title: Osmotherapy With Hypertonic Saline Attenuates Global Cerebral Edema Following Experimental Cardiac Arrest via Perivascular Pool of Aquaporin-4.
abstract: We tested the hypothesis that osmotherapy with hypertonic saline attenuates cerebral edema following experimental cardiac arrest and cardiopulmonary resuscitation by exerting its effect via the perivascular pool of aquaporin-4. We used mice with targeted disruption of the gene encoding α-syntrophin (α-Syn) that demonstrate diminished perivascular aquaporin-4 pool but retain the non-endfoot and ependymal pools.
  
  
  
  Laboratory animal study.
  
  
  
  University animal research laboratory.
  
  
  
  Isoflurane-anesthetized adult male wild-type C57B/6 or α-Syn mice were subjected to cardiac arrest/cardiopulmonary resuscitation and treated with either a continuous IV infusion of 0.9% saline or various concentrations of hypertonic saline. Serum osmolality, regional brain water content, blood-brain barrier disruption, and aquaporin-4 protein expression were determined at 24 hours after cardiac arrest/cardiopulmonary resuscitation.
  
  
  
  Hypertonic saline (7.5%) treatment significantly attenuated water content in the caudoputamen complex and cortex compared with 0.9% saline treatment in wild-type mice subjected to cardiac arrest/cardiopulmonary resuscitation. In contrast, in α-Syn mice subjected to cardiac arrest/cardiopulmonary resuscitation, 7.5% hypertonic saline treatment did not attenuate water content. Treatment with 7.5% hypertonic saline attenuated blood-brain barrier disruption at 24 hours following cardiac arrest/cardiopulmonary resuscitation in wild-type mice but not in α-Syn mice. Total aquaporin-4 protein expression was not different between 0.9% saline and hypertonic saline-treated wild-type mice.
  
  
  
  Following experimental cardiac arrest/cardiopulmonary resuscitation: 1) continuous hypertonic saline therapy maintained to achieve serum osmolality of ≈ 350 mOsm/L is beneficial for the treatment of cerebral edema; 2) perivascular pool of aquaporin-4 plays a critical role in water egress from brain; and 3) hypertonic saline attenuates blood-brain barrier disruption via perivascular aquaporin-4 pool.
authors.affiliation: 1Departments of Neurology, Neurological Surgery and Anesthesiology and Peri-Operative Medicine, Oregon Health and Science University, Portland, OR. 2Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Shin
authors.initials: S
authors.lastname: Nakayama
authors.forename: Elton
authors.initials: E
authors.lastname: Migliati
authors.forename: Mahmood
authors.initials: M
authors.lastname: Amiry-Moghaddam
authors.forename: Ole P
authors.initials: OP
authors.lastname: Ottersen
authors.forename: Anish
authors.initials: A
authors.lastname: Bhardwaj
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000473:pathology; D001929:Brain Edema / Q000209:etiology* / Q000517:prevention & control*; D002135:Calcium-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D006323:Heart Arrest / Q000150:complications*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000235:genetics; D009994:Osmolar Concentration; D011897:Random Allocation; D012462:Saline Solution, Hypertonic / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D051401:Aquaporin 4; D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D012462:Saline Solution, Hypertonic; C091825:syntrophin alpha1