Factors inhibiting ingestive behavior in chronic renal failure
Author: Mamoun, Abdel-Hafiz
Date: 1997-12-11
Location: Föreläsningssal, M63, Medicingatan 3, plan 6, Huddinge sjukhus
Time: 9.00
Abstract
FACTORS INHIBITING INGESTIVE BEHAVIOR IN CHRONIC RENAL FAILURE
THESIS BY ABDEL-HAFIZ MAMOUN, 1997, KAROLINSKA INSTITUTE, DIVISIONSOF
RENAL MEDICINE AND BAXTER NOVUM DEPARTMENT OF CLINICAL SCIENCE AND
DEPARTMENTOF APPLlED NEUROENDOCRINOLOGY S-l41 86 HUDDINGE, SWEDEN
Protein-energy malnutrition and wasting occur in many patients with
chronic renalfailure. Reduced nutrient intake because of anorexia, nausea
and vomiting, causedby uremic toxicity is an important factor. Regular
dialysis therapy results in thereduction or disappearance of anorexia,
suggesting that one or more dialyzable compoundscause these toxic
symptoms. We used a model for studying the ingestive behavior
ofconscious, free-moving rats. They were fitted with intraoral cannulas
and connectedto a peristaltic pump which delivers a diet solution
(Iml/min) and the time (volume)of ingestion was determined. The model was
used for basic physiological studies ofthe role of glucose, amino acids
and cholecystokinin octapeptide (CCK-8) in appetiteregulation as well as
for specific studies on the effect of peritoneal dialysis solutionsand
uremic toxins on ingestive behavior.
The inhibitory effect of CCK-8 on ingestion of a protein diet was
compared tothat on ingestion of a carbohydrate diet. This effect lasted
for 4 hrs. Injectionof CCK-8 inhibited intake of carbohydrate but not
protein. Conversely, injectionof the CCK-A receptor antagonist L-364,718
facilitated intake of carbohydrate, butnot protein. Ingestion of a
protein diet caused a marked increase in the plasma levelof CCK-8 which
declined to basal levels in about 4 hrs. Intake of protein also causeda
large increase in plasma levels of amino acids, some of them with a time
coursedescribing a mirror image of the inhibitory effect on ingestive
behavior. The resultssuggest that release of CCK-8 into the general
circulation is of no importance fortermination of the protein meal.
Release of amino acids may be important satietysignal for protein
ingestion.
Intraperitoneal injection of up to 40 ml saline had no effect on
carbohydrateor protien ingestion. Injection of 30 ml of peritoneal
dialysis fluids containmg13.6, 22.7 and 38.6 g/l of glucose mduced a dose
dependent inhibition of sucroseintake, but had no effect on protein
intake, whereas injection of dialysis fluidscontaining 11, 18 and 31 g/a
of amino acids reduced the intake of sucrose and proteinin a dose
dependent manner. Our results indicate that inbibition of appetite
causedby fluids containing glucose or amino acids is specific for each
nutritional constituentand not simply an effect of hyperosmolality or
large filling volume.
Uremic and normal urine ultrafiltrates injected i.p. inbibited the
ingestion ofboth carbohydrate and protein, but normal plasma
ultrafiltrate had no effect. The1-5 kd subfraction (the middle molecule
fraction, MM) isolated from uremic and normalurine ultrafiltrates
elicited a dose-dependent inhibition of carbohydrate or proteinintake,
whereas subfractions with lower molecular weight had no effect. These
resultssuggest that toxic MM fractions which are normally excreted in the
urine accumulatein uremia and may suppress appetite. Intraperitoneal and
intercerebroventricularinjections of the MM subfractions had a potent
inhibitory effect on ingestive behavior,but had a less marked effect when
given intravenously, suggesting that these MM subfractionsact on the
splanchnic region and brain to suppress ingestive behavior. To be
effectiveintravenously, these MM subfractions must be given in higher
doses to reach theirsite (s) of action because they are diluted in the
general circulation. The MM mayact directly in the brain or via modifying
neurotransmittors that regulate food intake.We demonstrated increased
serotonin synthesis and doparnine turnover in uremic rats.Whether the
effect of experimental uremia on cerebral monoamines is related to
theeffect of the MM observed here is, however, an open question.
Nitric oxide synthesis was markedly inhibited in predialyzed uremic
patients,but increased after hemodialysis (HD) and not influenced by
feeding. CCK-8 was increasedin HD patients at the end of the meal and
returned to the fasting level 4 hrs later.Leptin was 4-fold higher in HD
patients and remained unaffected after the meal. Hemodialysistreatment,
however, influenced neither the fasting concentrations of CCK-8 nor
leptin.These results suggest that accumulation of CCK-8 and leptin as
well as nitric oxidedepletion may inhibit ingestive behavior in HD
patients.
Key words: rat, uremia, cholecystokinin octapeptide, nitric oxide,
leptin, glucose,amino acids, anorexia, ingestive behavior, peritoneal
dialysis solutions, hemodialysis
ISBN 91-628-2682-4
Issue date: 1997-11-20
Publication year: 1997
ISBN: 91-628-2682-4
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