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Arginine-Vasopressin V1 but not V2 Receptor Antagonism Modulates Infarct Volume, Brain Water Content, and Aquaporin-4 Expression Following Experimental Stroke

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Abstract

Background

Aquaporin-4 (AQP4) plays an important role in the evolution of ischemia-evoked cerebral edema. Experimental studies have also demonstrated anti-edema effects of arginine-vasopressin (AVP) antagonists. In a well-characterized murine model of ischemic stroke, we tested the hypotheses that treatment with selective AVP V1 but not V2 receptor antagonist (1) attenuates injury volume and ischemia-evoked cerebral edema; and (2) modulates ischemia-evoked AQP4 expression.

Methods

Isoflurane-anesthetized adult male C57bl/6 mice were subjected to 60 min of middle cerebral artery occlusion (MCAO) by the intraluminal suture technique. Adequacy of MCAO and reperfusion was monitored with laser-Doppler flowmetry over the ipsilateral parietal cortex. Mice were treated with intracerebroventricular injection of selective AVP V1 and V2 receptor antagonist or control vehicle (0.9% saline). Infarct volume (tetrazolium staining), cerebral edema (wet-to-dry ratios) and AQP4 protein expression (immunoblotting) were determined in different treatment groups in separate sets of experiments at 24 h of reperfusion.

Results

Infarct volume (percentage of contralateral structure; mean ± SEM) was significantly attenuated in mice treated with 500 ng V1 receptor antagonist as well as at a dose of 1000 ng compared to controls. However, there was no difference in infarct volume following treatment with 1000 ng V2 antagonist as compared to controls. Water content in the ischemic hemisphere was significantly attenuated with V1 receptor antagonist (1000 ng) but not with V2 receptor antagonist as compared to controls. Treatment with AVP V1 receptor antagonist (1000 ng) but not V2 receptor antagonist, significantly upregulated AQP4 protein expression (% β-actin) compared to saline-treated mice in ipsilateral (ischemic) cerebral cortex.

Conclusions

These data demonstrate that following experimental stroke AVP V1 receptor antagonism: (1) attenuates injury volume and ischemia-evoked cerebral edema; (2) modulates AQP4 expression; and (3) may serve as an important therapeutic target for neuroprotection and ischemia-evoked cerebral edema.

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Acknowledgment

This work was supported by Public Health Service NIH Grant NS046379.

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Authors and Affiliations

  1. Department of Anesthesiology and Peri-Operative Medicine, Oregon Health & Science University, Portland, OR, USA

    Xiaoqin Liu, Shin Nakayama & Anish Bhardwaj

  2. Department of Neurology, Drum Tower Hospital, Nanjing Medical University, Nanjing, Jiangsu, China

    Xiaoqin Liu

  3. Center for Molecular Biology and Neuroscience and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, 0317, Oslo, Norway

    Mahmood Amiry-Moghaddam & Ole Petter Ottersen

  4. Department of Neurology, Oregon Health & Science University, Portland, OR, USA

    Anish Bhardwaj

  5. Department of Neurological Surgery, Oregon Health & Science University, Portland, OR, USA

    Anish Bhardwaj

  6. Department of Neurology, Tufts University School of Medicine, Tufts Medical Center, 800 Washington Street, Box 314, Boston, MA, USA

    Anish Bhardwaj

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  1. Xiaoqin Liu
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  2. Shin Nakayama
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  3. Mahmood Amiry-Moghaddam
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  5. Anish Bhardwaj
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Correspondence to Anish Bhardwaj.

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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 12, 124–131 (2010). https://doi.org/10.1007/s12028-009-9277-x

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