Endotoxin causes up-regulation of endothelin receptors in cultured hepaticstellate cells via nitric oxide-dependent and -independent mechanisms

1 Hepatic stellate cells (HSC) and their transformed phenotype found in the chronically injured liver play important roles in hepatic physiology and p athology. HSC produce and react to a potent contractile peptide endothelin- l (ET-I) and also synthesize a vasorelaxant nitric oxide (NO) upon stimulat ion with endotoxin. However, whether endotoxin affects ET-1 system of HSC a nd if this is a mechanism of endotoxin-induced hepatic injury is not known. 2 We characterized synthesis of ET-I and NO and PT-I receptors in cultured quiescent and transformed HSC subjected to endotoxin treatment. Endotoxin ( 1-1000 ng ml(-1)) stimulated synthesis of ET-I and NO and up-regulated ET-1 receptors in both cell types. 3 Inhibition of NO synthesis by NG-monomethyl-L-homoarginine strongly inhib ited endotox-ininduced increase in ET-1 receptors in transformed HSC but pr oduced small additional increase in quiescent HSC. Inhibition of soluble gu anylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one blocked the e ffect of endotoxin on ET-I receptors in both cell types. Moreover, ET-1 rec eptors 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. 4 These results demonstrate that endotoxin up-regulates ET-I receptors in H SC by NO-dependent and -independent mechanisms. Such effects of endotoxin c an be of importance in acute endotoxemia and during chronic injury of the l iver.