Endothelin-1 plays a major role in portal hypertension of biliary cirrhotic rats through endothelin receptor subtype B together with subtype A in vivo.
OBJECTIVE
Endothelin-1 has been suggested to play a key role in cirrhotic portal hypertension, but a role of its receptors in vivo is not fully elucidated.


METHODS
Biliary cirrhosis was induced by bile duct ligation. Expressions of endothelin-1 and its receptors were evaluated by radioimmunoassay and/or reverse-transcription polymerase chain reaction. Hemodynamics were studied using endothelin receptor agonist or antagonist.


RESULTS
Portal pressure and hepatic endothelin-1 concentrations progressively increased in parallel after bile duct ligation. Gene expression of hepatic prepro-endothelin-1 and endothelin B receptor enhanced after bile duct ligation, while that of endothelin A receptor was unchanged. Intraportal administration of endothelin-1 or endothelin B receptor agonist sarafotoxin 6c (0.5 nmol/kg, respectively) progressively raised portal pressure in both sham and cirrhotic rats. Portal hypertensive effect of sarafotoxin 6c was more intense in cirrhotic rats than sham animals. Neither endothelin A receptor antagonist FR139317 (1 mg/kg) nor endothelin B receptor antagonist BQ788 (1 mg/kg) alone ameliorated cirrhotic portal hypertension. Only the combined endothelin A and B blockade was associated with a decrease in portal pressure in cirrhotic rats.


CONCLUSIONS
These results indicate that endothelin-1 plays a major role in cirrhotic portal hypertension through endothelin receptor subtype B together with subtype A in vivo.
Kojima
H
H
Third Department of Internal Medicine, Nara Medical University, Kashihara-shi, Japan. kojima@nmu-gw.naramed-u.ac.jp
Sakurai
S
S
Kuriyama
S
S
Yoshiji
H
H
Imazu
H
H
Uemura
M
M
Nakatani
Y
Y
Yamao
J
J
Fukui
H
H
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001794:Blood Pressure; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics / Q000502:physiology*; D016232:Endothelins / Q000235:genetics; D015870:Gene Expression; D006439:Hemodynamics; D006975:Hypertension, Portal / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D008099:Liver / Q000503:physiopathology; D008105:Liver Cirrhosis, Biliary / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011498:Protein Precursors / Q000235:genetics; D012313:RNA / Q000235:genetics; D011863:Radioimmunoassay; D051381:Rats; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001381:Azepines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D007211:Indoles; D009842:Oligopeptides; D010880:Piperidines; D011498:Protein Precursors; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C079574:FR 139317; C086539:BQ 788; D012313:RNA