mean width (+/- S.E.M.) 2.3 (+/- 0.1) nm. 5. In four capillaries perfused with lanthanum nitrate before fixation, mean Lp (+/- S.E.M.) was 6.5 (+/- 0.02) x 10(-7) cm s-1 (cmH2O)-1. Segments of intercellular clefts, totalling 23.56 microns in length, were reconstructed from serial sections and throughout these, electron-dense deposits of lanthanum were observed to fill the luminal parts of the intercellular clefts up to the tight region. Lanthanum deposits filled the entire cleft to the abluminal surface at eleven sites, which accounted for a length of 2.52 microns out of the 23.56 microns. Only five of these regions were delimited within a continuous series of sections and their mean length (+/- S.E.M.) was 0.16 (+/- 0.063) microns.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Metabolic activation and genotoxicity of heterocyclic arylamines.

Because of the potential for human exposure to mutagenic and carcinogenic heterocyclic arylamines in the diet, the carcinogenicity of three HAAs, 2-amino-3-methylimidazo[4,5-f]quinoline, 2-amino-3,8-dimethyl-imidazo[4,5-f]quinoxaline, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, is being evaluated in nonhuman primates, especially cynomolgus monkeys. Concomitant with the carcinogenicity studies, the metabolic processing, disposition, and DNA-adduct formation of these compounds are being examined in these monkeys. This report highlights the results from studies in monkeys and from in vitro models examining metabolic activation and genotoxicity of HAAs. The extent of in vivo activation of HAAs in monkeys was assessed by measuring DNA adducts in various tissues. Both 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine form high levels of DNA adducts in a number of organs, particularly the liver, kidney, and heart. The implications of metabolic activation and DNA-adduct formation to the carcinogenicity of HAAs are discussed.

Animals↗
PubMed1992

Plasma proteins modify the endothelial cell glycocalyx of frog mesenteric microvessels.

1. We have investigated the interaction of plasma proteins with the endothelial cell using cationized ferritin as a marker of the cell surface glycocalyx. 2. Single microvessels of the frog mesentery were sequentially perfused using glass micropipettes with solutions containing cationized ferritin (CF, 6.7 mg ml-1) in 0.10 M-NaCl and then with either frog plasma or bovine serum albumin (BSA; 50 or 10 mg ml-1), or protein-free Ringer solution, before suffusion fixation in 2.5% glutaraldehyde. 3. A layer of CF, usually two to four molecules thick, was associated with the luminal endothelial cell surface. In vessels post-flushed with protein-free Ringer solution the CF layer was closely adherent to all regions of the luminal endothelium, including the plasma membrane, vesicle diaphragms, coated pits and the entrances to clefts. However, when plasma was present during fixation the CF layer was separated from the cell surface by up to 100 nm over all regions. In vessels post-flushed with BSA the CF layer was also separated from the membrane but the effect was less striking. 4. The association of cationized ferritin with the endothelial cell surface was assessed quantitatively using electron micrographs of transverse sections (approximately 50 nm thick) of the perfused vessels, and expressed in terms of the depth of the layer of CF associated with the endothelial cell surface, its separation from the plasma membrane of the luminal endothelium, and the concentration of CF in the layer. The mean (+/- S.D.) separation in the presence of plasma, 32.3 +/- 10.5 nm (n = 12), was significantly greater (P less than 0.01) than that with either protein-free Ringer solution, 3.0 +/- 1.4 nm (n = 9), or BSA in Ringer solution, 8.3 +/- 3.0 nm (n = 8). The separation seen with BSA in Ringer was also significantly greater than that measured with a final Ringer solution perfusion (P less than 0.01). The effects of 10 and 50 mg ml-1 BSA were not different from one another. The total glycocalyx thickness, defined as the sum of the separation layer and depth of CF layer, with plasma present, 56.2 +/- 13.7 nm, was twice the value seen with Ringer solution, 28.0 +/- 9.1 nm (P less than 0.01), while the total thickness with BSA, 30.9 +/- 5.4 nm, was not different from the Ringer solution value.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Carcinogenicity of 2-amino-3-methylimidazo[4,5-f]quinoline in nonhuman primates: induction of tumors in three macaques.

The carcinogenic potential of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) was evaluated in cynomolgus monkeys. Monkeys received IQ, beginning at the age of one year, at doses of 10 or 20 mg/kg by gavage. Thus far, IQ has induced hepatocellular carcinoma in three monkeys with a latent period of 27 to 37 months. Metastases to the lung occurred in two of the three monkeys. Microscopically, the hepatocellular carcinoma in all three cases demonstrated a trabecular pattern. These data demonstrate that IQ is a potent carcinogen in nonhuman primates and support the idea that it is a potential carcinogen for humans.

Animals↗
PubMed1990

Permeability of frog mesenteric capillaries after partial pronase digestion of the endothelial glycocalyx.

1. The proteolytic enzyme pronase, which degrades the endothelial cell glycocalyx, was perfused through single capillaries of frog mesentery. Hydraulic conductivity (Lp) of each vessel was determined before and after pronase perfusion. In three vessels in which Lp increased, the ultrastructure of interendothelial clefts was examined. In a separate group of frogs the effect of pronase on the endothelial glycocalyx was assessed by using cationized ferritin to label the capillary luminal surface. 2. Control Lp was 2.0 x 10(-7) cm s-1 cmH2O-1 (10 mg ml-1 bovine serum albumin, BSA, in frog Ringer solution). Vessels were then perfused with a solution containing 0.1 mg ml-1 pronase and 10 mg ml-1 BSA for 1 min. Lp measured in the same eleven vessels increased to 4.9 x 10(-7) cm s-1 cmH2O-1 (P less than 0.005). 3. Transverse sections of three of these vessels were examined by transmission electron microscopy at eight sites along each vessel. In these sections a total of 156 interendothelial cell clefts were found and photographed. No morphological features, such as fenestrations, transendothelial channels, or intercellular gaps associated with inflammation, were found which might account for the increases in Lp. 4. Measurement of cleft dimensions yielded a harmonic mean cleft depth (delta x) of 0.32 microns and an arithmetic mean cleft depth of 0.64 microns. Mean width (w) of the clefts outside the tight regions was 0.012 microns and the cleft length per unit area (L) was 1330 cm-1. The mean fractional pore area of vessel wall per unit cleft depth, Ap/delta x, calculated as Lw/delta x, was 48.7 cm-1. 5. There was less cationic ferritin (CF) labelling of the luminal glycocalyx in pronase-perfused than in control capillaries. On average, the proportion of the luminal surface covered by CF was 85% in controls and 42% in pronase-treated capillaries (P less than 0.01). In some vessels the CF pattern was greatly disrupted, indicating large changes in the glycocalyx structure. 6. It is concluded that the moderate increases in Lp induced by pronase perfusion are associated with partial digestion of the endothelial glycocalyx but are not accompanied by changes in the dimensions of the intercellular cleft. These observations support the fibre matrix hypothesis of capillary permeability and suggest that the endothelial glycocalyx contributes as much as 60% of the hydraulic resistance of the capillary wall.

Animals↗
PubMed1990

Metabolic processing and carcinogenicity of heterocyclic amines in nonhuman primates.

The potential for human exposure to heterocyclic amine (HAA) mutagens derived from cooking food prompted an evaluation of the disposition and carcinogenicity of three of the HAAs in nonhuman primates, especially cynomolgus monkeys. The three HAAs currently under study are 2-amino-3-methylimidazo [4, 5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx) and 2-amino-1-methyl-6-phenylimidazo [4,5,b]pyridine (PhIP). These three HAAs were selected on the basis of several factors including structure, mutagenic activity in vitro, concentration in cooked meat, activity in rodent carcinogenicity tests and availability. Studies on the disposition of IQ demonstrated that it was extensively metabolized in monkeys and excreted in urine and feces as metabolites. These metabolites represent predominantly detoxification products of IQ. The extent of in vivo activation of IQ and PhIP was assessed by measuring DNA adducts in various tissues and white blood cells of monkeys following administration of the compounds. Both compounds form high levels of DNA adducts in a number of organs, particularly the liver, kidney, and heart. The carcinogenicity of IQ, 8-MeIQx and PhIP in nonhuman primates has been under study for 5 years, 24 months, and 7 months, respectively. Thus far, IQ has induced hepatocellular carcinoma in 3 of 20 monkeys at doses of 10 mg/kg daily, 5 days/week and in 10 of 20 monkeys at 20 mg/kg on the same schedule. Thus, IQ is a potent liver carcinogen in nonhuman primates and a potential carcinogen for humans.

Animals↗
PubMed1989

Induction of hepatocellular carcinoma in nonhuman primates by chemical carcinogens.

Several compounds were evaluated in nonhuman primates for their potential to induce neoplasms, especially hepatocellular carcinoma (HCC). The compounds can be classified into three groups: food contaminants, model rodent carcinogens, and nitrosamines. All three compounds in the food contaminants group, namely, aflatoxin B1, sterigmatocystin, and methylazoxymethanol acetate, induced HCC. None of the model rodent carcinogens tested consistently induced HCC in rhesus and cynomolgus monkeys. Three of four nitrosamines evaluated induced HCC in rhesus and cynomolgus monkeys. One nitrosamine, diethylnitrosamine, is a predictable and potent inducer of HCC and is useful for establishment of a nonhuman primate model for numerous oncologic studies.

2-Acetylaminofluorene↗
PubMed1988

Use of the 32P-postlabeling method to detect DNA adducts of 2-amino-3-methylimidazolo[4,5-f]quinoline (IQ) in monkeys fed IQ: identification of the N-(deoxyguanosin-8-yl)-IQ adduct.

Eight DNA adducts of 2-amino-3-methylimidazolo[4,5-f]-quinoline (IQ) were found by the standard 32P-postlabeling method in livers from male Cynomolgus monkeys fed IQ (5 days/week, 3 weeks, 20 mg/kg, nasal-gastric intubation). The IQ-DNA adduct fingerprints observed in monkeys were identical to those observed in rats that received IQ (0.03%) in the diet for 2 weeks. The C8-guanine-IQ adduct was identified by comigration with the synthetic 3',5'-bisphosphate derivative of N(-deoxyguanosin-8-yl)-IQ. DNA modified in vitro with N-hydroxy-IQ showed seven adducts, including the C8-guanine-IQ adduct, that were identical to those found in monkeys and rats. Thus it appears that N-hydroxy-IQ, the reactive metabolite of IQ, was responsible for all adducts found in vivo, except one. In order to detect adducts in other organs that were present at lower levels, the intensification (ATP-deficient) method for 32P-postlabeling was used. Five of the adducts detected under standard conditions, including the C8-guanine-IQ adduct, were also detected under intensification conditions. The total level of DNA-IQ adducts was highest in the liver, followed by the kidney, colon and stomach, and bladder. The adduct patterns were identical in all organs examined. The results indicate that IQ is potentially genotoxic in primates and therefore a likely human carcinogen.

Animals↗
PubMed1988

Mutagenicity and in vitro covalent DNA binding of 2-hydroxyamino-3-methylimidazolo[4,5-f]quinoline.

The 2-hydroxyamino-3-methylimidazolo[4,5-f]quinoline (N-hydroxy-IQ), a metabolite of the food mutagen--carcinogen IQ, was mutagenic to Salmonella TA98 (nitroreductase deficient). When either rat hepatic cytosol, NADPH (1 mM) or ascorbate (0.5 mM) was added to the mutagenicity assay, mutagenicity increased up to 15-, 10- and 50-fold respectively. In light of the effects of ascorbate and NADPH, it appears likely that hepatic cytosol may contain factors that protect N-hydroxy-IQ from oxidative decomposition. In contrast, hepatic monooxygenase metabolism of N-hydroxy-IQ decreased mutagenicity. When pentachlorophenol, an inhibitor of O-acetyltransferase and sulfotransferase, was added to the mutagenicity assay, a dose-dependent inhibition of N-hydroxy-IQ mutagenicity was observed. 2,6-Dichloro-4-nitrophenol, a more specific inhibitor of sulfotransferase than O- acetyltransferase, did not inhibit the mutagenicity of N-hydroxy-IQ at concentrations which appear to selectively inhibit only bacterial sulfotransferase. The data suggest that bacterial O-acetyltransferase rather than sulfotransferase mutagenically activates N-hydroxy-IQ. N-hydroxy-IQ covalently bound to calf thymus DNA in vitro under non-enzymatic conditions at pH 7.4. Rat hepatic cytosolic O-acetyltransferase and sulfotransferase enhanced the covalent binding of N-hydroxy-IQ to DNA 30- and 5-fold respectively. The data suggest that the mutagenicity of N-hydroxy-IQ is due to the reactivity of N-hydroxy-IQ with DNA and the ability of N-hydroxy-IQ to be further activated by bacterial O-acetyltransferase.

Acetyltransferases↗
PubMed1988

Reaction of N-hydroxylamine and N-acetoxy derivatives of 2-amino-3-methylimidazolo[4,5-f]quinoline with DNA. Synthesis and identification of N-(deoxyguanosin-8-yl)-IQ.

The N-hydroxylamine of the carcinogen 2-amino-3-methylimidazolo[4,5-f]quinoline (IQ) covalently bound to calf thymus DNA at pH 7, and the binding was 11% higher under acidic conditions (pH 5). The extent of N-hydroxy-IQ binding to single-stranded polynucleotides at neutral pH was in the following order: polyguanylic acid much greater than polyadenylic acid greater than polycytidylic acid = polyuridylic acid. The binding of the carcinogen to DNA, polyguanylic acid and polyadenylic acid at neutral pH was enhanced 6-, 4- and 2-fold respectively by the presumed in situ formation of N-acetoxy-IQ from N-hydroxy-IQ and acetic anhydride. N-(Deoxyguanosin-8-yl)-IQ was synthesized by reaction at pH 7 of N-acetoxy-IQ (formed in situ with N-hydroxy-IQ and acetic anhydride) with deoxyguanosine and the structure characterized by NMR, mass spectral and UV absorption spectral analyses. Reverse phase HPLC of enzymatically hydrolyzed DNA which had been reacted with N-hydroxy-IQ in vitro showed a major adduct which was chromatographically identical to synthetic N-(deoxyguanosin-8-yl)-IQ. In addition, N-acetoxy-IQ, generated chemically by acetic anhydride or enzymatically with mammalian acetyltransferase, formed one major adduct with DNA which was chromatographically identical to the synthetic N-(deoxyguanosin-8-yl)-IQ. The results indicate that N-hydroxy-IQ and N-acetoxy-IQ react with DNA forming primarily the N-(deoxyguanosin-8-yl)-IQ adduct.

Acetates↗
PubMed1988

Single capillary permeability to proteins having similar size but different charge.

We investigated the hypothesis that solute charge modulates transcapillary exchange in microvessels with continuous endothelium. Two globular proteins, alpha-lactalbumin and ribonuclease, having approximately the same size (mol wt 14,176 and 13,683, respectively) but different net charge (-10 and +4, respectively) were test solutes. Each solute was labeled with the fluorescent probe tetramethylrhodamine isothiocyanate. Labeling did not significantly change solute size, but increased negative charge on each solute by one valency unit. An in vivo fluorescent microscope technique [Huxley et. al., Am. J. Physiol. 252 (Heart Circ. Physiol. 21): H188-H197, 1987] was used to measure solute permeability coefficients (P) in single microvessels of frog mesentery at 14-16 degrees C. The mean P for alpha-lactalbumin, measured when capillary pressure was 10 cmH2O, was 2.1 X 10(-6) cm/s and the mean P for ribonuclease was 4.3 X 10(-6) cm/s. Our results conform to the hypothesis that the transcapillary pathways of frog mesenteric microvessels are negatively charged. With the use of a Donnan-type model for electrostatic partitioning, charge density in the pathway is estimated as 11.4 meq/l. Comparison of measured Ps with those for small solutes in frog mesenteric microvessels indicates that molecular size is a proportionally more significant determinant of solute permeability in continuous capillaries than is solute charge.

Algorithms↗