%0 Journal Article
%T Sensitivity to endothelin-1 is decreased in isolated livers of endothelial constitutive nitric oxide synthase knockout mice
%A Andrea De Gottardi
%A Erwin Biecker
%A Abraham Koshy
%A Dieter Bohler
%A Sidney Shaw
%A Hans S£¿gesser
%A J¨¹rg Reichen
%J Comparative Hepatology
%D 2006
%I BioMed Central
%R 10.1186/1476-5926-5-9
%X Endothelin increased hepatic vascular resistance in a dose-dependent manner in both strains; however, this increase was significantly less in ecNOS knockout mice at physiologic concentrations. Expression of heme-oxygenases and adrenomedullin was similar in both groups, whereas inducible nitric oxide synthase (iNOS) protein was not detectable in either strain. mRNA levels of pre-pro-endothelin-1 and ETB receptor were comparable in both strains, while mRNA for ETA receptor was decreased in ecNOS knockouts.Livers of ecNOS knockout mice have a decreased sensitivity to endothelin at physiologic concentrations; this is associated with a decreased expression of ETA receptors, but not with other factors, such as iNOS, ETB receptors, adrenomedullin or heme-oxygenase. Further studies targeting adaptive changes in ETA receptor distribution and/or intracellular signaling downstream of the receptor are indicated.Sinusoidal perfusion is highly variable and regulated by different humoral substances including nitric oxide and endothelin [1-3]. Endothelin-1 (ET-1), one of the most potent endogenous vasoconstrictors [4], has extra- and intra-sinusoidal actions, the latter being more important at low endothelin concentrations [1,5] This effect has been associated to hepatic stellate cell contraction [6]. The resulting increase in shear stress activates endothelial nitric oxide (NO) production via ETB receptors [7].Intrahepatic vascular resistance is also regulated by vasoactive substances that may act locally or systemically. An excess of vasoconstrictors increases the vascular tone and may lead to an exaggerated response of the hepatic vascular bed. These factors include noradrenaline, angiotensin II and leukotrienes [8], but ET-1 seems to be the most potent one. In the rat liver, the ETA receptor subtype causes vasoconstriction, while the ETB receptor subtype is associated with a dual vascular response. ETB on hepatic stellate cells mediates their constriction, but this is normally
%U http://www.comparative-hepatology.com/content/5/1/9