Type A, but not type B, endothelin receptor antagonists significantly decrease portal pressure in portal hypertensive rats.
OBJECTIVE
Endothelin-1 plays an important role in the regulation of portal hypertension; endothelin antagonists have been extensively studied in portal hypertensive animals. We aimed to evaluate the efficacy of highly selective endothelin antagonists in partial portal vein ligated (PPVL) rats.


METHODS
Four groups of 7 male Sprague-Dawley rats were administered orally ABT-627 (ET(A)-selective), A-192621 (ET(B)-selective), or A-182086 (non-selective), with the fourth group serving as control. On the 3rd day after beginning treatment animals underwent PPVL. On the 11th day hemodynamics were studied and portal vein ET-1 was measured.


RESULTS
In the control group portal pressure was 13.4+/-SD 0.2 mmHg; this increased to 14.9+/-1.8 (p<0.05) in the ET(B) blocked group. In contrast, ET(A) blockade improved portal hypertension (11.7+/-1.1, p<0.05), while the treatment with the non-selective antagonist had no effect (12.3+/-0.7 n.s.). Mean arterial pressure was not significantly affected by any treatment. Portal vein ET-1 was increased in all groups compared to controls; this increase was limited to the pre-stenotic area (79+/-43 vs 194+/-76 in the pre- and post-stenotic portal vein; p<0.0025).


CONCLUSIONS
Oral administration of an ET(A) antagonist ameliorated portal hypertension; we suggest that long-term therapy of portal hypertension with selective ET(A) antagonists may be more beneficial than mixed antagonists.
De Gottardi
A
A
Department of Clinical Pharmacology, University of Berne, Switzerland.
Shaw
S
S
Sägesser
H
H
Reichen
J
J
D000818:Animals; D000077868:Atrasentan; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D017082:Portal Pressure / Q000187:drug effects*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D000077868:Atrasentan