The role of endothelin-1 and endothelin receptor antagonists in inflammatory response and sepsis

Abstract

Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor, mainly secreted by endothelial cells. It acts through two types of receptors: ETA and ETB. Apart from a vasoconstrictive action, ET-1 causes fibrosis of the vascular cells and stimulates production of reactive oxygen species. It is claimed that ET-1 induces proinflammatory mechanisms, increasing superoxide anion production and cytokine secretion. A recent study has shown that ET-1 is involved in the activation of transcription factors such as NF-κB and expression of proinflammatory cytokines including TNF-α, IL-1, and IL-6. It has been also indicated that during endotoxaemia, the plasma level of ET-1 is increased in various animal species. Some authors indicate a clear correlation between endothelin plasma level and morbidity/mortality rate in septic patients. These pathological effects of ET-1 may be abrogated at least partly by endothelin receptor blockade. ET-1 receptor antagonists may be useful for prevention of various vascular diseases. This review summarises the current knowledge regarding endothelin receptor antagonists and the role of ET-1 in sepsis and inflammation.

Fig. 1

ETA receptor-mediated VSMC signalling pathways. Activation of the ETA receptor stimulates phospholipase C (PLC) to generate inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG) from phosphatidylinositol 4.5-bisphosphate (PIP₂). IP₃ induces Ca²⁺ outflow from intracellular stores in sarcoplasmic reticulum (SR). Furthermore, the ETA receptor acts on nonselective plasmalemmal Ca²⁺ channels causing Ca²⁺ input from the extracellular space. Consequently, increased concentrations of Ca²⁺ leads to the contraction of VSMC. The activated ETA receptor also stimulates cell growth. Production of DAG activates protein kinase C (PKC), which is responsible for the mitogenic function of endothelin, and which also induces a Ca²⁺-independent pathway of VSMC contraction involving calponin phosphorylation. PKC affects gene transcription through activation of the Ras/Raf/MEK/MAPK cascade. MAPK phosphorylates caldesmon, which increases VSMC contraction (Hynynen and Khalil ; Khalil ; Lima et al. 2011)