H2S contributes to the hepatic arterial buffer response and mediates vasorelaxation of the hepatic artery via activation of KATP channels

Hepatic blood supply is uniquely regulated by the hepatic arterial buffer response (HABR), counteracting alterations of portal venous blood flow by flow changes of the hepatic artery. Hydrogen sulfide (H2S) has been recognized as a novel signaling molecule with vasoactive properties. However, the contribution of H2S in mediating the HABR is not yet studied. In pentobarbital-anesthetized and laparotomized rats, flow probes around the portal vein and hepatic artery allowed for assessment of the portal venous (PVBF) and hepatic arterial blood flow (HABF) under baseline conditions and stepwise reduction of PVBF for induction of HABR. Animals received either the H2S donor Na2S, DL-propargylglycine as inhibitor of the H2S synthesizing enzyme cystathionine-gamma-lyase (CSE), or saline alone. Additionally, animals were treated with Na2S and the ATP-sensitive potassium channel (K-ATP) inhibitor glibenclamide or with glibenclamide alone. Na2S markedly increased the buffer capacity to 27.4 +/- 3.0% (P < 0.05 vs. controls: 15.5 +/- 1.7%), whereas blockade of H2S formation by DL-propargylglycine significantly reduced the buffer capacity (8.5 +/- 1.4%). Glibenclamide completely reversed the H2S-induced increase of buffer capacity to the control level. By means of RT-PCR, Western blot analysis, and immunohistochemistry, we observed the expression of both H2S synthesizing enzymes (CSE and cystathionine-beta-synthase) in aorta, vena cava, hepatic artery, and portal vein, as well as in hepatic parenchymal tissue. Terminal branches of the hepatic afferent vessels expressed only CSE. We show for the first time that CSE-derived H2S contributes to HABR and partly mediates vasorelaxation of the hepatic artery via activation of K-ATP channels.