Role of arginine vasopressin V1 and V2 receptors for brain damage after transient focal cerebral ischemia

Brain edema formation is one of the most important mechanisms responsible for brain damage after ischemic stroke. Despite considerable efforts, no specific therapy is available yet. Arginine vasopressin (AVID) regulates cerebral water homeostasis and has been involved in brain edema formation. In the current study, we investigated the role of AVP V-1 and V-2 receptors on brain damage, brain edema formation, and functional outcome after transient focal cerebral ischemia, a condition comparable with that of stroke patients undergoing thrombolysis. C57/BL6 mice were subjected to 60-min middle cerebral artery occlusion (MCAO) followed by 23 h of reperfusion. Five minutes after MCAO, 100 or 500 ng of [deamino-Pen(1), O-Me-Tyr(2), Arg(8)]-vasopressin (AVP V-1 receptor antagonist) or [adamantaneacetyl(l), O-Et-D-Tyr(2), Val(4), Abu(6), Arg(8,9)]-vasopressin (AVP V-2 receptor antagonist) were injected into the left ventricle. Inhibition of AVP V-1 receptors reduced infarct volume in a dose-dependent manner by 54% and 70% (to 29 +/- 13 and 19 +/- 10 mm(3) versus 63 +/- 17 mm(3) in controls; P<0.001), brain edema formation by 67% (to 80.4%+/- 1.0% versus 82.7%+/- 11.2% in controls; P<0.001), blood-brain barrier disruption by 75% (P<0.001), and functional deficits 24 h after ischemia, while V-2 receptor inhibition had no effect. The current findings indicate that AVP V-1 but not V-2 receptors are involved in the pathophysiology of secondary brain damage after focal cerebral ischemia. Although further studies are needed to clarify the mechanisms of neuroprotection, AVP V-1 receptors seem to be promising targets for the treatment of ischemic stroke.