Endothelin

In addition to impaired endothelial production of NO, endothelial production of endothelin may be a major mechanism that contributes to vasospasm after SAH. Endothelin, the most powerful vasoconstrictor yet identified in biologic systems, as well as being a potent constrictor of cerebral arteries, may also participate in the pathogenesis of vascular injury. Although not well studied in the cerebral circulation, endothelin induces vascular inflammatory response and remodeling. It exercises proliferative actions on VSMCs, promotes the production of fibroblasts, modulates the synthesis of the extracellular matrix, and affects vascular permeability (60-64).

After SAH, levels of ET-1 are increased in the basilar artery and in CSF (65-67). Stimuli that cause endothelin gene expression after SAH are not well defined, but endothelin gene expression is inhibited by NO and cGMP and can be enhanced by several factors, including hemoglobin, thrombin, reactive oxygen species (ROS), transforming growth factor-ß, and tumor necrosis factor-a (68-73).

Two subtypes of endothelin receptors have been identified, endothelin-A (ET A) and endo-thelin-B (ET B) receptors. In general, ET A receptors are expressed in vascular muscle and mediate contraction (Fig. 2) (74). The response to activation of ET B receptors depends on localization of the receptor. ET B receptors are expressed in SMCs in some blood vessels and mediate contraction. In contrast, activation of endothelial ET B receptors produces relaxation of blood vessels through the release of prostacyclin or NO (73,74 ).

Both ET A and ET B receptors are coupled to phospholipase C (PLC) via a guanosine triphosphate (GTP)-binding protein (76). Activation of PLC causes phosphatidylinositol hydrolysis, rapid formation of 1,4,5-inositol triphosphate (IP 3), and accumulation of

Figure 2 Endothelin mechanism of action. Normal pathways of endothelin on endothelium and vascular smooth muscle cells. Source: From Ref. 75.

1,2-diacylglycerol. IP 3 stimulates the release of Ca2+ from intracellular stores, including endoplasmic reticulum. This initial transient increase in intracellular Ca2+ concentration is followed by a sustained increase, probably due to an influx of extracellular Ca2+ through dihydropyridine-sensitive, voltage-dependent, L-type Ca2+ channels, or receptor-operated cation channels, leading to sustained VSMC contraction (62). Furthermore, endothelin-1 also activates rhoA/rho kinase (77). The rhoA/rho kinase pathway plays a very important role in Ca2+ sensitization in cerebral arteries (78). Ca2+ activates myosin light chain kinase (MLCK) to increase myosin light chain (MLC) phosphorylation. Activated rhoA appears to inhibit MLC phospha-tase activity via rho kinase and to increase the level of MLC phosphorylation.

In addition to vasoconstriction, endothelin-1 also has mitogenic properties, causing proliferation and hypertrophy of SMCs and fibroblasts. Intracellular kinase cascades, including the sequential activation of raf-1, mitogen-activated protein kinase (MAPK), and S6 kinase II, are activated (62 ).

Several studies in experimental animals, including nonhuman primates, suggest that vaso-spasm after experimental SAH can be significantly attenuated by antagonists of ET A receptors, such as BQ-123, or combined ET A/ET B receptor antagonists (79-82). Endothelin-1 is produced from its precursor, big ET-1, by endothelin-converting enzyme (ECE). Activity of ECE in the basilar artery increases 3-fold after SAH, which may also contribute to vasospasm (81). Phosphoramidon and CGS-26303, inhibitors of ECE, attenuate vasospasm after SAH (83). Antisense oligonucleotides for prepro-ET-1 mRNA inhibit contraction of the basilar artery in response to hemolysate (84).

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