Rapid (24-Hour) Reaccumulation of Brain Organic Osmolytes (Particularly myo-Inositol) in Azotemic Rats after Correction of Chronic Hyponatremia

Abstract

Abstract. It was recently demonstrated that renal failure and exogenous urea prevent myelinolysis induced by rapid correction of experimental hyponatremia. To determine why elevated blood urea levels favorably affect brain tolerance to osmotic stress, the changes in brain solute composition that occur when chronic hyponatremia is rapidly corrected were studied in rats with or without mercuric chloride-induced renal failure. After 48 h of hyponatremia, the brains of azotemic and nonazotemic animals became depleted of sodium, potassium, and organic osmolytes. Twenty-four hours after rapid correction of hyponatremia, the brains of animals without azotemia remained depleted of organic osmolytes, with little increase in myoinositol or taurine contents above those observed in animals with uncorrected hyponatremia; brain electrolytes were rapidly reaccumulated, increasing the brain sodium content to a level 17% higher than values for normonatremic control animals. In contrast, within 2 h after correction of hyponatremia, brain myo-inositol contents in azotemic rats returned to control levels and brain taurine levels were significantly higher than those in azotemic animals with uncorrected hyponatremia (16.5 versus 9 mol/g dry weight). There was no "overshooting" of brain sodium and water contents after rapid correction in the azotemic animals. Rapid reaccumulation of brain organic osmolytes after correction of hyponatremia could explain why azotemia protects against myelinolysis.Organic osmolytes play a key role in cell volume homeostasis. Several organs, most notably the kidney and brain, are particularly dependent on adaptive mechanisms that regulate their volume during osmotic perturbations (1-3). The brain adapts to chronic (1-to 2-d) hyponatremia by extruding electrolytes and organic osmolytes, thus limiting brain cell swelling. Conversely, during correction of chronic hyponatremia, the restoration of brain osmolyte contents counters brain dehydration; however, this process normally requires several days for completion (4,5). Depletion of brain osmolytes during adaptation to chronic hyponatremia makes the brain vulnerable to injury when the hyponatremia is corrected. Brain myelinolysis is a well recognized consequence of excessive correction of chronic hyponatremia (6 -8). Among human subjects, additional risk factors, such as hypokalemia, chronic liver disease, diuretics (thiazides), or malnutrition, could also be implicated in the pathogenesis of this demyelinating disease (6). Areas of more severe injury are topographically correlated with sites that are more depleted of organic osmolytes after correction of hyponatremia (9).Urea has been successfully used to treat hyponatremia (10 -12). In previous studies, we demonstrated that exogenous urea protected animals against myelinolysis in a rat model of hyponatremia (6,13,14). Similarly, clinical observations suggest that uremic patients can tolerate large fluctuations in serum sodium levels without developing myelinolysis (15). We recently confirmed this hypothesi...

Minocycline Prevents Osmotic Demyelination Syndrome by Inhibiting the Activation of Microglia

“…26,27 Other interventions that reduced mortality after the rapid correction of hyponatremia include the administration of myoinositol 28 or urea, 29 which affect the brain's organic osmolyte content. However, it is sometimes difficult to control the serum sodium levels or administer compounds such as myoinositol and urea in clinical practice.…”

Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations

“…70 Uremia protects against myelinolysis and brain osmolytes are recovered more rapidly during correction of hyponatremia in animals that are uremic than in nonuremic animals. 71 Finally, infusion of myoinositol (a major osmolyte lost in the adaptation to hyponatremia) protects against mortality and myelinolysis from rapid correction of hyponatremia. 3 …”

Central Pontine and Extrapontine Myelinolysis after Rapid Correction of Hyponatremia by Hemodialysis in a Uremic Patient

“…[13] The possible mechanism of this protection is related to rapid reaccumulation of brain organic osmolytes, such as myo-inositol and taurine, in azotemic animals due to hypertonic stress to the brain. [14] Additionally, in this study, plasma urea levels continued to increase following the correction of hyponatremia and likely promoted hypertonic stress created by hypertonic saline administration. In uremic patients with hyponatremia, serum BUN levels declined during hemodialysis, and this decrease may counteract hypertonic stress by the usual administration of dialysate sodium 140 mEq/L.…”