Inhibition of K-Ca channels restores blunted hypoxic pulmonary vasoconstriction in rats with cirrhosis

Rats with liver cirrhosis exhibit the hepatopulmonary syndrome composed of blunted hypoxic pulmonary vasoconstriction and arterial hypoxemia. The purp ose of this study was to investigate the roles of nitric oxide (NO) and end othelin-1 (ET-1) in the blunted hypoxic pressor response (HPR) in rats with common bile duct ligation (CBDL). Lungs from CBDL rats exhibited markedly blunted HPR, increased endothelial NO synthase (NOS) protein expression, an d decreased ET-1 mRNA and peptide expression. The blunted HPR was not rever sed by sequential NOS and soluble guanylyl cyclase inhibition by nitro-L-ar ginine and 1H-[1,2,4]oxadiazolo[4,3-a] quinoxaline-1-one (ODQ), respectivel y, or by NOS inhibition combined with ET-1 addition. The blunted HPR was no t due to a generalized inability to vasoconstrict because perfusion pressur e was equally elevated by increased perfusate KCl in CBDL and sham lungs. A fter KCl vasoconstriction, HPR was potentiated and did not differ between C BDL and sham lungs. Blunted HPR was also completely restored in CBDL lungs treated with nitro-L-arginine, ODQ, and the Ca2+-activated K+ channel block ers apamin and charybdotoxin. These results indicate that although CBDL-ind uced liver cirrhosis is associated with increased NO and decreased ET-1 in the lung, the blunted HPR is a result of additional factors and appears to involve Ca2+ activated K+ channel activation.