Arginine-Vasopressin Receptor Blocker Conivaptan Reduces Brain Edema and Blood-Brain Barrier Disruption after Experimental Stroke in Mice.
BACKGROUND
Stroke is a major cause of morbidity and mortality. Stroke is complicated by brain edema and blood-brain barrier (BBB) disruption, and is often accompanied by increased release of arginine-vasopressin (AVP). AVP acts through V1a and V2 receptors to trigger hyponatremia, vasospasm, and platelet aggregation which can exacerbate brain edema. The AVP receptor blockers conivaptan (V1a and V2) and tolvaptan (V2) are used to correct hyponatremia, but their effect on post-ischemic brain edema and BBB disruption remains to be elucidated. Therefore, we conducted this study to investigate if these drugs can prevent brain edema and BBB disruption in mice after stroke.


METHODS
Experimental mice underwent the filament model of middle cerebral artery occlusion (MCAO) with reperfusion. Mice were treated with conivaptan, tolvaptan, or vehicle. Treatments were initiated immediately at reperfusion and administered IV (conivaptan) or orally (tolvaptan) for 48 hours. Physiological variables, neurological deficit scores (NDS), plasma and urine sodium and osmolality were recorded. Brain water content (BWC) and Evans Blue (EB) extravasation index were evaluated at the end point.


RESULTS
Both conivaptan and tolvaptan produced aquaresis as indicated by changes in plasma and urine sodium levels. However plasma and urine osmolality was changed only by conivaptan. Unlike tolvaptan, conivaptan improved NDS and reduced BWC in the ipsilateral hemisphere: from 81.66 ± 0.43% (vehicle) to 78.28 ± 0.48% (conivaptan, 0.2 mg, p < 0.05 vs vehicle). Conivaptan also attenuated the EB extravasation from 1.22 ± 0.08 (vehicle) to 1.01 ± 0.02 (conivaptan, 0.2 mg, p < 0.05).


CONCLUSIONS
Continuous IV infusion with conivaptan for 48 hours after experimental stroke reduces brain edema, and BBB disruption. Conivaptan but not tolvaptan may potentially be used in patients to prevent brain edema after stroke.
Swedish Medical Center, Neurotrauma Research, Englewood, Colorado, United States of America.
Emil
E
Zeynalov
Swedish Medical Center, Neurotrauma Research, Englewood, Colorado, United States of America.
Susan M
SM
Jones
Swedish Medical Center, Neurotrauma Research, Englewood, Colorado, United States of America.
Jeong-Woo
JW
Seo
Colorado Neurological Institute, Englewood, Colorado, United States of America.
Lawrence D
LD
Snell
Colorado Brain and Spine Institute, Englewood, Colorado, United States of America.
J Paul
JP
Elliott
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D001929:Brain Edema / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D051379:Mice; D017483:Receptors, Vasopressin / Q000378:metabolism*; D020521:Stroke / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D014882:Water-Electrolyte Balance / Q000187:drug effects
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D017483:Receptors, Vasopressin; C106389:conivaptan