gms | German Medical Science

Objective: Various studies indicate acute vasoconstriction and a consecutive decrease of cerebral blood flow (CBF) in the first hours after subarachnoid hemorrhage (SAH), which may decisively contribute to early brain damage. Endothelin 1 acting via the Endothelin-A receptor may be a possible factor in the pathogenesis of this phenomenon. This study was conceived to investigate if an early therapy with a selective Endothelin-A antagonist immediately after SAH can enhance the early perfusion deficit.

Method: 36 male Sprague-Dawley rats were subjected to SAH by the endovascular filament model. The animals were randomly assigned to receive an intravenous therapy with Clazosentan (0.1, 1.0, or 10.0 mg/kg/h) or vehicle treatment (n = 9) starting 15 minutes after induction of SAH until the end of the observation period. Mean arterial blood pressure (MABP), intracranial pressure (ICP), and local CBF (laser-Doppler flowmetry) over both hemispheres were measured from 30 minutes before until 3 hours after SAH. After a neurological assessment 24 later, the animals were sacrificed and the hippocampal damage was assessed histologically.

Results: After vessel perforation, CBF equally decreased in both groups. Initial recovery was similar in both groups, too. The administration of Clazosentan in a dose of 0.1 and 1.0 mg/kg/h caused a moderate increase, in a dose of 10.0 mg/kg/h a significant increase of CBF. MABP, ICP, and CPP remained unaffected. Neurological performance was improved and hippocampal damage reduced after a treatment with 10.0 mg/kg/h compare with vehicle-treated animals.

Conclusions: Early treatment with an Endothelin-antagonist can enhance the early perfusion deficit after SAH and possibly counteracts the reversal of a surplus excretion of Endothelin early after SAH. The effect seems to be dose-dependent and result in a reduced histological damage.