Functional link between ETB receptors and eNOS maintain tissue oxygenation in the normal liver.
OBJECTIVE
Endothelins and their receptors play a crucial role in regulating liver microcirculation in pathophysiological conditions. The authors investigated the functional significance of the coupling of ET(B) receptors and eNOS in maintaining regional perfusion and tissue oxygenation in the normal liver.


METHODS
The effect of endothelin-1 or the ET(B) agonist IRL1620 on oxygen consumption was determined in isolated perfused liver and isolated hepatocytes. Oxygen delivery to the liver tissue was determined in vivo. Following eNOS or iNOS blockade, either ET-1 or IRL1620 was infused via the portal vein. Hepatic tissue oxygenation, redox state, and microcirculation were investigated by intravital microscopy. Injury was estimated by serum LDH.


RESULTS
Although IRL1620 and endothelin-1 increased oxygen consumption in isolated hepatocytes, in intact liver, endothelin decreased oxygen consumption while IRL1620 produced no change. In vivo, ET(B) stimulation modestly altered hepatic tissue P(O(2)), redox potential, and microcirculation. eNOS inhibition and ET(B) activation dramatically reduced microcirculatory blood flow, oxygen supply, and increased LDH release. Inhibition of iNOS resulted in small but not significant changes in these parameters. Concomitant ET(A)/ET(B) receptor activation increased microcirculatory failure and decreased tissue oxygen even without NOS inhibition. In contrast, hepatocellular injury was significantly increased following eNOS inhibition.


CONCLUSIONS
Coupling between ET(B) receptor stimulation and eNOS activation decreases sinusoidal constriction and plays a functionally important role in maintaining microcirculation and tissue oxygenation in the normal liver.
Paxian
Markus
M
Department of Biology, University of North Carolina at Charlotte, Charlotte, North Carolina 28223, USA.
Keller
Steve A
SA
Baveja
Rajiv
R
Korneszczuk
Katarzyna
K
Huynh
Toan T
TT
Clemens
Mark G
MG
D000818:Animals; D019332:Endothelin-1 / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008833:Microcirculation; D018715:Microscopy, Video; D019001:Nitric Oxide Synthase / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption; D051381:Rats; D044023:Receptor, Endothelin B / Q000502:physiology*
D019332:Endothelin-1; D044023:Receptor, Endothelin B; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D010100:Oxygen