Biomedical subjects

R J Price

Publications and source records attributed to R J Price.

At least 73 records · Page 4Linked to original sources

PubMed1995

Toxicity of 3-methylindole, 1-nitronaphthalene and paraquat in precision-cut rat lung slices.

The toxicity of 3-methylindole, 1-nitronaphthalene and paraquat has been studied in precision-cut rat lung slice cultures. Lung slices were prepared from male Sprague-Dawley rats using an agarose gel instilling technique with a Krumdieck tissue slicer and cultured for 24 h in a dynamic organ culture system. Treatment of rat lung slices with 3-methylindole, 1-nitronaphthalene or paraquat produced concentration dependent decreases in lung slice protein synthesis and potassium content. EC50 values (concentration to produce a 50% inhibition) for protein synthesis were 0.024, 0.27 and 0.57 mM for paraquat, 1-nitronaphthalene and 3-methylindole, respectively. These results demonstrate that precision-cut lung slices are a useful in vitro model system for studying the pulmonary toxicity of xenobiotics. Lung slices offer the potential as a rapid in vitro screen for identifying pulmonary toxicants and to evaluate species differences in response.

Animals↗

PubMed1995

Comparison of the metabolism of 7-ethoxycoumarin and coumarin in precision-cut rat liver and lung slices.

The metabolism of 7-ethoxycoumarin and [3-(14)C]coumarin was compared in precision-cut rat liver and lung slices. The lung slices were prepared using an agarose gel instilling technique enabling the production of tissue cylinders followed by lung slices employing a Krumdieck tissue slicer. Both 50 microM 7-ethoxycoumarin and 50 microM [3-(14)C]coumarin were metabolized by rat liver and lung slices. 7-Ethoxycoumarin was converted to 7-hydroxycoumarin (7-HC) which was conjugated with both D-glucuronic acid and sulfate. 7-HC sulfate was the major metabolite formed by both liver and lung slices. [3-(14)C]Coumarin was metabolized by rat liver and lung slices to both polar products and to metabolite(s) that bound covalently to tissue slice proteins. The polar products included unidentified metabolites and 3-hydroxylation pathway products, with only very small quantities of 7-HC being formed. These results demonstrate that precision-cut lung slices are a useful model in vitro system for studying the pulmonary metabolism of xenobiotics. Moreover, the precision-cut tissue slice technique may be employed for comparisons of hepatic and extrahepatic xenobiotic metabolism.

Animals↗

PubMed1995

Metabolism of coumarin by precision-cut calf liver slices and calf liver microsomes.

1. The metabolism of 50 microM [3-14C]coumarin has been studied in precision-cut-calf liver slices. 2. The metabolism of 50 microM coumarin to 7-hydroxycoumarin has also been examined in calf, rat, Cynomolgus monkey and human liver microsomal preparations. 3. In precision-cut calf liver slices, [3-14C]coumarin was metabolized to various polar products and to metabolite(s) that bound covalently to calf liver slice proteins. The polar products included 7-hydroxycoumarin (which was extensively conjugated with D-glucuronic acid and/or sulphate), metabolites of the 3-hydroxylation pathway (mainly o-hydroxyphenylethanol and o-hydroxyphenylacetic acid), and unknown metabolites. 4. Coumarin 7-hydroxylase activity was readily detectable in calf, Cynomolgus monkey and human liver microsomes, but only barely detectable in rat liver microsomes. Enzyme activity in calf, Cynomolgus monkey and human liver microsomes was inhibited by 8-methoxypsoralen (methoxsalen) with IC50's (concentration required to produce a 50% inhibition of enzyme activity) ranging from 0.3 to 2.8 microM. 5. These results and those of other studies demonstrate that precision-cut liver slices are a valuable in vitro model system for investigating species differences in xenobiotic metabolism. Coumarin is metabolized in calf liver by various pathways including both 3- and 7-hydroxylation. The inhibition of coumarin 7-hydroxylase activity by 8-methoxypsoralen suggests that calf liver microsomes contain P450A isoenzyme(s) similar to mouse 2A5 and human 2A6.

Animals↗

PubMed1995

A circumferential stress-growth rule predicts arcade arteriole formation in a network model.

OBJECTIVE: To test the hypothesis that terminal arteriolar remodeling that is stimulated by elevated levels of circumferential wall stress (sigma theta) will proceed in a network pattern that gives rise to new arcade arterioles. METHODS: A network model of two interconnected skeletal muscle arterio-capillary-venous units that incorporated diameter- and hematocrit-dependent blood viscosity was constructed. After computing the control values for wall shear stresses (tau ij) and sigma theta ij, a stimulus was provided by dilating the arterioles and raising input pressure. Wall shear stresses and sigma theta ij were then recomputed. The diameters of transverse arteriolar segments with sigma theta ij greater than a sigma theta threshold were increased by an amount that was dependent on the original diameter and the difference between sigma theta ij and the sigma theta threshold. Capillaries with an intraluminal pressure greater than a specified threshold were converted to terminal arterioles. Separate simulations in which remodeling was stimulated by elevated levels of tau ij were also performed for comparison. RESULTS: Arterialization patterns from simulations of sigma theta ij stimulated arteriolar remodeling were representative of those seen in vivo with arterialization of back-connection capillaries leading to arcade arteriole formation. Simulations based on similar rules for tau ij yielded arterio-venous shunts, which are rarely seen in vivo, but no arcade arterioles. CONCLUSION: The simulations presented here are consistent with the hypothesis that arteriolar remodeling is stimulated by increased levels of circumferential wall stress and that new arcade arteriole formation is a consequence of terminal arteriolar growth.

Animals↗

PubMed1994

Circumferential wall stress as a mechanism for arteriolar rarefaction and proliferation in a network model.

Hypertension results in structural rarefaction of the microvascular arteriolar network while, conversely, decreasing pressure results in arteriolar proliferation. A remodeling mechanism capable of unifying these results remains elusive. A network model of a transverse arteriole tree was used to test whether adaptations to changes in mean circumferential wall stress (sigma theta) could produce realistic structural remodeling. Vessel diameters and network boundary pressures were assigned using experimental data, and control flows (Qij) and sigma theta ij for each vessel were calculated. Mean sigma theta ij in A2 (Strahler order) vessels (sigma m) was 6.62 x 10(4) dynes/cm2. Input pressure was increased by 35% in simulated one-kidney, one-clip (s1K1C) hypertension or decreased by 30% in simulated main feeder ligation (sMFL). Vessel diameters were adjusted iteratively until each Qij was restored, simulating autoregulation. Wall stresses decreased 15.9% for hypertension (sigma m = 5.57 x 10(4) dynes/cm2), but were elevated 60.9% for main feeder ligation (sigma m = 10.65 x 10(4) dynes/cm2), A stress-growth principle was applied, so that stresses above an upper threshold cause growth while stresses below a lower threshold cause resorption. Individual vessels with sigma theta ij < 5.24 x 10(4) dynes/cm2 were removed while new A2 segments were added to A2 vessels with sigma theta ij > 8.27 x 10(4) dynes/cm2. The network structure was adjusted until all sigma theta ij were within these stress thresholds. The number of A2s decreased 22% in s1K1C and increased 96% in sMFL in quantitative agreement with experimental data, consistent with the hypothesis that wall stress may be an important determinant of network remodeling. Arteriolar proliferation and rarefaction represent adaptations to different hemodynamic conditions, but may be governed by a common stress-growth principle.

Adaptation, Physiological↗

PubMed1994

Studies on the acute effects of coumarin and some coumarin derivatives in the rat.

The mechanism of acute coumarin-induced hepatotoxicity in the rat has been investigated by comparing the effects of coumarin with those of a number of methyl-substituted coumarin derivatives. Male Sprague-Dawley rats were given single ip doses of corn oil (control), coumarin (0.86 and 1.71 mmol/kg body weight), 3,4-dimethylcoumarin (3,4-DMC, 1.71 and 2.57 mmol/kg), 3-, 4- and 6-methylcoumarins (3-MC, 4-MC and 6-MC, 1.71 mmol/kg) and 3- and 4-methyloctahydrocoumarins (3-MOHC and 4-MOHC, 2.57 mmol/kg) and hepatotoxicity assessed after 24 hr. Coumarin administration produced dose-related hepatic necrosis and a marked elevation of plasma alanine aminotransferase and aspartate aminotransferase activities. In contrast, none of the coumarin derivatives examined produced either hepatic necrosis or elevated plasma transaminase activities. Treatment with coumarin reduced hepatic microsomal ethylmorphine N-demethylase and 7-ethoxycoumarin O-deethylase activities, whereas one or both mixed-function oxidases appeared to be induced by treatment with 3,4-DMC, 4-MC, 3-MOHC and 4-MOHC. These results provide further evidence that acute coumarin-induced hepatotoxicity in the rat is due to the formation of a coumarin 3,4-epoxide intermediate. That 3- and/or 4-methyl substitution (i.e. 3-MC, 4-MC and 3,4-DMC) leads to a reduction in coumarin-induced hepatotoxicity, due to diminished formation of 3,4-epoxide intermediates, was confirmed by the results of molecular orbital calculations.

7-Alkoxycoumarin O-Dealkylase↗

PubMed1994

Sex and strain differences in mouse hepatic microsomal coumarin 7-hydroxylase activity.

Hepatic microsomal coumarin 7-hydroxylase activity has been determined in male and female mice of strains A/J, AKR, BALB/c, CBA/Ca, C3H/He, C57BL/6J, DBA/2 and 129. In males, coumarin 7-hydroxylase activity was highest in liver microsomes from DBA/2 mice and lowest in BALB/c mice. With female mice enzyme activity was highest in DBA/2 and 129 strains, intermediate in the CBA/Ca strain and comparatively low in the other five strains. Marked sex differences were observed in coumarin 7-hydroxylase activity with enzyme activity in female animals from strains DBA/2, 129 and CBA/Ca being 4.8-, 6.2- and 4.8-fold higher, respectively, than in male mice. In contrast, only minor sex and strain differences in levels of total microsomal cytochrome P-450 were observed. These results demonstrate marked sex and strain differences in mouse hepatic microsomal coumarin 7-hydroxylase activity. Such differences may be due to variations in particular cytochrome P-450 isoenzymes such as CYP2A5, not all of which can be explained by the known allelic difference in the Cyp2a-5 locus.

Animals↗

PubMed1994

Use of precision-cut liver slices for studies of unscheduled DNA synthesis.

Precision-cut liver slices were prepared from untreated and Aroclor 1254 (ARO)-treated male Sprague-Dawley rats with a Krumdieck tissue slicer. Liver slices were cultured for 24 hr in medium containing [3H]thymidine and 0-0.1 mM 2-acetylaminofluorene (2-AAF) using a dynamic organ culture system and processed for autoradiographic evaluation of unscheduled DNA synthesis (UDS). Compared with control (i.e. 0 mM 2-AAF) liver slice cultures, 2-AAF produced a concentration-dependent increase in UDS, the effect being more marked in liver slices from ARO-treated than from untreated rats. With liver slices from untreated rats, 2-AAF produced the greatest increase in UDS in centrilobular hepatocytes. 2-AAF-induced UDS in liver slices from ARO-treated rats was most marked in centrilobular hepatocytes but the effect also extended to other areas of the liver lobule. These results demonstrate that precision-cut liver slices may be a valuable alternative in vitro system to hepatocyte cultures for screening chemicals for potential genotoxicity. Unlike hepatocyte cultures, liver slices permit the study of zonal differences in UDS. Moreover, this technique could be applied to other tissues and the study of species differences in response.

2-Acetylaminofluorene↗

PubMed1994

Comparison of the hepatic effects of coumarin, 3,4-dimethylcoumarin, dihydrocoumarin and 6-methylcoumarin in the rat.

The mechanism of coumarin-induced hepatotoxicity in the rat has been investigated by comparing the effects of coumarin with those of three coumarin derivatives, namely 3,4-dihydrocoumarin (DHC), 3,4-dimethylcoumarin (3,4-DMC) and 6-methylcoumarin (6-MC). Male Sprague-Dawley rats were fed either control diet or diets containing 0.5 or 0.75% coumarin, 0.76% DHC, 0.6 or 0.9% 3,4-DMC or 0.82% 6-MC for 13 wk. The dietary levels of 0.5% coumarin and 0.6% 3,4-DMC, were equimolar (3.43 mmol/100 g diet), as were the dietary levels of 0.75% coumarin, 0.76% DHC, 0.9% 3,4-DMC and 0.82% 6-MC (5.14 mmol/100 g diet). All treatments resulted in an increase in relative liver weight, but only coumarin increased plasma alanine aminotransferase and aspartate aminotransferase activities. Morphological examination of liver sections from coumarin treated rats revealed vacuolation of centrilobular hepatocytes and bile duct hyperplasia. Cholangiofibrosis was also observed, particularly in rats given 0.75% coumarin. Treatment with DHC produced no abnormalities, whereas a slight hypertrophy of centrilobular hepatocytes was observed in some 3,4-DMC treated animals and a slight vacuolation of individual hepatocytes was noted in some 6-MC treated rats. DHC, 6-MC and particularly 3,4-DMC treatment resulted in an induction of cytochrome P-450 dependent mixed function oxidase enzyme activities. All treatments induced hepatic GSHS-transferase and gamma-glutamyltransferase activities, induction being most marked in rats given coumarin and 6-MC. These results provide further evidence that coumarin-induced hepatotoxicity in the rat is due to the formation of a 3,4-epoxide intermediate.

Animals↗

PubMed1994

Effect of some peroxisome proliferators on transforming growth factor-beta 1 gene expression and insulin-like growth factor II/mannose-6-phosphate receptor gene expression in rat liver.

Male Sprague-Dawley rats were given daily oral doses of either corn oil (control), 80 mg/kg nafenopin (NAF), 50 mg/kg methylclofenapate (MCP), 50 mg/kg Wy-14,643 (WY) or 250 mg/kg clofibric acid (CA) for 7 days. All four compounds increased relative liver weight and produced hepatic peroxisome proliferation as assessed by induction of both peroxisomal (palmitoyl-CoA oxidation) and microsomal (lauric acid 12-hydroxylase) fatty acid oxidising enzyme activities. RNA was extracted from liver samples and analysed for expression of transforming growth factor-beta 1 (TGF-beta 1) and the insulin-like growth factor II/mannose-6-phosphate (IGFII/Man6P) receptor (which may be involved in transporting latent TGF-beta 1 into hepatocytes). TGF-beta 1 mRNA levels were increased to 151-178% of control by all four compounds, whereas NAF, MCP and WY, but not CA, increased IGFII/Man6P receptor mRNA levels to 195-209% of control. The induction of TGF-beta 1 and IGFII/Man6P receptor expression by short term treatment with peroxisome proliferators may represent an adaptive response to limit the initial hyperplastic effects of such compounds.

Animals↗

PubMed1994

Immunohistochemical identification of arteriolar development using markers of smooth muscle differentiation. Evidence that capillary arterialization proceeds from terminal arterioles.

Arteriolar growth is an important event in the adaptation of normal tissues as well as in important pathologies, but the site of origin of new arterioles remains unknown. The network pattern of arteriolar development in skeletal muscle was detected by use of a new immunohistochemical technique that is based on the observation that fully differentiated (mature) vascular smooth muscle (SM) cells express both SM alpha-actin and the two myosin heavy chains (MHCs) SM-1 and SM-2, whereas less differentiated (immature) vascular SM cells do not express MHC. The anterior gracilis muscle microvasculatures of 4- and 9-week-old Sprague-Dawley rats were labeled with monoclonal antibodies to SM alpha-actin and to SM MHC. Whole transverse arteriole networks were observed, and terminal arterioles, defined as terminal segments labeled with SM alpha-actin, were classified on the basis of the presence or absence of SM MHC. A significantly different percentage of terminal arteriolar endings per network without SM MHC was observed in the two groups (66.1 +/- 17.3% for 4 weeks and 27.1 +/- 18.5% for 9 weeks), suggesting that arteriolar development is more nearly complete in the older animals. Sparsely distributed capillaries exhibited thin extensions of SM alpha-actin that crossed collecting venules and joined similar extensions from an adjacent transverse arteriole, effectively forming the basis for new arcade arterioles. SM alpha-actin and SM MHC labeling in terminal arterioles was always continuous with upstream arterioles.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗

PubMed1994

Metabolism of [3-14C] coumarin by human liver microsomes.

1. The metabolism of 50 microM [3-14C] coumarin has been studied in a panel of 12 human liver microsomal samples of known P450 isoenzyme profile. 2. [3-14C] coumarin was metabolized by human liver microsomes to various polar products including 3-, 4- and 7-hydroxycoumarins (3-HC, 4-HC and 7-HC) 6,7-dihydroxycoumarin (6,7-DiHC), o-coumaric acid (o-CA), o-hydroxyphenyl-acetaldehyde (o-HPA), o-hydroxyphenylethanol (o-HPE), o-hydroxyphenylacetic acid (o-HPAA) and o-hydroxyphenylpropionic acid (o-HPPA) and to product(s) that bind covalently to microsomal proteins. 3. For all 12 subjects, mean rates of [3-14C] coumarin metabolism to total polar products (metabolism to all products except product(s) covalently bound to microsomal proteins), 7-HC, the 3-hydroxylation pathway (sum of 3-HC, o-HPA, o-HPE and o-HPAA), o-HPPA, 6,7-DiHC and covalent binding were 1420, 1230, 73.8, 52.5, 9.5 and 4.8 pmol/min/mg protein respectively. 4. Marked interindividual differences in [3-14C] coumarin metabolism to total polar products (30-fold variation) and 7-HC (2250-fold variation) were observed. 5. Good correlations were observed between [3-14C] coumarin metabolism and total polar products, 7-HC, o-HPPA and 6,7-DiHC, but not to 3-hydroxylation pathway products and levels of 2A6 and 2B6 in human liver microsomes. 6. [3-14C] coumarin metabolism to any polar products did not correlate with levels of 1A2, 2C8, 2C9, 2E1, 3A3/4 and 4A1 in human liver microsomes.

Biotransformation↗

PubMed1994

Metabolism of coumarin and 7-ethoxycoumarin by rat, mouse, guinea pig, cynomolgus monkey and human precision-cut liver slices.

1. The metabolism of 50 microM 7-ethoxycoumarin and 50 microM [3-14C]coumarin has been studied in precision-cut liver slices from the male Sprague-Dawley rat, female DBA/2 mouse, male Dunkin-Hartley guinea pig, male Cynomolgus monkey and man. 2. In liver slices from all five species 7-ethoxycoumarin was metabolized to 7-hydroxycoumarin (7-HC), which was extensively conjugated with D-glucuronic acid and sulphate. In rat and mouse, 7-HC was preferentially conjugated with sulphate, whereas rates of glucuronidation and sulphation were similar in the other three species. 3. [3-14C]coumarin was metabolized by liver slices from all five species to various polar products and to metabolite(s) that bound covalently to liver slice proteins. In Cynomolgus monkey and both human subjects studied, 7-HC was the major metabolite that was conjugated with D-glucuronic acid and sulphate, whereas in rat the major metabolites were products of the 3-hydroxylation pathway and unknown metabolites. Major metabolites in mouse liver slices were 7-HC, 3-hydroxylation pathway products and unknown metabolites, and in guinea pig liver slices, 7-HC and unknown metabolites. 4. The metabolism of 7-ethoxycoumarin to free and conjugated 7-HC and [3-14C]coumarin to total polar products was greater in liver slices from mouse and Cynomolgus monkey than the other three species. 5. With liver slices from all five species there appeared to be little difference in the extent of metabolism of 7-ethoxycoumarin and [3-14C]coumarin to various products in either a complex tissue culture medium (RPMI 1640 plus foetal calf serum) or a simple balanced salt solution (Earle's balanced salt solution). 6. These results demonstrate that precision-cut liver slices are a valuable in vitro model system for investigating species differences in xenobiotic metabolism. Generally, the observed species differences in coumarin metabolism in vitro agree well with available in vivo data.

Animals↗

PubMed1993

Culture of precision-cut liver slices: effect of some peroxisome proliferators.

Precision-cut rat liver slices were prepared with a Krumdieck tissue slicer and cultured in three standard hepatocyte culture media. Rat liver slices cultured in either RPMI 1640 medium or Williams Medium E could be maintained in culture for up to 72 hr. In contrast, Leibovitz's L-15 medium was unsatisfactory in that slice viability, assessed either by morphological examination or by measurement of enzyme activities, could not be maintained for periods greater than 24 hr. As a measure of functional viability liver slices were cultured with some known rodent peroxisome proliferators, namely clofibric acid, nafenopin, ciprofibrate and Wy-14,643. The peroxisome proliferators induced both palmitoyl CoA oxidation and carnitine acetyltransferase activities in 48- and 72-hr slice cultures. Ultrastructural examination of liver slices cultured with either ciprofibrate or Wy-14,643 for 72 hr revealed an increase in the number of peroxisomes. These results demonstrate that rat liver slices may be maintained in culture for up to 72 hr, and that they respond in a similar manner to rat primary hepatocyte cultures to some peroxisome proliferators. Precision-cut liver slices may therefore be a useful alternative in vitro system to hepatocyte cultures for screening compounds for effects on enzyme activities and for assessing species differences in response.

Animals↗

PubMed1993

Induction of cytochrome P-450-dependent enzyme activities in cultured rat liver slices.

Precision-cut liver slices were prepared from male Sprague-Dawley rats with a Krumdieck tissue slicer and cultured in RPMI 1640 medium for up to 72 hr. After 48 hr, cytochrome P-450 content in the slices declined to 36% of levels present in freshly cut rat liver slices. The addition of either beta-naphthoflavone (BNF) or Aroclor 1254 (ARO) partially prevented the loss of cytochrome P-450. Culture of liver slices with phenobarbitone (PB), BNF and ARO resulted in the induction of 7-ethoxycoumarin O-deethylase, 7-benzoxyresorufin O-debenzylase and 7-ethoxyresorufin O-deethylase activities. Generally, the induction of mixed-function oxidase enzymes was greater in 72- than in 48-hr cultured slices, and at the concentrations examined ARO produced a greater stimulation of enzyme activities than did either PB or BNF. These results demonstrate that rat liver slices may be maintained in culture for up to 72 hr, and that they respond in a similar manner to rat primary hepatocyte cultures to some inducers of xenobiotic metabolism. Precision-cut liver slices may therefore be a useful alternative in vitro system to hepatocyte cultures for screening compounds for effects on mixed-function oxidases and for assessing species differences in response.

Animals↗

PubMed1993

Comparison of the acute and chronic mitogenic effects of the peroxisome proliferators methylclofenapate and clofibric acid in rat liver.

Peroxisome proliferators are well known to cause liver enlargement in rodents. In this investigation, we have examined the effect of acute (1 week) and chronic (26 week) exposure to the peroxisome proliferators methylclofenapate (MCP) and clofibric acid (CA), at 0.05 and 0.5% in the diet respectively, on hepatocyte replication in the Sprague-Dawley rat. Both compounds induced an early increase in hepatocyte replication, with a concomitant increase in peroxisome proliferation as assessed by induction of palmitoyl CoA oxidation. However, after 26 weeks of treatment, there was no difference in the labelling index (LI) of control and CA-treated rat livers, while in MCP-treated rats the LI was 5- to 6-fold above control. Palmitoyl CoA oxidation remained elevated in both treated groups at 26 weeks. Analysis of the slides by a 'zonal' scoring procedure demonstrated that the induced replication was predominantly periportal after 1 week of treatment with either compound. The number of 5-bromo-2'-deoxyuridine (BrdU)-positive hepatocyte nuclei per field in the periportal region increased approximately 4-fold after CA treatment and 7-fold after MCP treatment. There was no significant difference in the number of BrdU-positive nuclei per field in the centrilobular areas of control and treated rats after 1 week. After 26 weeks of treatment, periportal replication was still elevated in the MCP-treated animals (approximately 10-fold above control), but there was no difference in periportal replication between control and CA-treated rats. CA induced a significant reduction in the replication of centrilobular areas at 26 weeks, while there was no effect of MCP. In summary, these results demonstrate that the acute mitogenic effects of MCP and CA are predominantly periportal, and, in the case of MCP, the mitogenicity is sustained up to 26 weeks of treatment.

Animals↗

PubMed1993

Microvascular volume contribution to hemorrhage compensation.

Regulation of systemic blood pressure during small changes in blood volume is partially achieved by blood volume shifts from microcirculation to macrocirculation that cause a decrease in systemic hematocrit [LaForte, A., L. Lee, G. Rich, T. Skalak, and J. Lee. Am. J. Physiol. 262 (Heart Circ. Physiol. 31): H190-H199, 1992]. Diameters of 4-100 microns arterioles and 5-80 microns venules in spinotrapezius muscles of anesthetized rats were measured during control conditions and immediately after a 13% (of total blood volume) hemorrhage to determine the role of the microvasculature in hemorrhage compensation. The Strahler orders, mean control diameters (microns), and posthemorrhage diameters (% of control) were as follows: TA2, 5.7 (91.2%); TA3, 8.7 (90.4%); TA4, 12.5 (85.4%); TA5, 31.4 (95.8%); AA, 39.6 (94.6%); CV2, 8.0 (94.7%); CV3, 14.8 (93.7%); CV4, 24.6 (95.2%); CV5, 41.5 (98.8%); and AV, 47.8 (97.8%), where TA, AA, CV, and AV designate transverse arteriole, arcade arteriole, collecting venule, and arcade venule, respectively. The diameter reductions were heterogeneous for arterioles and venules, with significant variation in small arterioles (< 25 microns), which exhibited dimensions ranging from 61 to 100% of control, whereas larger arterioles ranged from 81 to 100% of control. The data were used with an anatomic model to estimate the systemic hematocrit decrease (0.73%) and the blood volume shifted from the microcirculation to the macrocirculation (3.74% of total control blood volume). These results agree well with direct measurements of the systemic hematocrit decrease and thus provide the microvascular basis for the rapid blood volume shift during moderate hemorrhage.

Adaptation, Physiological↗

PubMed1993

Comparison of the hepatic effects of nafenopin and WY-14,643 on peroxisome proliferation and cell replication in the rat and Syrian hamster.

Male Sprague-Dawley rats were fed control diet or diet containing 0.05% nafenopin (NAF) or 0.025% WY-14,643 (WY) and male Syrian hamsters were fed control diet or diet containing 0.25% NAF or 0.025% WY for periods of 1, 15, 40, and 60 weeks. Both NAF and WY produced a sustained increase in liver weight and induction of peroxisomal fatty acid beta-oxidation in the rat and Syrian hamster. Replicative DNA synthesis was studied by implanting osmotic pumps containing [3H] thymidine during weeks 0-1, 14-15, 39-40, and 59-60. Cell replication, determined either as the hepatocyte labelling index or by incorporation of radioactivity into liver whole homogenate DNA, was increased in rats given NAF and WY for 1 week. However, only WY produced a sustained increased in cell replication after 15-60 weeks. After 40 weeks, liver nodules and tumors were present in WY-treated rats, and these lesions were observed in all WY-treated and some NAF-treated rats after 60 weeks. In contrast to the rat, no marked effect on replicative DNA synthesis and no liver nodules and tumors were observed in Syrian hamsters given NAF and WY for up to 60 weeks. The rat study demonstrates that liver tumors are produced more rapidly by doses of peroxisome proliferators that produce a sustained stimulation of cell replication, whereas the hamster study suggests that species differences may exist in both peroxisome proliferator-induced cell replication and liver tumor formation.

Animals↗