Blocking Vascular Smooth Muscle Activation

The literature suggests that after 24 to 48 hours, vasospasm is largely mediated by vascular and smooth muscle activation, triggered by the release of endothelin and subsequent initiation of a VEGF-mediated cascade, the activation of rho kinase II pathways, and the presence of reactive oxygen species.

Endothelin/VEGF Cascade

It is hypothesized that oxyhemoglobin released from lysed erythrocytes in the subarach-noid space causes vessel contraction, which is potentiated by endothelin-1 (ET-1). The downstream effects of ET-1 are likely mediated by the release of vascular endothelial growth factor (VEGF), one of the most potent mediators of cerebral angiogenesis (37 ). Studies have implicated this pathway in vitro by measuring cerebrovascular smooth muscle contraction in the presence of varying amounts of ET-1 and inhibitors of the endothelin receptor (38-41). Studies have also shown that plasma ET-1 concentrations correlate with the incidence of DINDs after SAH (42). Based on these studies, a double-blinded Phase 2 trial of an endothelin receptor antagonist (TAK-044), consisting of 420 randomized patients, has been reported (43). Endpoints included DINDS within 10 days and three months of first dose of medication, evidence of new cerebral infarct (on CT or postmortem), GOS at three months, and adverse events. The authors reported a lower incidence of DINDs at three months in the treatment group (29.5% vs. 36.6%, RR, 0.8; 95% CI 0.61-1.06), with no other significantly different endpoints. The authors intend to conduct a full Phase 3 trial, with appropriate power (43 ). Data from a Phase 2a trial, soon to be published, demonstrate that a selective ET-A receptor antagonist (clazosentan) reduces the frequency and severity of vasospasm and is well tolerated. A major clinical trial involving North American centers is about to be launched to further examine this agent.

Reactive Oxygen Species

Owing to the release of oxyhemoglobin by hemolyzed erythrocytes in the subarachnoid space, many hypothesize that the concentration of reactive oxygen species increases in the subarach-noid environment, thereby contributing to vasospasm (44). A multicentered, placebo-controlled, double-blinded clinical trial of 162 patients was conducted to verify the beneficial effects of free radical scavenging on DINDs and the overall outcomes (45). The authors reported a reduction in the incidence of DINDs in the treated group compared to placebo (35.5% vs. 54.2%, p <0.05), a significantly improved GOS at one month ( p < 0.05), a marginal improvement in outcomes at three months, and a significantly reduced cumulative incidence of death ( p <0.05) (45).

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