Experimental investigation of the role of endothelin-1 in idiopathic portal hypertension.
OBJECTIVE
The authors' previous report revealed that endothelin-1 might be released from B lymphocytes in cirrhotic patients with hypersplenism. Other investigators have shown that persistent exposure to environmental contaminants including arsenic might induce idiopathic portal hypertension. The aim of this study was to experimentally identify how endothelin-1 is involved in the development of idiopathic portal hypertension and which cells produce endothelin-1 in the spleen.


METHODS
Portal pressure and venous endothelin-1 concentrations were measured in rats that were given sodium arsenate orally for long periods, and endothelin-1 expression levels in the spleen were assessed by staining. In a second experiment, B and T lymphocytes and monocyte-derived macrophages cultured from healthy human peripheral blood were stimulated with sodium arsenite, sodium arsenate, lipopolysaccharide and interferon-gamma. Endothelin-1 concentrations in the supernatants were measured by ELISA.


RESULTS
Arsenic exposure gradually increased portal pressure and venous endothelin-1 levels in rats. Endothelin-1 concentration in the supernatant did not change in every cell type stimulated with arsenic, but it increased in B lymphocytes and monocyte-derived macrophages treated with lipopolysaccharide and interferon-gamma.


CONCLUSIONS
The in vivo study indicated that arsenic might elevate portal pressure through mechanisms involving endothelin-1. In the in vitro study, lipopolysaccharide and interferon-gamma clearly induced endothelin-1 synthesis not only in monocyte-derived macrophages but also in B lymphocytes, although arsenic treatment did not affect those cells. This study partially supports the hypothesis that idiopathic portal hypertension might be promoted by endothelin-1 overproduction from splenic B lymphocytes in response to certain substances.
Yamaguchi
Emi
E
Department of Digestive and General Surgery, School of Medicine, Shimane University, Izumo, Japan. emi-med-ml@poppy.ocn.ne.jp
Yamanoi
Akira
A
Ono
Takashi
T
Nagasue
Naofumi
N
D000818:Animals; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000502:physiology*; D006801:Humans; D006975:Hypertension, Portal / Q000209:etiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D019332:Endothelin-1