Inhibition of bradykinin B2 receptors before, not after onset of experimental subarachnoid hemorrhage prevents brain edema formation and improves functional outcome

Abstract

Objective: Brain edema following subarachnoid hemorrhage (SAH) is a result of impairment of cerebral autoregulation and breakdown of the blood-brain barrier. We investigated the role of bradykinin B2 receptors (BrdB2Rs) on brain edema formation after SAH.

Design: In vivo and ex vivo animal study.

Setting: University research laboratory.

Subjects: Male Sprague-Dawley rats.

Interventions and measurements: Rats were subjected to an endovascular perforation of the circle of Willis and were randomly assigned to a) vehicle, b) immediate treatment (30 minutes before and 300 minutes post-SAH) or c) delayed treatment (30 and 300 minutes post-SAH) with the B2 receptor antagonist Anatibant (LF 16-0687 Ms), and d) sham surgery. BrdB2R, kininogen (Kng1), and kallikrein mRNA expression was determined 6 hours after SAH or sham surgery.

Main results: SAH resulted in a significant increase in brain water content (vehicle: 80.3% +/- 1.2% vs. sham: 79.1% +/- 0.2%, p < 0.01) after 24 hours. Blockade of BrdB2Rs before SAH significantly prevented brain edema formation (79.0% +/- 0.3%, p < 0.05) and significantly improved neurologic recovery. BrdB2Rs and Kng1 mRNA were significantly increased 6 hours post-SAH (BrdB2R: 216%; Kng1: 2729%; p < 0.02 vs. sham). Delayed treatment regimen failed to reduce brain water content and neurologic impairment.

Conclusions: Our results indicate that BrdB2Rs play a key role in the initial phase after SAH contributing to brain edema formation. Inhibition of B2 receptors in a posttreatment regimen did not influence brain edema formation. Delayed pathophysiologic processes after SAH seem to be independent of B2 receptors.