Transformation of hepatic sinusoidal endothelium related to the pathogenesis of portal hypertension in liver cirrhosis - Alterations tn expression ofendothelin receptor subtypes and plasma membrane Ca++-ATPase activities

We have reported that the sinusoidal endothelial fenestrae are reduced in d iameter and number in liver cirrhosis, possibly contributing to the pathoge nesis of portal hypertension. In recent years there has been increasing evi dence that potent vasoconstrictive peptides, endothelins (ETs) are involved in the mechanism of portal hypertension in liver cirrhosis. On the other h and, it is well known that Ca++-pump ATPase is essential for maintaining in tracytoplasmic free calcium ion concentration [Ca++](i) at a constant low l evel against a high concentration of extracellular Ca++. Therefore the pres ent study was designed to elucidate how the distributions of ET receptor su btypes, ETA and ETB receptors and plasma membrane Ca++-ATPase activities ar e altered in experimental rat liver cirrhosis. Female Wistar strain rats (150g) were divided into a control and a carbon t etrachloride (CCl4)-induced liver cirrhosis group. Under anesthesia with so dium pentobarbital, portal pres- sure was measured with an amplifier connec ted with an mesenteric vein catheter inserted into the main branch of the p ortal trunk. Plasma levels of ET-I in blood samples taken from a fermoral v ein catheter were measured by RIA. The light and electron microscopic local izations of ETA and ETB receptors in liver tissue were observed by the indi rect immunoperoxidase and immunogold method using antibodies against ETA an d ETB receptors respectively (IBL). Electron cytochemical activities of Ca+-ATPase were examined by the method of Ando. Portal pressure was significantly higher in liver cirrhosis than in control . ET-1 levels in plasma were markedly elevated particularly in liver cirrho sis with ascites. By immuno-histochemistry ETA and ETB receptors wen: expre ssed on the hepatic sinusoidal lining cells, particularly on the sinusoidal endothelial cells (SECs) and hepatic stellate cells (HSCs) in control live r. By immunogold electron microscopy, in control liver, ETA receptors were expressed mainly on the HSCs and partially on the SECs, wheres ETB receptor s were mainly expressed on the SECs, In liver cirrhosis, the expressions of ETA and ETB receptors were found to be enhanced on the HSCs and SECs respe ctively. Electron cytochemistry has revealed that the electron dense partic les indicating the ultrastructural sires of Ca++-ATPase activities are loca lized on the fenestral plasma membranes of the SECs in control liver. These enzyme activities were proved to be decreased in liver cirrhosis, resultin g in an increase of intracytoplasmic free calcium ion concentration. In conclusion, plasma ET-1 elevated in liver cirrhosis would act not only o n the HSCs via the ETA receptors as paracrine and autocrine effect, but als o on the SECs mainly via the ETB receptors as autocine and paracrine effect , leading to the contractions of HSCs and sinusoidal endothelial fenestrae and thereby contributing to an increase in sinusoidal microvascular resista nce as a pathogenetic factor of portal hypertension in cirrhosis.