Bradykinin, an endogenous nonapeptide produced by activation of the kallikrein-kinin system, promotes neuronal tissue damage as well as disturbances in blood-brain barrier function through activation of B2 receptors. In a rat model of focal
cerebral ischemia, blockade of B2 receptors before initiation of
ischemia with the B2 receptor antagonist,
LF 16-0687 Ms, afforded substantial neuroprotection. In order to assess the potential clinical value of this approach, we evaluated the effect of
LF 16-0687 Ms given at reperfusion following focal
cerebral ischemia on local cerebral blood flow (LCBF), neurological outcome, and
infarct size. Sprague-Dawley rats were subjected to MCA occlusion for 90 min by an intraluminal filament. Animals were assigned to one of four treatment arms (n = 7 each): (1) vehicle, (2)
LF 16-0687 Ms (1.0 mg/kg/day), (3)
LF 16-0687 Ms (3.0 mg/kg/day), or (4)
LF 16-0687 Ms (10.0 mg/kg/day) given at reperfusion and repetitively over 2 days. Neurological recovery was examined daily, and
infarct volume was assessed histologically on day 7 after
ischemia. Physiological parameters and local CBF were not influenced by the treatment. Significant improvement of neurological outcome was observed on postischemic day 3 in animals receiving 1.0 and 3.0 mg/kg/day of
LF 16-0687 Ms (P < 0.05). Inhibition of B2 receptors significantly reduced
infarct volume in all treated animals predominantly in the cortex. B2 receptor blockade with
LF 16-0687 Ms showed neuroprotective effectiveness even when
therapy was initiated upon reperfusion, i.e. 90 min after induction of
ischemia. Therefore, blockade of B2 receptors seems to be a promising therapeutic approach after focal
cerebral ischemia, which deserves further experimental and clinical evaluation.