Neurocritical Care

, Volume 24, Issue 2, pp 273–282 | Cite as

Conivaptan, a Selective Arginine Vasopressin V1a and V2 Receptor Antagonist Attenuates Global Cerebral Edema Following Experimental Cardiac Arrest via Perivascular Pool of Aquaporin-4

  • Shin Nakayama
  • Mahmood Amiry-Moghaddam
  • Ole Petter Ottersen
  • Anish Bhardwaj
Translational Research



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.


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.


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.


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.


Conivaptan Global cerebral ischemia Cardiac arrest Cerebral edema Aquaporins 


  1. 1.
    Adrie C, Haouache H, Saleh M, et al. An underrecognized source of organ donors: patients with brain death after successfully resuscitated cardiac arrest. Intensive Care Med. 2008;34(1):132–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Manley GT, Fujimura M, Ma T, et al. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med. 2000;6(2):159–63.CrossRefPubMedGoogle Scholar
  3. 3.
    Badaut J, Lasbennes F, Magistretti PJ, et al. Aquaporins in brain: distribution, physiology, and pathophysiology. J Cereb Blood Flow Metab. 2002;22(4):367–78.CrossRefPubMedGoogle Scholar
  4. 4.
    Vajda Z, Pedersen M, Fuchtbauer EM, et al. Delayed onset of brain edema and mislocalization of aquaporin-4 in dystrophin-null transgenic mice. Proc Natl Acad Sci USA. 2002;99(20):13131–6.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Amiry-Moghaddam M, Otsuka T, Hurn PD, et al. An alpha-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain. Proc Natl Acad Sci USA. 2003;100(4):2106–11.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Amiry-Moghaddam M, Williamson A, Palomba M, et al. Delayed K + clearance associated with aquaporin-4 mislocalization: phenotypic defects in brains of alpha-syntrophin-null mice. Proc Natl Acad Sci USA. 2003;100(23):13615–20.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Amiry-Moghaddam M, Xue R, Haug FM, et al. Alpha-syntrophin deletion removes the perivascular but not endothelial pool of aquaporin-4 at the blood-brain barrier and delays the development of brain edema in an experimental model of acute hyponatremia. FASEB J. 2004;18(3):542–4.PubMedGoogle Scholar
  8. 8.
    Nagelhus EA, Ottersen OP. Physiological roles of aquaporin-4 in brain. Physiol Rev. 2013;93(4):1543–62.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Haj-Yasein NN, Vindedal GF, Eilert-Olsen M, et al. Glial-conditional deletion of aquaporin-4 (Aqp4) reduces blood-brain water uptake and confers barrier function on perivascular astrocyte endfeet. Proc Natl Acad Sci USA. 2011;108(43):17815–20.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Neely JD, Amiry-Moghaddam M, Ottersen OP, et al. Syntrophin-dependent expression and localization of aquaporin-4 water channel protein. Proc Natl Acad Sci USA. 2001;98(24):14108–13.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Migliati E, Meurice N, DuBois P, et al. Inhibition of aquaporin-1 and aquaporin-4 water permeability by a derivative of the loop diuretic bumetanide acting at an internal pore-occluding binding site. Mol Pharmacol. 2009;76(1):105–12.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Zeynalov E, Chen CH, Froehner SC, et al. The perivascular pool of aquaporin-4 mediates the effect of osmotherapy in postischemic cerebral edema. Crit Care Med. 2008;36(9):2634–40.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Doczi T, Laszlo FA, Szerdahelyi P, et al. Involvement of vasopressin in brain edema formation: further evidence obtained from the Brattleboro diabetes insipidus rat with experimental subarachnoid hemorrhage. Neurosurgery. 1984;14(4):436–41.CrossRefPubMedGoogle Scholar
  14. 14.
    Trabold R, Krieg S, Scholler K, et al. Role of vasopressin V(1a) and V2 receptors for the development of secondary brain damage after traumatic brain injury in mice. J Neurotrauma. 2008;25(12):1459–65.CrossRefPubMedGoogle Scholar
  15. 15.
    Rosenberg GA, Scremin O, Estrada E, et al. Arginine vasopressin V1-antagonist and atrial natriuretic peptide reduce hemorrhagic brain edema in rats. Stroke. 1992;23(12):1767–73 (discussion 1773–1764).CrossRefPubMedGoogle Scholar
  16. 16.
    Molnar AH, Varga C, Berko A, et al. Prevention of hypoxic brain oedema by the administration of vasopressin receptor antagonist OPC-31260. Prog Brain Res. 2008;170:519–25.CrossRefPubMedGoogle Scholar
  17. 17.
    Phillips PA, Abrahams JM, Kelly J, et al. Localization of vasopressin binding sites in rat brain by in vitro autoradiography using a radioiodinated V1 receptor antagonist. Neuroscience. 1988;27(3):749–61.CrossRefPubMedGoogle Scholar
  18. 18.
    Okuno K, Taya K, Marmarou CR, et al. The modulation of aquaporin-4 by using PKC-activator (phorbol myristate acetate) and V1a receptor antagonist (SR49059) following middle cerebral artery occlusion/reperfusion in the rat. Acta Neurochir Suppl. 2008;102:431–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Kleindienst A, Dunbar JG, Glisson R, et al. The role of vasopressin V1a receptors in cytotoxic brain edema formation following brain injury. Acta Neurochir (Wien). 2013;155(1):151–64.CrossRefGoogle Scholar
  20. 20.
    Manaenko A, Fathali N, Khatibi NH, et al. Arginine-vasopressin V1a receptor inhibition improves neurologic outcomes following an intracerebral hemorrhagic brain injury. Neurochem Int. 2011;58(4):542–8.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Croiset G, De Wied D. Proconvulsive effect of vasopressin; mediation by a putative V2 receptor subtype in the central nervous system. Brain Res. 1997;759(1):18–23.CrossRefPubMedGoogle Scholar
  22. 22.
    Decaux G, Soupart A, Vassart G. Non-peptide arginine-vasopressin antagonists: the vaptans. Lancet. 2008;371(9624):1624–32.CrossRefPubMedGoogle Scholar
  23. 23.
    Adams ME, Kramarcy N, Krall SP, et al. Absence of alpha-syntrophin leads to structurally aberrant neuromuscular synapses deficient in utrophin. J Cell Biol. 2000;150(6):1385–98.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Allen D, Nakayama S, Kuroiwa M, et al. SK2 channels are neuroprotective for ischemia-induced neuronal cell death. J Cereb Blood Flow Metab. 2011;31(12):2302–12.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Nakayama S, Vest R, Traystman RJ, et al. Sexually dimorphic response of TRPM2 inhibition following cardiac arrest-induced global cerebral ischemia in mice. J Mol Neurosci. 2013;51(1):92–8.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Chen CH, Toung TJ, Sapirstein A, et al. Effect of duration of osmotherapy on blood-brain barrier disruption and regional cerebral edema after experimental stroke. J Cereb Blood Flow Metab. 2006;26(7):951–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Toung TJ, Chen CH, Lin C, et al. Osmotherapy with hypertonic saline attenuates water content in brain and extracerebral organs. Crit Care Med. 2007;35(2):526–31.CrossRefPubMedGoogle Scholar
  28. 28.
    Uyama O, Okamura N, Yanase M, et al. Quantitative evaluation of vascular permeability in the gerbil brain after transient ischemia using Evans blue fluorescence. J Cereb Blood Flow Metab. 1988;8(2):282–4.CrossRefPubMedGoogle Scholar
  29. 29.
    Nakano T, Hurn PD, Herson PS, et al. Testosterone exacerbates neuronal damage following cardiac arrest and cardiopulmonary resuscitation in mouse. Brain Res. 2010;1357:124–30.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Nielsen S, Nagelhus EA, Amiry-Moghaddam M, et al. Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci. 1997;17(1):171–80.PubMedGoogle Scholar
  31. 31.
    Papadopoulos MC, Verkman AS. Aquaporin water channels in the nervous system. Nat Rev Neurosci. 2013;14(4):265–77.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Frydenlund DS, Bhardwaj A, Otsuka T, et al. Temporary loss of perivascular aquaporin-4 in neocortex after transient middle cerebral artery occlusion in mice. Proc Natl Acad Sci USA. 2006;103(36):13532–6.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Papadopoulos MC, Manley GT, Krishna S, et al. Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema. FASEB J. 2004;18(11):1291–3.PubMedGoogle Scholar
  34. 34.
    Chen CH, Xue R, Zhang J, et al. Effect of osmotherapy with hypertonic saline on regional cerebral edema following experimental stroke: a study utilizing magnetic resonance imaging. Neurocrit Care. 2007;7(1):92–100.CrossRefPubMedGoogle Scholar
  35. 35.
    Chang Y, Chen TY, Chen CH, et al. Plasma arginine-vasopressin following experimental stroke: effect of osmotherapy. J Appl Physiol. 2006;100(5):1445–51.CrossRefPubMedGoogle Scholar
  36. 36.
    Liu X, Nakayama S, Amiry-Moghaddam M, et al. Arginine-vasopressin V1 but not V2 receptor antagonism modulates infarct volume, brain water content, and aquaporin-4 expression following experimental stroke. Neurocrit Care. 2010;12(1):124–31.CrossRefPubMedGoogle Scholar
  37. 37.
    Vakili A, Kataoka H, Plesnila N. Role of arginine vasopressin V1 and V2 receptors for brain damage after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2005;25(8):1012–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Niermann H, Amiry-Moghaddam M, Holthoff K, et al. A novel role of vasopressin in the brain: modulation of activity-dependent water flux in the neocortex. J Neurosci. 2001;21(9):3045–51.PubMedGoogle Scholar
  39. 39.
    Shuaib A, Xu Wang C, Yang T, et al. Effects of nonpeptide V(1) vasopressin receptor antagonist SR-49059 on infarction volume and recovery of function in a focal embolic stroke model. Stroke. 2002;33(12):3033–7.CrossRefPubMedGoogle Scholar
  40. 40.
    Taya K, Gulsen S, Okuno K, et al. Modulation of AQP4 expression by the selective V1a receptor antagonist, SR49059, decreases trauma-induced brain edema. Acta Neurochir Suppl. 2008;102:425–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Landgraf R, Ramirez AD, Ramirez VD. The positive feedback action of vasopressin on its own release from rat septal tissue in vitro is receptor-mediated. Brain Res. 1991;545(1–2):137–41.CrossRefPubMedGoogle Scholar
  42. 42.
    Yeung PK, Lo AC, Leung JW, et al. Targeted overexpression of endothelin-1 in astrocytes leads to more severe cytotoxic brain edema and higher mortality. J Cereb Blood Flow Metab. 2009;29(12):1891–902.CrossRefPubMedGoogle Scholar
  43. 43.
    Aditya S, Rattan A. Vaptans: a new option in the management of hyponatremia. Int J Appl Basic Med Res. 2012;2(2):77–83.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Fields JD, Bhardwaj A. Non-peptide arginine-vasopressin antagonists (vaptans) for the treatment of hyponatremia in neurocritical care: a new alternative. Neurocrit Care. 2009;11:1–4.CrossRefPubMedGoogle Scholar
  45. 45.
    Galton C, Deem S, Yanez ND, et al. Open-label randomized trial of the safety and efficacy of a single dose conivaptan to raise serum sodium in patients with traumatic brain injury. Neurocrit Care. 2011;14(3):354–60.CrossRefPubMedGoogle Scholar
  46. 46.
    Dhar R, Murphy-Human T. A bolus of conivaptan lowers intracranial pressure in a patient with hyponatremia after traumatic brain injury. Neurocrit Care. 2011;14(1):97–102.CrossRefPubMedGoogle Scholar
  47. 47.
    Zeynalov E, Jones SM, Seo JW, et al. Arginine-vasopressin receptor blocker conivaptan reduces brain edema and blood-brain barrier disruption after experimental stroke in mice. PLoS ONE. 2015;10(8):e0136121.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Hockel K, Scholler K, Trabold R, et al. Vasopressin V(1a) receptors mediate posthemorrhagic systemic hypertension thereby determining rebleeding rate and outcome after experimental subarachnoid hemorrhage. Stroke. 2012;43(1):227–32.CrossRefPubMedGoogle Scholar
  49. 49.
    Udelson JE, Smith WB, Hendrix GH, et al. Acute hemodynamic effects of conivaptan, a dual V(1A) and V(2) vasopressin receptor antagonist, in patients with advanced heart failure. Circulation. 2001;104(20):2417–23.CrossRefPubMedGoogle Scholar
  50. 50.
    Zeltser D, Rosansky S, van Rensburg H, et al. Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia. Am J Nephrol. 2007;27(5):447–57.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Shin Nakayama
    • 1
    • 2
  • Mahmood Amiry-Moghaddam
    • 3
  • Ole Petter Ottersen
    • 3
  • Anish Bhardwaj
    • 1
    • 4
  1. 1.Departments of NeurologyNeurological Surgery and Anesthesiology & Peri-Operative Medicine, Oregon Health and Science UniversityPortlandUSA
  2. 2.Department of Anesthesiology, Faculty of MedicineUniversity of TsukubaTsukubaJapan
  3. 3.Institute of Basic Medical SciencesUniversity of OsloOsloNorway
  4. 4.Department of NeurologyUniversity of Texas Medical Branch (UTMB)GalvestonUSA

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