Effect of LF 16-0687MS, a new nonpeptide bradykinin B2 receptor antagonist, in a rat model of closed head trauma

Bradykinin is an endogenous nonapeptide which potently dilates the cerebral vasculature and markedly increases vascular permeability. These effects are mediated by B-2 receptors located on the vascular endothelium. Previous experimental studies have shown that blockade of the kallikrein-kinin system, which mediates the formation of bradykinin, afforded a reduction of the brain edema that developed following a cryogenic cortical lesion. In the present study, we investigated the effect of LF 16-0687MS, a novel nonpeptide B-2 receptor antagonist, on cerebral edema and neurological severity score (NSS) after closed head injury to rats. LF 16-0687MS or its vehicle (NaCl 0.9%) was continuously infused at 10, 30, and 100 mu g/kg/min over 23 h starting 1 h after a focal trauma to the left hemisphere was induced using a weight-drop device. The extent of edema formation was evaluated 24 h after trauma from left and right hemispheres samples by measurement of specific gravity and water content. In a separate study, a neurological severity score based on scoring of behavioural and motor functions was evaluated 1 h and over 1 week after trauma. LF 16-0687MS at 100 mu g/kg/min markedly reduced the development of brain edema as indicated by a 68% increase in specific gravity (p < 0.05) and a 64% decrease of water content (p < 0.05) in the left hemisphere. In addition the recovery of neurological function was significantly improved by 100 mu g/kg/min LF 16-0687MS from day 3 to day 7 after CHT. In a separate experiment, we also showed that LF 16-0687MS at 100 mu g/kg/min given either 1 h before or 30 min after CHT did not affect mean arterial blood pressure. These results show that blockade of bradykinin B-2 receptors is an effective approach to reduce cerebral edema and to improve neurological outcome after a focal contusion to the cranium.