Endothelin B receptor-mediated protection against anoxia-reoxygenation injury in perfused rat liver

Nitric oxide-dependent and-independent mechanisms

H. Taniai, M. Suematsu, T. Susuki, S. Norimizu, R. Hori, Y. Ishimura, Y. Nimura

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

This study aimed to investigate the roles of endothelin (ET) receptors in biliary dysfunction and cell injury in post-ischemic 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 ETA and ETB 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 ETB blockade. The BQ-788 treatment attenuated the reoxygenation-induced cGMP elevation and induced bile acid-dependent choleresis. However, such a change upon the ETB 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. NW-Nitro-L-arginine methyl ester, an NO synthase inhibitor, mimicked biliary changes elicited by the ETB 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 ETB blockade. These results suggest that ETB-mediated signaling limits excessive bile acid excretion and plays a protective role against reoxygenation injury through mechanisms involving both NO-dependent and -independent processes.

Original languageEnglish
Pages (from-to)894-901
Number of pages8
JournalHepatology
Volume33
Issue number4
DOIs
Publication statusPublished - 2001

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Endothelin B Receptors
Nitric Oxide
Cyclic GMP
Liver
Wounds and Injuries
Bile Acids and Salts
Bile
Clotrimazole
Endothelin Receptors
Oxygenases
Penicillamine
Endothelin-1
Vasoconstriction
Nitric Oxide Synthase
Cytochrome P-450 Enzyme System
Phospholipids
Perfusion
Hypoxia
BQ 788

ASJC Scopus subject areas

  • Hepatology

Cite this

Endothelin B receptor-mediated protection against anoxia-reoxygenation injury in perfused rat liver : Nitric oxide-dependent and-independent mechanisms. / Taniai, H.; Suematsu, M.; Susuki, T.; Norimizu, S.; Hori, R.; Ishimura, Y.; Nimura, Y.

In: Hepatology, Vol. 33, No. 4, 2001, p. 894-901.

Research output: Contribution to journalArticle

Taniai, H. ; Suematsu, M. ; Susuki, T. ; Norimizu, S. ; Hori, R. ; Ishimura, Y. ; Nimura, Y. / Endothelin B receptor-mediated protection against anoxia-reoxygenation injury in perfused rat liver : Nitric oxide-dependent and-independent mechanisms. In: Hepatology. 2001 ; Vol. 33, No. 4. pp. 894-901.
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AB - This study aimed to investigate the roles of endothelin (ET) receptors in biliary dysfunction and cell injury in post-ischemic 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 ETA and ETB 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 ETB blockade. The BQ-788 treatment attenuated the reoxygenation-induced cGMP elevation and induced bile acid-dependent choleresis. However, such a change upon the ETB 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. NW-Nitro-L-arginine methyl ester, an NO synthase inhibitor, mimicked biliary changes elicited by the ETB 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 ETB blockade. These results suggest that ETB-mediated signaling limits excessive bile acid excretion and plays a protective role against reoxygenation injury through mechanisms involving both NO-dependent and -independent processes.

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