Treatment of brain edema with a nonpeptide arginine vasopressin V1 receptor antagonist OPC-21268 in rats.
OBJECTIVE
Recent experimental evidence suggests that centrally released arginine vasopressin plays a significant role in brain capillary water permeability as well as in pathogenesis of vasogenic brain edema. The purpose of this study was to examine the effects of orally administered OPC-21268, a nonpeptide arginine vasopressin V1 receptor antagonist, on cold-induced brain edema in rats.


METHODS
Cold brain injury was induced for 1 minute in 140 rats. Treatment with OPC-21268, at dosages of 100 mg (n = 20), 200 mg (n = 20), and 300 mg/kg (n = 15), or with saline (n = 17) was started 1 hour after the induction of cold injury and was continued every 8 hours for 24 hours. Two percent Evans blue in saline (1 ml/kg) was administered intravenously before cold injury in another group of rats, 15 of which were saline-treated and 55 of which were OPC-21268-treated at the above dosages. After 24 hours, brain tissue water and electrolytes, brain tissue swelling, blood-brain barrier permeability to Evans blue, and plasma electrolytes and osmolality were determined.


RESULTS
Compared with the saline-treated group, OPC-21268 treatment at the dosages of 200 and 300 mg/kg significantly reduced brain water content in both hemispheres (P<0.01). Swelling of the traumatized hemispheres was also significantly reduced at 200 and 300 mg/kg dosages (P<0.05). Brain tissue sodium content was significantly reduced at the dosage of 300 mg/kg (P<0.05). Blood-brain barrier permeability to Evans blue was significantly decreased in a dose-dependent manner compared with the saline-treated group (P<0.01). No significant changes were observed in other parameters.


CONCLUSIONS
Our results indicate that OPC-21268 predominantly exerts a protective effect in areas where the maximum amount of blood-brain barrier breakdown occurs, and it is effective in the treatment of cold-induced vasogenic brain edema.
Bemana
I
I
Department of Neurological Surgery, Kagawa Medical University, Kita-Gun, Japan.
Nagao
S
S
D000284:Administration, Oral; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001812:Blood-Brain Barrier / Q000187:drug effects; D001929:Brain Edema / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014882:Water-Electrolyte Balance / Q000187:drug effects
D065092:Antidiuretic Hormone Receptor Antagonists; D010880:Piperidines; D015363:Quinolones; C068644:OPC 21268