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Taurine and Osmoregulation: Taurine Is a Cerebral Osmoprotective Molecule in Chronic Hypernatremic Dehydration1

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Taurine and Osmoregulation: Taurine Is a Cerebral Osmoprotective Molecule in Chronic Hypernatremic Dehydration1 003 1-3998/88/2301-0035$02.00/0 PEDIATRIC RESEARCH Vol. 23, No. 1, 1988 Copyright 0 1988 International Pediatric Research Foundation, Inc. Printed in US.A. Taurine and Osmoregulation: Taurine Is a Cerebral Osmoprotective Molecule in Chronic Hypernatremic Dehydration1 HOWARD TRACHTMAN, RANDY BARBOUR, JOHN A. STURMAN, AND LAURENCE FINBERG Departments of Pediatrics and Clinical Chemistry, State University of New York, Health Science Center at Brooklyn; and the Department of Developmental Biochemistry, Institute for Basic Research in Developmental Disabilities, Staten Island, New York ABSTRACT. We studied the effect of 8-wk dietary taurine ative during more prolonged hypernatremia, namely the intra- depletion on the vulnerability to hypernatremic dehydra- cellular accumulation of osmoprotective molecules. These sol- tion in postweanling kittens. While experimental taurine utes, previously referred to as "idiogenic" (3), consist in part of depletion was not associated with increased susceptibility amino acids, taurine in particular (4). If rapid rehydration is to acute hypernatremia (1.5 M NaCl/NaHC03 35 ml/kg attempted, these molecules cannot exit from the cells quickly body weight, single injection), there was an increase in enough and cellular swelling may ensue due to the sudden mortality (five of seven versus one of seven, p = 0.05) and reversal of the osmolal gradient. seizure activity (three of seven versus none of seven, p = The present studies were designed in kittens to assess the role 0.08) in taurine-depleted compared to taurine-replete kit- of taurine as a cerebral osmoprotective molecule in CHD. These tens rendered chronically hypernatremic over 96 h. Fur- animals synthesize little taurine owing to low levels of CSAD thermore, there was a significant decrease in brain cell activity (5, 6). In addition, the cat uses taurine to synthesize the water (517.4 + 21.7 versus 671.6 2 32.3 m1/100 g fat-free bile salt taurocholate and is unable to switch to glycocholate dry weight, p < 0.05), derived almost exclusively from the under conditions of taurine deprivation (7). The cat is, therefore, intracellular compartment (352.5 + 12.3 versus 483.8 + dependent on dietary sources for taurine (5, 6), and is a useful 34.6 m1/100 g fat-free dry weight, p < 0.05) that correlated model for study of the role of taurine as an osmoprotective with the reduction in the cerebral taurine content in the molecule. taurine-depleted versus control kittens during chronic hy- pernatremic dehydration. These results suggest that tau- METHODS rine is an important cerebral osmoprotective molecule. This aminoacid constitutes nearly 50% of the adaptable intra- Domestic kittens obtained from a breeding colony at the cellular osmolal pool whose concentration varies in the Animal Research Facility of the State University of New York course of osmoregulating in response to perturbations in Health Science Center at Brooklyn, and ranging in weight from the extracellular fluid tonicity. (Pediatr Res 23: 35-39, 600 to 800 g, were fed an experimental casein-based taurine-free 1988) diet or a control diet supplemented with 0.05% taurine (BioServ, Inc., Frenchtown, NJ). Control animals differed from "experi- Abbreviations mental" animals only in the diet ingested for the 8-wk prepara- CHD, chronic hypernatremic dehydration tory period. The diets were provided in color-coded pellet form CSAD, cysteinesulfinic acid decarboxylase beginning at 8-10 wk of age and continued for 8 wk. Body weight was measured weekly to ensure adequate food intake and growth by the kittens. Water was provided ad libitum during the dietary preparation. After 8 wk, groups of kittens were subjected to the following protocol to induce CHD. On the day of the study, after Recent evidence suggests that in many animal species taurine, the animals were weighed, a venous blood sample was drawn for a p-aminosulfonic acid formed in the metabolism of methionine determination of serum osmolality and chemical analyses in- and cysteine or present in the diet, acts as an osmoprotective cluding plasma taurine concentration. Fluid intake was then molecule under stressful conditions (I). Hypernatremic dehydra- totally restricted for 24 h, after which a repeat blood specimen tion is a formidable problem in clinical pediatrics. Rapid onset was removed for measurement of serum osmolality and chemical of hypernatremia and hasty rehydration are associated with the analyses. For the next 72 h, the only fluid provided was thrice occurrence of cerebral shrinkage or swelling, respectively, caused daily 1 M NaCl solution via orogastric feeding, a dose designed by two distinct phenomena (2). The first is the slow diffusion of to raise the serum Naf concentration gradually to 180, 185, and solute through the "blood brain bamer" so that an osmolal 190 mmol/liter on days 2, 3, and 4, respectively (8). All animals gradient will be initially relieved by the movement of water alone were observed several times daily during the dehydration phase causing a volume change in the brain. The cerebral volume for seizure activity or other abnormal neurological behavior. The change is gradually attenuated by a second process that is oper- kittens were immediately dissected at the time of death or sacrificed and dissected 96 h after commencing the dehydration Received May 15, 1987; accepted August 28, 1987. protocol. In no instance did an animal remain in its cage for Correspondence: Howard Trachtman, M.D., Division of Pediatric Nephrology, longer than 15 min after dying and before dissection. Blood Schneider Children's Hospital of Long Island Jewish Medical Center, Suite 365, samples were retained for measurement of serum osmolality and 271-16 76th Avenue, New Hyde Park, NY 10042. ' Presented at the annual meeting of the Society for Pediatric Research on May chemical analyses. A segment of the brain from the frontal lobe 7, 1986 in Washington, D.C. and a portion of the vastus medialis muscle were rapidly excised 36 TRACHTMAN ET AL. within 15 min of sacrifice or death. Each tissue specimen was in the percentage water content of muscle specimens obtained divided into three segments for determination of percentage from these animals. water content, tissue electrolyte concentrations, and taurine con- Table 3 summarizes the changes in extracellular and intracel- tent, respectively. lular water content of the brain and muscle specimens obtained Analytic methods. Serum osmolality was determined using a from the taurine-depleted and control animals with CHD. In freezing point depression osmometer (Advanced Instruments, brain, a significant reduction in water content, derived almost Needham, MA) and chemical analyses were performed using a exclusively from the intracellular compartment, was detected in Klinaflame automated analyzer (Beckman Instruments, Brea, the taurine-deficient kittens compared to control taurine-replete CA). The brain and muscle tissue specimens were dried to animals. A similar pattern was not demonstrable in muscle tissue. constant weight in an oven at 40" C for determination of per- The intracellular concentrations of Na' and K' are shown for centage water content. The specimens used for tissue electrolyte the same animals in Table 4. While no significant differences in concentrations were first extracted twice in ether and redried to intracellular Na' and K' (mmol/liter) concentrations of the brain constant weight. The tissues were digested in 8 volumes of a 5 N and muscle were seen, intracellular Na' concentrations tended HN03 solution for 72 h and the extracts were then neutralized to be higher in experimental versus control animals. In most with CaC03. Measurements of sodium and potassium contents were conducted using an automated analyzer, while tissue chlo- ride content was determined using a chloridometer (Buchler, Table 1. Initial andfinal serum sodium concentration and Saddle River, NJ). The brain and muscle tissue samples used for osmolalitv achieved durinn CHD (mean + SEM)* determination of taurine concentration was homogenized in 9 Experimental Control volumes of cold 10% trichloroacetic acid using a Polytron ho- In = 7) (n = 7) mogenizer (Brinkmann Instruments, Westbury, NY) and centri- fuged at 20,000 x g for 30 min. The plasma and tissue taurine Sodium (mmol/liter) contents were determined using an automatic amino acid ana- Initial 149 k 1.2 146 a 1.8 lyzer (Beckman Instruments) on-line to a computer (Spectra 24-H 153 0.4 152 0.7 Physics, Oxnard, CA) for data acquisition and calculation. Final 183 k 4.0t 177 + 2.lt Calculations. The extracellular water content of the tissue samples was calculated as the chloride space. The latter was Osmolality (mosmol/kg) determined by dividing the tissue chloride content by the chloride Initial 311 k2.1 309 1.1 concentration corrected by the Donnan factor (0.96) and for the 24-H 317 + 1.3 314 + 1.5 water content of plasma (0.93) (3). The intracellular water con- Final 425 a 12.3ts$ 376 + 9.lt tent was derived as equal to the total tissue water content minus * Abbreviations: E, experimental (taurine depleted); C, control (taurine the extracellular water component (3). replete). Statistical methods. The results were analyzed using Fisher's t p < 0.00 1 versus initial value. exact test and Student's t test, paired or unpaired, as dictated by $ p < 0.0 1 versus control value, final. the experimental conditions. Results were considered statistically significant if p < 0.05. Table 2. Percentage dehydration, mortality, and morbidity in RESULTS CHD (mean f SEMI* Experimental Control All kittens adjusted to the pelleted diets and ingested an (n = 7) (n = 7) adequate daily amount of food to sustain normal growth. As demonstrated in Table 1, a severe state of hypernatremic dehy- Body wt (g) dration was successfully induced during the protocol. The dis- Initial 1896 + 123 1934 + 62 crepancy consistently observed (10 to 59 mosmol/kg) between Final 1661 + 118 1553 5 56 the serum Na' concentration and osmolality may be a reflection % Weight Loss 13.3 k 3.0 19.8 + 1.2 of the hyperglycemia associated with hypernatremic dehydration Mortality 517 1/7t (2, 9).
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