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.
