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

Neurocritical Care volume 24, pages273–282(2016)Cite this article

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.

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Acknowledgments

This work was supported by Public Health Service NIH grants NS046379. We thank Marvin Adams, MD, Ph.D., and Stanley C. Froehner, Ph.D. for providing the α-syntrophin knockout mice and Stephanie J. Murphy, DVM, Ph.D., and Sarah Mader for maintaining the animal colony.

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Affiliations

  1. Departments of Neurology, Neurological Surgery and Anesthesiology & Peri-Operative Medicine, Oregon Health and Science University, Portland, OR, USA

    Shin Nakayama & Anish Bhardwaj

  2. Department of Anesthesiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

    Shin Nakayama

  3. Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway

    Mahmood Amiry-Moghaddam & Ole Petter Ottersen

  4. Department of Neurology, University of Texas Medical Branch (UTMB), 9.128 John Sealy Annex, Route 0539, 301 University Blvd, Galveston, TX, 77555, USA

    Anish Bhardwaj

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  1. Shin Nakayama
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  2. Mahmood Amiry-Moghaddam
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  3. Ole Petter Ottersen
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  4. Anish Bhardwaj
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Correspondence to Anish Bhardwaj.

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Nakayama, S., Amiry-Moghaddam, M., Ottersen, O.P. et al. Conivaptan, a Selective Arginine Vasopressin V1a and V2 Receptor Antagonist Attenuates Global Cerebral Edema Following Experimental Cardiac Arrest via Perivascular Pool of Aquaporin-4. Neurocrit Care 24, 273–282 (2016). https://doi.org/10.1007/s12028-015-0236-4

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Keywords

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