Endotoxin causes up‐regulation of endothelin receptors in cultured hepatic stellate cells via nitric oxide‐dependent and ‐independent mechanisms

Hepatic stellate cells (HSC) and their transformed phenotype found in the chronically injured liver play important roles in hepatic physiology and pathology. HSC produce and react to a potent contractile peptide endothelin‐1 (ET‐1) and also synthesize a vasorelaxant nitric oxide (NO) upon stimulation with endotoxin. However, whether endotoxin affects ET‐1 system of HSC and if this is a mechanism of endotoxin‐induced hepatic injury is not known. We characterized synthesis of ET‐1 and NO and ET‐1 receptors in cultured quiescent and transformed HSC subjected to endotoxin treatment. Endotoxin (1–1000 ng ml −1 ) stimulated synthesis of ET‐1 and NO and up‐regulated ET‐1 receptors in both cell types. Inhibition of NO synthesis by N G ‐monomethyl‐ L ‐homoarginine strongly inhibited endotoxin‐induced increase in ET‐1 receptors in transformed HSC but produced small additional increase in quiescent HSC. Inhibition of soluble guanylyl cyclase by 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one blocked the effect of endotoxin on ET‐1 receptors in both cell types. Moreover, ET‐1 receptors were increased in both cell types during earlier time points (1–4 h) of endotoxin treatment in the absence of the stimulation of NO synthesis. These results demonstrate that endotoxin up‐regulates ET‐1 receptors in HSC by NO‐dependent and ‐independent mechanisms. Such effects of endotoxin can be of importance in acute endotoxemia and during chronic injury of the liver.British Journal of Pharmacology (2000) 131 , 319–327; doi: 10.1038/sj.bjp.0703577