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Cirrhosis ameliorates monocrotaline-induced pulmonary hypertension in rats

¹ Laboratoire de Chirurgie Expérimentale-UPRES (EA-2705), Hopital Marie Lannelongue, Université Paris Sud, Le Plessis Robinson, ² INSERM U492, Hopital Henri Mondor, Créteil, and ³ Laboratoire d'Hémodynamique Splanchnique et de Biologie Vasculaire, INSERM U481, Hopital Beaujon, Clichy, France.

CORRESPONDENCE: P. Herve, Centre Chirurgical Marie Lannelongue, 133 Avenue de la Résistance, 92350 Le Plessis Robinson, France. E-mail: pherve{at}ccml.com

Keywords: Endothelin, inflammation, macrophages, nitric oxide

Received: January 15, 2008
Accepted March 12, 2009

Common bile duct ligation (CBDL) induces biliary cirrhosis and pulmonary vasodilatation. We tested whether CBDL ameliorates monocrotaline (MCT)-induced pulmonary hypertension (PH) in rats.

Five groups of rats were studied: controls; rats dosed with MCT (60 mg·kg^–1 subcutaneously); CBDL; rats dosed with MCT followed by CBDL on day 7; and rats dosed with MCT followed by CBDL (day 7) and L-NAME therapy between days 24 and 28. 28-day survival was 26% in the MCT group and 72% in the MCT+CBDL group. Pulmonary vascular resistance measured on days 21 and 28 increased in the MCT and MCT+CBDL+L-NAME groups, but returned to normal in the MCT+CBDL group on day 28. Pulmonary artery (PA) medial hypertrophy persisted in MCT+CBDL rats. PA inflammation increased in MCT+CBDL rats, with accumulation of both intra- and perivascular macrophages. Exhaled nitric oxide (NO) levels decreased in the MCT group and increased in the MCT+CBDL group, which showed upregulation of inducible NO synthase and normal endothelial NO synthase. Blood endothelin (ET)-1 increased in CBDL, MCT, and MCT+CBDL rats. Levels of ET_B receptors increased and ET_A receptors decreased in the MCT+CBDL group, whereas the opposite changes occurred in the MCT group.

Biliary cirrhosis induces pulmonary vasodilation that ameliorates MCT-induced PH and improves survival. Upregulation of inducible NO synthase and ET_B receptor and downregulation of ET_A receptor may be involved.