The general objective of the proposed 4-year series of animal investigations is to study the effect of hyponatremia, the most common electrolyte disorder in clinical medicine, on brain pH, brain function, and brain morphology. Hyponatremia is associated with many central nervous system (CNS) symptoms and lesions and its correction has been implicated in causing central pontine myelinolysis. The proposed studies in rats in both acute and chronic hyponatremia will determine the morphologic and functional CNS effects accompanying the adaptation to acute and chronic sustained hyponatremia, and the CNS effects occurring during its correction (deadaptation). Chronic, stable, non-catabolic hyponatremia will be produced in rats by constant subcutaneous DDAVP infusion. DDAVP will be administered via osmotic minipumps implanted subcutaneously in the back. Animals will be fed volume-limited liquid diets. In general, studies in these hyponatremia rats (1-14 days) will include: (1) 31P-NMR spectroscopy to measure resistance to changes in brain pH during acute metabolic acidosis; (2) intactness of the blood brain barrier using Gadolinium-DTPA contrast 1H-NMR imaging; (3) 31P-NMR in vivo spectroscopy to evaluate bioenergetics and brain buffering; the latter assessed by response to changes in CO2 tension; (4) phospholipid metabolism using high resolution 31P-NMR on brain extracts, (5) brain perfusion measured by trifluoromethane washout using 19F-NMR spectroscopy. Results will be compared to perfusion measurements made with 14C-iodoantipyrine; (6) regulation of brain buffering using specific inhibitors given into the cerebral ventricle; (7) brain water and electrolyte determination using standard methods; and, (8) brain histopathology. These methods will be used to study CNS effects of slow, moderate, and rapid correction of variable durations of hyponatremia. The effect of correcting hypoosmolality without altering sodium will be determined by giving mannitol IP and comparing results to isoosmolar correction of plasma sodium. Changes found in correction will be used to predict development of neurologic dysfunction and brain pathology. The knowledge obtained should lead to better understanding of the processes involved in adaptation to and correction of hyponatremia; better clinical management of this condition; and determination of whether hyponatremia is only a marker for increased morbidity and mortality or whether the condition makes the brain more susceptible to damage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS026610-01A3
Application #
3412540
Study Section
Neurology A Study Section (NEUA)
Project Start
1991-04-01
Project End
1992-04-29
Budget Start
1991-04-01
Budget End
1992-04-29
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Montefiore Medical Center (Bronx, NY)
Department
Type
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Adler, S; Martinez, J; Williams, D S et al. (2000) Positive association between blood brain barrier disruption and osmotically-induced demyelination. Mult Scler 6:24-31
Adler, S; Verbalis, J G; Meyers, S et al. (2000) Changes in cerebral blood flow and distribution associated with acute increases in plasma sodium and osmolality of chronic hyponatremic rats. Exp Neurol 163:63-71
Baker, E A; Tian, Y; Adler, S et al. (2000) Blood-brain barrier disruption and complement activation in the brain following rapid correction of chronic hyponatremia. Exp Neurol 165:221-30
Adler, S; Verbalis, J G; Williams, D (1995) Effect of rapid correction of hyponatremia on the blood-brain barrier of rats. Brain Res 679:135-43
Adler, S; Verbalis, J G; Williams, D (1994) Brain buffering is restored in hyponatremic rats by correcting their plasma sodium concentration. J Am Soc Nephrol 5:85-92
Adler, S; Williams, D; Verbalis, J G (1993) Effect of acute and chronic hyponatremia on blood-brain barrier function in the rat. NMR Biomed 6:119-24
Adler, S; Verbalis, J G; Williams, D (1993) Effect of acute and chronic hyponatremia on brain buffering in rats. Am J Physiol 264:F968-74