Arginine-vasopressin V1 but not V2 receptor antagonism modulates infarct volume, brain water content, and aquaporin-4 expression following experimental stroke.
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 V(1) but not V(2) 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 V(1) and V(2) 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 V(1) 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 V(2) antagonist as compared to controls. Water content in the ischemic hemisphere was significantly attenuated with V(1) receptor antagonist (1000 ng) but not with V(2) receptor antagonist as compared to controls. Treatment with AVP V(1) receptor antagonist (1000 ng) but not V(2) receptor antagonist, significantly upregulated AQP4 protein expression (% beta-actin) compared to saline-treated mice in ipsilateral (ischemic) cerebral cortex.


CONCLUSIONS
These data demonstrate that following experimental stroke AVP V(1) 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.
Liu
Xiaoqin
X
Department of Anesthesiology and Peri-Operative Medicine, Oregon Health & Science University, Portland, OR, USA.
Nakayama
Shin
S
Amiry-Moghaddam
Mahmood
M
Ottersen
Ole Petter
OP
Bhardwaj
Anish
A
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D051401:Aquaporin 4 / Q000235:genetics*; D001127:Arginine Vasopressin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000473:pathology; D001929:Brain Edema / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics* / Q000473:pathology*; D002546:Ischemic Attack, Transient / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017483:Receptors, Vasopressin / Q000502:physiology
D065092:Antidiuretic Hormone Receptor Antagonists; C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D017483:Receptors, Vasopressin; C549396:vasopressin, 1-adamantaneacetyl-O-Et-Tyr(2)-Val(4)-aminobutyryl(6)-Arg(8,9)-; C549395:vasopressin, deaminoPen(1)-O-Me-Tyr(2)-Arg(8)-; D001127:Arginine Vasopressin