Prevention of portal hypertension by propranolol and spironolactone in rats with bile duct ligation.
OBJECTIVE
It has been suggested that the early administration of propranolol (PR) and a low sodium diet may prevent the development of portosystemic shunts in animals with presinusoidal portal hypertension. Our aim was to study the hemodynamic effects of the early and chronic administration of PR and spironolactone (SPN), alone or in combination, in a model of hepatic fibrosis and sinusoidal portal hypertension induced in rats by bile duct ligation.


METHODS
A blind study was performed in 40 Sprague-Dawley rats divided into four groups: placebo (PL), PR (75 mg/kg per day), SPN (100 mg/kg per day), and PR+SPN at the same doses. Drugs were administered by daily gavage over a 4-week period as soon as bile duct ligation was performed. At day 28, the splanchnic and systemic hemodynamics (radiolabeled microspheres) were evaluated.


RESULTS
a) Systemic hemodynamics: PR significantly reduced cardiac index and increased vascular resistance, SPN had no significant effect and PR+SPN significantly decreased mean arterial pressure. b) Splanchnic hemodynamics: portal venous pressure (PL: 15.5 +/- 1.5, PR: 14.8 +/- 1.0, SPN: 13.5 +/- 2.1, PR+SPN: 15.0 +/- 1.3 mmHg, p < 0.05) and portosystemic shunts (PL: 30 +/- 31, PR: 13 +/- 14, SPN: 5 +/- 4, PR+SPN: 29 +/- 33%, p < 0.05) were significantly reduced in the SPN group; other hemodynamic parameters were not significantly altered. In multivariate analysis, the only determinant of portosystemic shunts was portal pressure but with a low R2 (0.2).


CONCLUSIONS
In this model, the early administration of PR, alone or in combination with SPN, had no beneficial hemodynamic effects. On the other hand, SPN alone decreased portal pressure and prevented portosystemic shunts. Therefore, this drug may have beneficial effects in patients with early portal hypertension.
Oberti
F
F
Laboratoire d'Hémodynamique Splanchnique, UFR de Médecine, Université d'Angers, France.
Rifflet
H
H
Maïga
M Y
MY
Pilette
C
C
Gallois
Y
Y
Douay
O
O
Le Jeune
J J
JJ
Saumet
J L
JL
Calès
P
P
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D002779:Cholestasis / Q000150:complications*; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D006439:Hemodynamics / Q000187:drug effects; D006975:Hypertension, Portal / Q000209:etiology / Q000517:prevention & control*; D008106:Liver Cirrhosis, Experimental / Q000150:complications*; D008297:Male; D015999:Multivariate Analysis; D011433:Propranolol / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013148:Spironolactone / Q000627:therapeutic use*; D013152:Splanchnic Circulation / Q000187:drug effects; D013997:Time Factors
D000959:Antihypertensive Agents; D013148:Spironolactone; D011433:Propranolol