Endothelin and Subarachnoid Hemorrhage: An Overview

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Delayed cerebral vasospasm occurring after subarachnoid hemorrhage (SAH) is still responsible for a considerable percentage of the morbidity and mortality in patients with aneurysms. It has been suggested that the pathogenesis of delayed cerebral vasospasm is related to a number of pathological processes, including endothelial damage and smooth muscle cell contraction resulting from spasmogenic substances generated during lysis of subarachnoid blood clots, changes in vascular responsiveness, and inflammatory or immunological reactions of the vascular wall. It has been recognized that the endothelium plays an important role in the regulation of the cerebral vascular tone. In 1988, endothelin (ET)-1, a potent vasoconstrictor, was isolated from cultured porcine aortic endothelial cells.


ET-1, which is one of three distinct isoforms of ETs (ET-1, ET-2, and ET-3), has a more marked effect on cerebral arteries than do the other two isoforms. Elevated levels of ETs have been demonstrated in the cerebrospinal fluid and plasma of patients after SAH and cerebral infarction. ETs act by at least three different receptor subtypes, the ETA receptor, which is localized in vascular smooth muscle cells and mediates vasoconstriction, and two different ETB receptor subtypes. The ETB1 receptor subtype is present in vascular endothelial cells and mediates the endothelium-dependent vasodilation. The ETB2 receptor subtype is present in smooth muscle cells causing vasoconstriction. ET-1 acts from the adventitial but not from the luminal side of cerebral arteries. In vivo and in vitro ET-1 causes a dose-dependent and long-lasting vasoconstriction, similar to cerebral vasospasm after SAH. The vasoconstriction caused by ET-1 can be reversed by selective ETA receptor antagonists or combined ETA and ETB receptor antagonists.


The results of current clinical and experimental investigations support the hypothesis that ET-1 is a major cause of cerebral vasospasm after SAH. Other studies indicate that SAH causes complex changes in the ET system and increased ET-1 levels after SAH, which are not solely responsible for the development of vasospasm but may occur after cerebral ischemia. Further investigations are therefore needed to clarify these different hypotheses.

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