Role of Renal Compensation and dDAVP in a Mouse Model of Hyponatremia and Brain Edema induced by Water Intoxication
Authors: Bordoni Luca , Jimenez Eugenio Gutierrez , Nielsen Søren , Østergaard Leif , Frische Sebastian 
Published: November 2023

IntroductionHyponatremia is the most common electrolyte disorder in clinical practice. Acute hyponatremia can induce brain edema (BE), a condition for which no targeted therapeutical agent has been developed. A range of studies have previously used water intoxication (WI) to create experimental hyponatremia induced BE. Most of these studies have also used desmopressin acetate (dDAVP) to accentuate the effects of WI by inhibiting renal free‐water excretion. However, renal compensation in terms of urine production during WI induced BE has rarely been measured.Aim of the studyTo determine urine production and changes in cardiovascular parameters during WI and the effect of dDAVP on key physiological parameters.Methods4 groups of mice (n=6) (C57Bl/6) were anesthetized with isoflurane (ISO). WI‐groups received distilled water (20% BW), either with or without dDAVP (0.4 μg/kg) by IP injection. Sham‐ groups received no water load with or without dDAVP. Mean arterial pressure (MAP), heart rate (HR), end‐tidal CO2 (EtCO2), pH, pCO2, blood gasses, strong ion difference (SID) and urine production were evaluated during development of BE. Brain water content was evaluated post‐ mortem by wet‐dry method. In a separate group (n=4) intracranial pressure (ICP) was measured during WI + dDAVP.ResultsBrain water content (%) was significantly higher in WI groups compared to Sham (82.7±0.4 vs 80.9±0.7 for +dDAVP, 81.4±0.5 vs 80.2±0.3 for −dDAVP) (p=0.0089) and a borderline‐ significant increase in brain water was observed as effect of dDAVP (p= 0.068). Drastic increase in ICP was observed during WI further documenting BE development. MAP followed a very reproducible pattern for all experimental mice after WI, characterized by increasing hypertension/ peak / drop / hypotension. The use of dDAVP increased the magnitude of WI‐induced changes in MAP, resulting in a significant reduction of 2.9 ± 1.1 min to reach peak value during WI (p=0.036). Similarly, dDAVP had a significant effect on HR (~56 BMP higher than WI‐dDAVP (p= 0.0085)). In both WI groups, EtCO2 peaks pattern synchronized completely with artificial ventilation after 30 min, documenting compression of respiratory centers in the brain stem. Plasma ions (mmol/L) were significantly decreased in both WI groups already 5 min after water injection (Na+: 128±1.4 for +dDAVP, 130±5.0 for −dDAVP.) and metabolic acidosis developed (pH: 7.34±0.03; 7.34±0.05) (HCO3−:19±0.5; 17±0.75); (SID=−3.36; −3.10) for +dDAVP and − dDAVP, respectively. Surprisingly, dDAVP had no significant effect on urine production after WI (0.10 ± 0.11 for +dDAVP vs 0.21±0.15 for −dDAVP, μl/min*BW, p=0.757).ConclusionWater intoxication in this model results in rapid development of BE, cardiovascular changes and ICP‐changes leading to herniation irrespective of the use of dDAVP. No increased renal water excretion is seen upon WI. Urine water excretion in the model is drastically reduced irrespective of dDAVP injection. These results question the previously held assumption of renal compensation during experimental WI.Support or Funding InformationThe Danish Council for Independent Research | Medical Sciences, grant ID 4004‐00504 Title: Aquaporins: roles in pathogenesis and treatment of hyponatremia;MEMBRANE research center, Aarhus University;The Graduate School of Health, Aarhus University