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Arterial vasospasm is the major cause of disability and death
in patients with subarachnoid hemorrhage (SAH) subsequent to the
rupture of a cerebral aneurysm. Clinically there are 3 factors
related to the prognosis: 1) rebleeding of aneurysm; 2) cerebral
infarction due to cerebral vasospasm; 3) hydrocephalus.
Rebleeding and hydrocephalus can be effectively treated by
surgical management. But effective treatment of cerebral
vasospasm has not yet been established. Reduced cerebral
perfusion secondary to SAH has been well documented. Once
aneurysmal SAH, happens, a resulting complex pathological
reaction has direct effect causing increased intracranial
pressure, and acute ischemic brain dysfunction. In the mean
time, these results may produce free radical, which could
stimulate lipid peroxidation, facilitate increased endothelial
cell permeability, cause damage of endothelial cell, increase
production of eicosanoids, decrease production of PGI2 and
endothelium-dependent relaxing factor. Oxyhemoglobin inhibits
acetylcholin-mediated relaxation. Hemolysate itself will
activate neurogenic vasoconstriction; and will stimulate the
increased production of protein kinase C via lipid peroxidation.
These reactions increased endothelial cell permeability, intima
proliferation, and lumen stenosis; and increased fibrinogen
induced increase of blood viscosity, and caused severe delayed
vasospasm. In eicosanoid study, leukotrienes and prostaglandin
increased after SAH, but is a secondary role to other spasmogens
in the initiation of cerebrovascular spasm. Recently, endothelin
acting as a potent vasoconstrictor was widely accepted.
Clinically, we examined the significant increase of endothelin
in plasma and CSF following SAH. Experimental study showed
endothelium damage after SAH. In order to investigate how the
endothelium injuries, we studied the direct effect of hemolysate
induced structural and functional injury to cultured cerebral
endothelial cells, and the effect in cell permeability. The
result indicated hemolysate will directly damage endothelial
cell, and increase their permeability. These effects will be
attenuated by treatment with iron chelator or NOS inhibitor. We
believe that endothelin and endothelial damage played an
important role in the pathogenesis of cerebrospasm. Current
studies showed Endothelin-1 (ET-1) is the most potent
vasoconstrictor, and it produces vasoconstriction by activating
Big endothelin-1 (Big ET-1). Because Endothelial Converting
Enzyme (ECE) can activate Big ET-1 to ET-1, blocking the
activating effect of ECE may improve vasospasm after to SAH. In
our final result, we successfully proved that Big ET-1 could be
converted into ET-1 by ECE, and ECE inhibitor CGS 26303 will
significantly improve vasospasm. These present findings are
encouraging because they provide direct evidence for the
feasibility of targeting the proteolytic activation of
endothelin within a realistic time frame following SAH. In
addition, potassium channels play a variety of roles in the
physiological regulation of vascular tone. Vascular narrowing
following experimental SAH could be reversed by topical
application of potassium channel activator cromakalim. Our
result indicated that systemic administration of the potassium
channel activator cromakalim attenuated cerebral vasospasm after
experimental SAH. Nonetheless, a future studies will be made to
carefully evaluate the impact of these potential side effects on
post SAH animals in order to validate the utility of this
compound for treating vasospasm.
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