Endothelin-1 in Subarachnoid Hemorrhage

Abstract

Background and Purpose-The most potent vasoconstrictor known, endothelin-1, is currently considered to mediate cerebral vasospasm in subarachnoid hemorrhage (SAH), which can cause delayed cerebral ischemia. In our study, we performed clinical and in vitro experiments to investigate the origin and the mechanisms of the secretion of endothelin-1 in SAH. Methods-Endothelin-1 and markers of inflammatory host response (interleukin [IL]-1␤, IL-6, and tumor necrosis factor-␣) were comparatively quantified in the cerebrospinal fluid (CSF) of SAH patients and control subjects, and concentrations were related to clinical characteristics. Furthermore, mononuclear leukocytes isolated from the CSF of SAH patients and control subjects were analyzed regarding their mRNA expression of endothelin-1 and inflammatory cytokines. Finally, complementary in vitro experiments were performed to investigate whether coincubation of blood and CSF can trigger leukocytic mRNA expression and release of these factors. Results-Activated mononuclear leukocytes in the CSF of SAH patients synthesize and release endothelin-1 in parallel with known acute-phase reactants (IL-1␤, IL-6, and tumor necrosis factor-␣). Complementary in vitro experiments not only further confirmed this leukocytic origin of endothelin-1 but also showed that aging and subsequent hemolysis of blood is sufficient to induce such endothelin-1 production. Conclusions-The demonstration that endothelin-1 is produced by activated CSF mononuclear leukocytes suggests that subarachnoid inflammation may represent a therapeutic target to prevent vasospasm and delayed cerebral ischemia after SAH. (Stroke. 2000;31:2971-2975.)

Inflammation, Vasospasm, and Brain Injury after Subarachnoid Hemorrhage

“…ET-1 has been detected in CSF from patients with SAH and can be produced by monocytes isolated from CSF of SAH patients [13, 14]. ET-1 has been implicated in the development of vasospasm after SAH [15] and will be discussed in detail later in this review.…”

“…ET-1 has been implicated in the development of vasospasm after SAH [15] and will be discussed in detail later in this review. As with many other proinflammatory molecules, the expression of ET-1 is highly variable: in a study by Fassbender and colleagues, ET-1 was not found in CSF of control subjects, and only 46% of patients with SAH had detectable levels of ET-1 [13]. Though the averaged results of both groups revealed a significant increase in ET-1 after SAH, this demonstrates that not all patients with SAH experience the same inflammatory response.…”

Metamorphosis of Subarachnoid Hemorrhage Research: from Delayed Vasospasm to Early Brain Injury

“…ET-1 is a potent vasoconstrictor released by astrocytes and leukocytes in response to inflammation and early ischemia after SAH [68, 69]. ET-1 is implicated in early brain injury and in the pathogenesis of delayed vasospasm and delayed ischemic deficits after SAH [70–72].…”

The Role of the Host Defense System in the Development of Cerebral Vasospasm: Analogies between Atherosclerosis and Subarachnoid Hemorrhage

“…Accumulating pro and contra evidence related to endothelin-1 [14,15,16,17,18], in a phase II randomized clinical trial (RCT) of clazosentan, a selective endothelin A receptor antagonist, it was found that clazosentan significantly reduced the incidence of ‘moderate to severe (<67% of control) vasospasm on the angiogram’, from 88% in placebo-treated individuals to 40% in the treated group (n = 32) [19]. However, the results of the latest phase III RCT (n = 1,157) did not demonstrate a beneficial effect of the drug in patients with SAH as regards functional outcome, vasospasm-related morbidity or mortality.…”