This study aimed to investigate the roles of
endothelin (ET) receptors in biliary dysfunction and cell injury in postischemic livers. Rat livers perfused with oxygenated
Krebs-Henseleit solution were exposed to reoxygenation following 20-minute
hypoxia. The anoxic perfusion decreased bile output and reduced cyclic
guanosine monophosphate (cGMP) contents, an index of
nitric oxide (NO) generation. Upon reoxygenation, the decreased bile was not fully recovered, and the resistance increased biphasically: an early transient spike accompanied by an elevated release of ET-1 and a rise accompanied by a cGMP elevation in the later period. The initial vasoconstriction appeared to be mediated by both ET(A) and ET(B) receptors, as judged by inhibitory effects of their antagonists,
BQ-485 and
BQ-788, respectively, while the late elevation of the resistance was not attenuated by these
reagents, but rather enhanced by the ET(B) blockade. The
BQ-788 treatment attenuated the reoxygenation-induced cGMP elevation and induced
bile acid-dependent choleresis. However, such a change upon the ET(B) blockade coincided with dissociation of a recovery of
phospholipids and aggravation of cell injury. The BQ-788-elicited deterioration of reoxygenation-elicited changes was attenuated by NO supplement with S-nitroso-N-acetyl
penicillamine.
N(omega)-Nitro-L-arginine methyl ester, an
NO synthase inhibitor, mimicked biliary changes elicited by the ET(B) blockade but without causing notable cell injury. Under these circumstances, coadministration of
clotrimazole, an inhibitor of
cytochrome P450 mono-
oxygenases, elicited the injury comparable with that observed under the ET(B) blockade. These results suggest that ET(B)-mediated signaling limits excessive
bile acid excretion and plays a protective role against reoxygenation injury through mechanisms involving both NO-dependent and -independent processes.