gms | German Medical Science

Objective: Subarachnoid hemorrhage (SAH) is a devastating subtype of stroke with high mortality and morbidity. For decades spasms of large cerebral vessels occurring later than five days after SAH were believed to be the main factor for bad outcome of SAH patients. Recently, however, clinical and experimental data suggest that long-lasting spasms of the cerebral microcirculation developing within the first few hours after SAH may be an important factor contributing to post-hemorrhagic brain injury and delayed ischemia. So far, however, the etiology of this microcirculatory dysfunction is largely unknown. Among others, overabundance of vasoconstrictors like Endothelin-1 (ET-1) is a putative mechanism of cerebrovascular microvasospasm. The aim of the current study was to assess the impact of an ET-1 receptor antagonist on microcirculatory dysfunction and outcome after experimental SAH.

Method: We performed a dose finding study using the ET-1-receptor antagonist Clazosentan at different i.v. doses and evaluated possible side effects of the drug. SAH was induced by the MCA filament perforation model in C57BL/6 mice. 3 hours after SAH the cerebral microcirculation was studied before, during, and after i.v. Clazosentan application (10 mg/kg/min) using epifluorescence intravital microscopy. In a second part of the study neurological outcome and brain edema formation were evaluated up to 3 days after SAH with or without Clazosentan treatment.

Results: Clazosentan did not influence MAP, ICP, and CBF when given at 1, 3, or 10 mg/kg bodyweight, MAP tended to be lower at 20 mg/kg b.w. All further experiments were therefore conducted using 10 mg/kg b.w. Clazosentan did not reduce number and intensity of cerebral microvasospasms in the pial microcirculation. While ET-1-receptor inhibition showed a trend towards dilating larger arterioles (< 35 μm diameter), the diameter of smaller arterioles (10-35 μm) remained unchanged. Three days after SAH brain water content was significantly lower in Clazosentan-treated mice. However, functional outcome was not different to the control group.

Conclusions: ET-1 receptors do not seem to play a role in the formation of microarterial spasms early after SAH and their inhibition does not improve neurological outcome. The effect of Clazosentan on larger vessels was confirmed and may contribute to the reduction in brain edema formation observed in this study. Further studies are needed in order to improve understanding of the pathophysiology of microvasospasm formation.