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

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalNeurocritical Care
DOIs
StateAccepted/In press - Jan 5 2016

Fingerprint

Aquaporin 4
Vasopressin Receptors
Brain Edema
Heart Arrest
Cardiopulmonary Resuscitation
Osmolar Concentration
Water
conivaptan
Aquaporins
Arginine Vasopressin
Isoflurane
Serum

Keywords

  • Aquaporins
  • Cardiac arrest
  • Cerebral edema
  • Conivaptan
  • Global cerebral ischemia

ASJC Scopus subject areas

  • Clinical Neurology
  • Critical Care and Intensive Care Medicine

Cite this

@article{67d087f290ab4c44920eb8d7fc6e3470,
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.",
keywords = "Aquaporins, Cardiac arrest, Cerebral edema, Conivaptan, Global cerebral ischemia",
author = "Shin Nakayama and Mahmood Amiry-Moghaddam and Ottersen, {Ole Petter} and Anish Bhardwaj",
year = "2016",
month = "1",
day = "5",
doi = "10.1007/s12028-015-0236-4",
language = "English (US)",
pages = "1--10",
journal = "Neurocritical Care",
issn = "1541-6933",
publisher = "Humana Press",

}

TY - JOUR

T1 - Conivaptan, a Selective Arginine Vasopressin V1a and V2 Receptor Antagonist Attenuates Global Cerebral Edema Following Experimental Cardiac Arrest via Perivascular Pool of Aquaporin-4

AU - Nakayama, Shin

AU - Amiry-Moghaddam, Mahmood

AU - Ottersen, Ole Petter

AU - Bhardwaj, Anish

PY - 2016/1/5

Y1 - 2016/1/5

N2 - 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.

AB - 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.

KW - Aquaporins

KW - Cardiac arrest

KW - Cerebral edema

KW - Conivaptan

KW - Global cerebral ischemia

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U2 - 10.1007/s12028-015-0236-4

DO - 10.1007/s12028-015-0236-4

M3 - Article

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AN - SCOPUS:84953227443

SP - 1

EP - 10

JO - Neurocritical Care

JF - Neurocritical Care

SN - 1541-6933

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