title: Conivaptan, a Selective Arginine Vasopressin V1a and V2 Receptor Antagonist Attenuates Global Cerebral Edema Following Experimental Cardiac Arrest via Perivascular Pool of Aquaporin-4.
abstract: BACKGROUND
  Cerebral edema is a major cause of mortality following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Arginine vasopressin (AVP) and water channel aquaporin-4 (AQP4) have been implicated in the pathogenesis of CA-evoked cerebral edema. In this study, we examined if conivaptan, a V1a and V2 antagonist, attenuates cerebral edema following CA/CPR in wild type (WT) mice as well as mice with targeted disruption of the gene encoding α-syntrophin (α-syn(-/-)) that demonstrate diminished perivascular AQP4 pool.
  
  
  METHODS
  Isoflurane-anesthetized adult male WT C57Bl/6 and α-syn(-/-) mice were subjected to 8 min CA/CPR and treated with either bolus IV injection (0.15 or 0.3 mg/kg) followed by continuous infusion of conivaptan (0.15 mg/kg/day or 0.3 mg/kg/day), or vehicle infusion for 48 h. Serum osmolality, regional brain water content, and blood-brain barrier (BBB) disruption were determined at the end of the experiment. Sham-operated mice in both strains served as controls.
  
  
  RESULTS
  Treatment with conivaptan elevated serum osmolality in a dose-dependent manner. In WT mice, conivaptan at 0.3 mg dose significantly attenuated regional water content in the caudoputamen (81.0 ± 0.5 vs. 82.5 ± 0.4% in controls; mean ± SEM) and cortex (78.8 ± 0.2 vs. 79.4 ± 0.2% in controls), while conivaptan at 0.15 mg was not effective. In α-syn(-/-) mice, conivaptan at 0.3 mg dose did not attenuate water content compared with controls. Conivaptan (0.3 mg/kg/day) attenuated post-CA BBB disruption at 48 h in WT mice but not in α-syn(-/-) mice.
  
  
  CONCLUSIONS
  Continuous IV infusion of conivaptan attenuates cerebral edema and BBB disruption following CA. These effects of conivaptan that are dependent on the presence of perivascular pool of AQP4 appear be mediated via its dual effect on V1 and V2 receptors.
authors.affiliation: Departments of Neurology, Neurological Surgery and Anesthesiology & Peri-Operative Medicine, Oregon Health and Science University, Portland, OR, USA.|Department of Anesthesiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Nakayama
authors.affiliation: Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Mahmood
authors.initials: M
authors.lastname: Amiry-Moghaddam
authors.affiliation: Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Ole Petter
authors.initials: OP
authors.lastname: Ottersen
authors.affiliation: Departments of Neurology, Neurological Surgery and Anesthesiology & Peri-Operative Medicine, Oregon Health and Science University, Portland, OR, USA. anbhardw@utmb.edu.|Department of Neurology, University of Texas Medical Branch (UTMB), 9.128 John Sealy Annex, Route 0539, 301 University Blvd, Galveston, TX, 77555, USA. anbhardw@utmb.edu.
authors.forename: Anish
authors.initials: A
authors.lastname: Bhardwaj
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D051401:Aquaporin 4 / Q000378:metabolism*; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology*; D001929:Brain Edema / Q000188:drug therapy* / Q000209:etiology; D016887:Cardiopulmonary Resuscitation; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006323:Heart Arrest / Q000150:complications*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D051401:Aquaporin 4; D001552:Benzazepines; C106389:conivaptan
keywords: Aquaporins; Cardiac arrest; Cerebral edema; Conivaptan; Global cerebral ischemia