Effects of endothelin-1 on portal-systemic collaterals of common bile duct-ligated cirrhotic rats.
OBJECTIVE
Endothelin-1 (ET-1) may induce intrahepatic vasoconstriction and consequently increase portal pressure. Endothelin-1 has been shown to exert a direct vasoconstrictive effect on the collateral vessels in partially portal vein-ligated rats with a high degree of portal-systemic shunting. This study investigated the collateral vascular responses to ET-1, the receptors in mediation and the regulation of ET-1 action by nitric oxide and prostaglandin in cirrhotic rats with a relatively low degree of portal-systemic shunting.


METHODS
The portal-systemic collaterals of common bile duct-ligated (BDL) cirrhotic rats were tested by in situ perfusion. The concentration-response curves of collaterals to graded concentrations of ET-1 (10(-10)-10(-7) m) with or without BQ-123 (ET(A) receptor antagonist, 2 x 10(-6) m), BQ-788 (ET(B) receptor antagonist, 10(-7) m) or both were recorded. In addition, the collateral responses to ET-1 with preincubation of N(omega)-nitro-L-arginine (NNA, 10(-4) M), indomethacin (INDO, 10(-5) M) or in combination were assessed.


RESULTS
Endothelin-1 significantly increased the perfusion pressures of portal-systemic collaterals. The ET-1-induced constrictive effects were inhibited by BQ-123 or BQ-123 plus BQ-788 but not by BQ-788 alone. The inhibitory effect was greater in the combination group. Pretreatment of NNA or NNA plus INDO equivalently enhanced the response of ET-1 while pretreatment of INDO alone exerted no effect.


CONCLUSIONS
Endothelin-1 has a direct vasoconstrictive effect on the collaterals of BDL cirrhotic rats, mainly mediated by ET(A) receptor. Endogenous nitric oxide may play an important role in modulating the effects of ET-1 in the portal-systemic collaterals of BDL cirrhotic rats.
Chan
C-C
CC
Taipei Veterans General Hospital, Taipei, Taiwan.
Wang
S-S
SS
Lee
F-Y
FY
Chang
F-Y
FY
Lin
H-C
HC
Hou
M-C
MC
Huang
H-C
HC
Lee
S-D
SD
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology; D003097:Collateral Circulation / Q000187:drug effects*; D003135:Common Bile Duct / Q000503:physiopathology / Q000601:surgery; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006975:Hypertension, Portal / Q000503:physiopathology; D007213:Indomethacin / Q000494:pharmacology; D008026:Ligation; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011168:Portal System / Q000187:drug effects*; D011448:Prostaglandin Antagonists / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D011448:Prostaglandin Antagonists; D014662:Vasoconstrictor Agents; D019335:Nitroarginine; D009569:Nitric Oxide; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D007213:Indomethacin