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Biomedical subjects

M L Gardner

Publications and source records attributed to M L Gardner.

At least 37 records · Page 2Linked to original sources
PubMed1982

Absorption of intact peptides: studies on transport of protein digests and dipeptides across rat small intestine in vitro.

Passage of intact peptides across isolated rat small intestine has been studied during luminal perfusion with partial digests of proteins or with dipeptides. Significant passage of intact peptide does occur, the amount depending upon the luminal concentration. It probably reflects the 'digestibility' of the protein or protein digest. Previous studies are discussed and, although intact peptide transport is probably not of major nutritional importance, it is suggested that the pathophysiological significance of this process and of peptidaemia merits further attention.

Animals↗
PubMed1981

Differential toxicity and pharmacokinetics of sodium and Tris salts of 5-fluorouracil in the rat.

1. Rats injected intraperitoneally (i.p.) with the Tris salt of 5-fluorouracil (1.44 mmol/kg) showed severe toxic symptoms and a 15% mortality. No mortality and no obvious toxicity, apart from intestinal toxicity, resulted after injection of the sodium salt at equimolar dosage. 2. The plasma pharmacokinetics of the two salts of 5-fluorouracil (1.44 mmol/kg) were different after i.p. injection: higher plasma levels were achieved and were sustained for longer after the Tris salt than after the sodium salt. 3. No differences in plasma pharmacokinetics were observed after intra-arterial (i.a.) injection of the two salts of 5-fluorouracil (6.576 mmol/kg). 4. Thus there are fundamental (and potentially important) differences between the biological properties of the sodium and Tris salts of 5-fluorouracil. These cannot be explained at present.

Animals↗
PubMed1981

Diurnal variation in the intestinal toxicity of 5-fluorouracil in the rat.

1. Water absorption rates by small intestine in vitro and the incidence of diarrhoea in vivo were estimated after 5-fluorouracil was injected into rats at various times of day and night. 2. Impairment of water absorption and the incidence of diarrhoea were minimal in rats on a normal dietary regimen when the 5-fluorouracil was injected at around 02.00 hours. 3. The DNA content of the mucosa of the small intestine from uninjected animals also showed a diurnal variation, with a maximum at around 03.00 hours. 4. Manipulation of the time of injections (possibly in relation to feeding time) provides a potential means for increasing the therapeutic value of 5-fluorouracil.

Animals↗
PubMed1981

Studies on the absorption of the pancreatic function test peptide, N-benzoyl-L-tyrosyl-p-aminobenzoic acid, and related compounds by isolated rat small intestine.

The peptide, N-benzoyl-L-tyrosyl-p-aminobenzoic acid, which is used in an oral test of pancreatic function, has been perfused through isolated rat small intestine in order to determine whether it can be absorbed across the intestine in intact form, and whether it is hydrolysed appreciably by intestinal enzymes. For comparison, transport of N-benzoyl-DL-tyrosine, L-tyrosine, L-tyrosyl-L-leucine and p-aminobenzoic acid has also been studied. Very small amounts of bound tyrosine (probably mainly intact peptide plus some benzoyl-tyrosine) and of free p-aminobenzoic acid crossed the intestine during perfusion with N-benzoyl-L-tyrosyl-p-aminobenzoic acid. Adsorbed pancreatic enzymes were possibly responsible for the very small amount of hydrolysis of the peptide. However, no detectable free tyrosine crossed the intestine during perfusion with N-benzoyl-L-tyrosyl-p-aminobenzoic acid or with N-benzoyl-DL-tyrosine. In contrast, substantial quantities of free tyrosine crossed the intestine during perfusion with L-tyrosine or with L-tyrosyl-L-leucine. Net transport of tyrosine from L-tyrosyl-L-leucine was less than that from equimolar free L-tyrosine; no detectable intact L-tyrosyl-L-leucine crossed the intestine. During perfusion with free p-aminobenzoic acid the concentration in the serosal secretion apparently exceeded that in the lumen by a factor of 1.7; this suggests active transport of p-aminobenzoic acid.

4-Aminobenzoic Acid↗
PubMed1981

Responding under sequence schedules of electric shock presentation.

Lever pressing by squirrel monkeys was examined under second-order schedules of electric shock presentation in which different discriminative stimuli were associated with consecutive components (sequence schedules). Components were always two-minute fixed-interval schedules, and three different overall schedules were studied. Under an overall eight-minute fixed-interval schedule, the first component completion after at least eight minutes had elapsed produced electric shock. The number of components actually completed ranged from one to four; thus, different discriminative stimuli were occasionally associated with electric shock presentation. Under an overall "yoked" variable-ratio schedule, electric shock was presented after completion of a variable number of components; the required number and the distribution of components were matched to those obtained under the overall eight-minute fixed-interval schedule. Under an overall fixed-ratio schedule, electric shock was presented after completion of four components (chained schedule). Under all three sequence schedules, responding in early components was characterized by a pause followed by a single response after the end of the two-minute interval; responding in later components was characterized by a shorter pause followed by positively accelerated responding. Manipulation of overall schedules of shock presentation in these complex behavioral situations produced changes in responding comparable to those ordinarily obtained after similar manipulation of dependencies under both single and second-order schedules of food presentation. These experiments extend the range of conditions and levels of complexity under which responding can be maintained by presentation of electric shock.

Journal Article↗
PubMed1981

Responding maintained under intermittent schedules of electric-shock presentation: "Safety" or schedule effects?

Four experiments were conducted in which lever pressing by squirrel monkeys was maintained under multiple, mixed, or chained schedules of electric-shock presentation. In the first two experiments, a multiple schedule was employed in which a fixed-interval schedule of shock presentation alternated with a signaled two-minute component. Initially, no events were scheduled during the two-minute component (a safety period). In the first experiment, the safety period was "degraded" by introducing and systematically increasing the frequency of periodic shocks presented during that component. In the second experiment, the proportion of overall safe time to unsafe time was decreased by decreasing the value of the fixed-interval schedule while holding constant shock frequency during the two-minute component. In the third experiment, the overall arrangement was changed from a multiple to a mixed schedule in an attempt to determine whether fixed-interval responding would be maintained when a single exteroceptive stimulus was associated with both components. In the fourth experiment, the overall arrangement was changed from a multiple to a chained schedule in an effort to determine whether fixed-interval responding would be maintained when its consequence was presentation of a signaled "unsafe" period. Fixed-interval responding was well maintained under all experimental conditions; the varied relationships obtained lend more support to conceptualizations of shock-maintained behavior as exemplifying schedule-controlled behavior than to suggestions that such behavior may be readily accounted for by "safety theory."

Journal Article↗
PubMed1979

Effects of 'elemental' diets on absorptive and enzymic activities and on 5-fluorouracil toxicity in rat small intestine.

1. Water absorption and cytoplasmic dipeptidase activities were determined in isolated rat small intestine after animals had fed on various 'elemental' diets or a standard rat diet and after a single injection of 5-fluorouracil. 2. Vivonex diets were associated with a decrease in dry weight of the small intestine and an increase in glucose and water absorption in vitro. 3. The nature of the dietary nitrogen profoundly affects the activities of intestinal peptidases. 4. Water absorption was severly depressed 3 days after 5-fluorouracil administration: the extent of depression was independent of the diet. Thus, any ameliorative effects of 'elemental' diets on 5-fluorouracil toxicity are unlikely to be mediated by direct protection of intestinal absorption.

Animals↗
PubMed1979

Superficial or membrane digestion of peptides in dinitrophenol-inhibited rat small intestine.

1. Hydrolysis of peptides has been measured in isolated rat small intestine perfused with a pancreatic digest of lactalbumin in the presence of 2,4-dinitrophenol. 2. Although transport of water and amino acids was severely inhibited by 2,4-dinitrophenol, peptide hydrolysis to free amino acids was apparently unimpaired. 3. Only a small fraction of the hydrolysis observed could be accounted for by leakage of enzymes into the lumen. 4. The results show that the brush-border enzymes proximal to the transport mechanism(s) can be an important site of hydrolysis of peptides to amino acids under conditions where the transport of unhydrolysed peptides is inhibited. The results are consistent with the concept of membrane (contact) digestion, although the significance of intracellular hydrolysis and of transmural transport of intact peptides is also discussed.

Absorption↗
PubMed1979

Release of dipeptide hydrolase activities from rat small intestine perfused in vitro and in vivo.

1. Hydrolase activities against three dipeptides were measured in mucosal cytoplasm in unperfused intestines and in mucosal cytoplasm, luminal effluents and serosal secretions after perfusion in vitro and in vivo for 1 h. Intestines in vitro were preparted both from anaesthetized rats and from freshly killed rats. 2. Only 0.6--1.9% of the initial cytoplasmic activity was recovered in the luminal effluent when intestines in vitro were prepared from anaesthetized rats. Recoveries in luminal effluents were similar (1.3--3.3%) during perfusion in vivo. 3. Losses of dipeptidases into the luminal effluent were four to eight times greater when intestines in vitro were prepared from freshly killed animals. 4. Similar losses of dipeptidases into the secretion on to the serosal surface were observed: they too were much greater when intestines were prepared from freshly killed animals. 5. Small losses of mucosal DNA during perfusion were also observed; however, losses of cytoplasmic peptidases were consistently slightly greater. 6. Enzyme loss therefore probably occurs both by sloughing of whole cells and by a more specific process which is greatly influenced by experimental procedure. Caution is necessary in the interpretation of peptide transport experiments in vitro, although the possibility that intraluminal hydrolysis is of physiological significance must not be excluded.

Animals↗
PubMed1978

Changes in absorptive and peptide hydrolase activities in rat small intestine after administration of 5-fluorouracil.

1. Glucose absorption, water absorption and dipeptide hydrolase activities have been determined in isolated rat small intestine at 1, 3, 5 and 21 days after a single intraperitoneal injection of 5-fluorouracil. 2. Absorption rates and enzyme activities were elevated 1 day after treatment, but were reduced to 40% of control values at 3 and 5 days. Changes were seen regardless of whether absorption was expressed per unit length or per unit dry weight of intestine. 3. There were highly significant positive correlations between glucose or water absorption rates and peptidase activities, especially in proximal jejunum. The most significant correlation was observed between water absorption rate and jejunal L-Leu-Gly hydrolase activity. 4. Malabsorption may account for some of the gastrointestinal side effects associated with treatment with 5-fluorouracil. Enzyme measurements may be useful as an index of intestinal function.

Animals↗
PubMed1978

Amino acid and peptide absorption from partial digests of proteins in isolated rat small intestine.

1. Absorption of each of sixteen amino acids, free and peptide-bound, has been measured in isolated rat small intestine perfused with five partial digests of proteins. 2. At low concentrations net absorption of each amino acid was proportional to its luminal concentration and independent of the nature of the amino acid. 3. A series of first-order multiple regressions was found to describe well the characteristics of absorption. 4. Rate constants for disappearance of free and peptide-bound amino acids from the lumen were closely similar. However, substantial back-flux occurred of amino acids derived from peptide hydrolysis. Hence 60-70% of the amino-N entering the serosal tissue fluid probably had left the lumen as free amino acids. 5. Intact peptides crossed the mucosa during absorption from a soy bean hydrolysate and in substantial quantities during absorption from one casein digest but not from another. With other hydrolysates there was no evidence for passage of peptides to the serosa. 6. In several cases there was a serious discrepancy between the amount of amino-N absorbed from the lumen and the amount accounted for as peptide or free amino acid in the serosal secretion. 7. The characteristics of absorption were similar (apart from the exceptions in 5 above) for all the digests studied except for soy bean hydrolysate.

Amino Acids↗