Increased pulmonary vascular endothelin B receptor expression and responsiveness to endothelin-1 in cirrhotic and portal hypertensive rats: a potential mechanism in experimental hepatopulmonary syndrome.
OBJECTIVE
In experimental hepatopulmonary syndrome (HPS), hepatic endothelin-1 (ET-1) release during common bile duct ligation (CBDL) and ET-1 infusion in pre-hepatic portal hypertension after portal vein ligation (PVL) initiate vasodilatation through an endothelin B receptor mediated increase in pulmonary endothelial nitric oxide synthase (eNOS). We evaluated if pulmonary ET receptor expression changes in experimental cirrhosis and portal hypertension and confers susceptibility to HPS.


METHODS
In normal, PVL and CBDL animals, lung ET receptor expression and localization were assessed and ET receptor levels and functional analysis of ET-1 effects on eNOS levels were evaluated in intralobar pulmonary artery (PA) and aortic (AO) segments. Normal rats underwent evaluation for HPS after ET-1 infusion.


RESULTS
There was a selective increase in ET(B) receptor expression in the pulmonary vasculature from PVL and CBDL animals. ET-1 stimulated NO production and an ET(B) receptor mediated increase in eNOS levels in PA segments from PVL and CBDL animals, but not normal animals. ET-1 did not alter lung eNOS levels or cause HPS in normal rats.


CONCLUSIONS
ET(B) receptor expression and ET-1 mediated eNOS and NO production are enhanced in the lung vasculature in cirrhotic and portal hypertensive animals and correlate with in vivo susceptibility to ET-1 mediated HPS.
Luo
Bao
B
Department of Internal Medicine, Liver Center, University of Alabama at Birmingham, 290 MCLM, 1918 University Boulevard, Birmingham, AL 35294-0005, USA.
Liu
Lichuan
L
Tang
Liping
L
Zhang
Junlan
J
Stockard
Cecil R
CR
Grizzle
William E
WE
Fallon
Michael B
MB
D000818:Animals; D003135:Common Bile Duct; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D020065:Hepatopulmonary Syndrome / Q000378:metabolism / Q000503:physiopathology*; D006975:Hypertension, Portal / Q000378:metabolism / Q000503:physiopathology*; D008026:Ligation; D008103:Liver Cirrhosis / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D011169:Portal Vein; D011651:Pulmonary Artery / Q000502:physiology*; D011652:Pulmonary Circulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B / Q000235:genetics* / Q000378:metabolism
D019332:Endothelin-1; D044023:Receptor, Endothelin B; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat